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Zhu Y, Li X, Lei X, Tang L, Wen D, Zeng B, Zhang X, Huang Z, Guo Z. The potential mechanism and clinical application value of remote ischemic conditioning in stroke. Neural Regen Res 2025; 20:1613-1627. [PMID: 38845225 PMCID: PMC11688546 DOI: 10.4103/nrr.nrr-d-23-01800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/30/2024] [Accepted: 03/19/2024] [Indexed: 08/07/2024] Open
Abstract
Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may be related to neuroinflammation, cellular immunity, apoptosis, and autophagy, the exact underlying molecular mechanisms are unclear. This review summarizes the current status of different types of remote ischemic conditioning methods in animal and clinical studies and analyzes their commonalities and differences in neuroprotective mechanisms and signaling pathways. Remote ischemic conditioning has emerged as a potential therapeutic approach for improving stroke-induced brain injury owing to its simplicity, non-invasiveness, safety, and patient tolerability. Different forms of remote ischemic conditioning exhibit distinct intervention patterns, timing, and application range. Mechanistically, remote ischemic conditioning can exert neuroprotective effects by activating the Notch1/phosphatidylinositol 3-kinase/Akt signaling pathway, improving cerebral perfusion, suppressing neuroinflammation, inhibiting cell apoptosis, activating autophagy, and promoting neural regeneration. While remote ischemic conditioning has shown potential in improving stroke outcomes, its full clinical translation has not yet been achieved.
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Affiliation(s)
- Yajun Zhu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoguo Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xingwei Lei
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liuyang Tang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Daochen Wen
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Zeng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaofeng Zhang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zichao Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zongduo Guo
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Saito M, Hoshino T, Ishizuka K, Iwasaki S, Toi S, Shibata N, Kitagawa K. Remote Ischemic Conditioning Enhances Collateral Circulation Through Leptomeningeal Anastomosis and Diminishes Early Ischemic Lesions and Infarct Volume in Middle Cerebral Artery Occlusion. Transl Stroke Res 2024; 15:41-52. [PMID: 36441491 DOI: 10.1007/s12975-022-01108-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/29/2022]
Abstract
Remote ischemic conditioning (RIC) has attracted much attention as a protective strategy for the heart and brain, although the underlying mechanisms remain unclear. We hypothesized that RIC enhances collateral circulation during cerebral ischemia through endothelial function and mitigates both early ischemic change and final infarct volume. We tested the RIC and sham procedure 30 min after permanent middle cerebral artery occlusion (MCAO) in male mice. Collateral circulation was examined during the procedure with 2D color-coded ultrasound imaging. Immediately after four cycles of RIC, early ischemic lesions on magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and development of pial collateral vessels were examined. The neurological signs and infarct volume with TTC were examined until 48 h after daily RIC. As compared with sham procedure, RIC enhanced collateral circulation, diminished early ischemic lesions, enlarged pial collaterals, and mitigated infarct volume. Next, we examined the effect of inhibitor of nitric oxide synthase (NOS) and Akt on the beneficial effect of RIC in MCAO. Both allosteric Akt inhibitor, 8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK2206), and two NOS inhibitors, N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) and NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), counteracted the beneficial effect of RIC on collateral circulation, early lesions, pial anastomosis, and infarct volume. In permanent MCAO, RIC could enhance collateral circulation through leptomeningeal anastomosis with Akt-eNOS pathway and diminish early lesion and final infarct volume.
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Affiliation(s)
- Moeko Saito
- Department of Neurology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjyuku-Ku, Tokyo, 162-8666, Japan
| | - Takao Hoshino
- Department of Neurology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjyuku-Ku, Tokyo, 162-8666, Japan
| | - Kentaro Ishizuka
- Department of Neurology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjyuku-Ku, Tokyo, 162-8666, Japan
| | - Shuichi Iwasaki
- Department of Pathology (SI, NS), Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Sono Toi
- Department of Neurology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjyuku-Ku, Tokyo, 162-8666, Japan
| | - Noriyuki Shibata
- Department of Pathology (SI, NS), Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Kazuo Kitagawa
- Department of Neurology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjyuku-Ku, Tokyo, 162-8666, Japan.
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Sun YY, Zhu HJ, Zhao RY, Zhou SY, Wang MQ, Yang Y, Guo ZN. Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2/HO-1 pathway in MCAO mice. Redox Biol 2023; 66:102852. [PMID: 37598463 PMCID: PMC10462885 DOI: 10.1016/j.redox.2023.102852] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/10/2023] [Accepted: 08/13/2023] [Indexed: 08/22/2023] Open
Abstract
The protective effects of remote ischemic conditioning (RIC) on acute ischemic stroke have been reported. However, the protective mechanisms of RIC have not been fully elucidated. This study aimed to investigate whether RIC could reduce oxidative stress and inflammatory responses in middle cerebral artery occlusion (MCAO)-reperfusion mice via the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. C57BL/6 mice were subjected to MCAO and underwent RIC twice daily at 1, 3, and 7 days after MCAO. ML385 was used to specifically inhibit Nrf2 in MCAO mice. Neurological deficit scores, infarct volume, and hematoxylin-eosin (HE) staining were assessed. Oxidative stress levels were assessed based on total antioxidant capacity (TAC), malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione/glutathione disulfide (GSH/GSSG). mRNA levels were detected using real-time polymerase chain reaction (PCR), and protein levels were detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Protein localization was investigated using immunofluorescence staining. RIC significantly reduced infarct volume and improved neurological function and histological changes after MCAO. RIC significantly increased TAC, SOD, and GSH/GSSG levels and decreased MDA levels. RIC significantly increased Nrf2 and HO-1 mRNA levels and decreased Keap1, NLRP3, and Cleaved Caspase-1 mRNA levels. RIC significantly increased Nrf2, HO-1, and NQO1 protein expression and decreased Keap1, NLRP3, Cleaved Caspase-1, Cleaved IL-1β, IL-6, and TNF-α protein expression. RIC promoted the activation and translocation of Nrf2 into the nucleus. The protective effects of RIC were abolished by ML385 treatment. In conclusion, our findings suggest that RIC alleviates oxidative stress and inflammatory responses via the Nrf2/HO-1 pathway, which in turn improves neurobehavioral function. RIC may provide novel therapeutic options for acute ischemic stroke.
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Affiliation(s)
- Ying-Ying Sun
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China
| | - Hong-Jing Zhu
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China
| | - Ruo-Yu Zhao
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China
| | - Sheng-Yu Zhou
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China
| | - Mei-Qi Wang
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China
| | - Yi Yang
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, Changchun, China.
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, Jilin, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, Changchun, China; Neuroscience Research Center, The First Hospital of Jilin University, Chang Chun, Jilin, China.
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Yang H, Hu Z, Gao X, Su J, Jiang H, Yang S, Zhang Q, Ni W, Gu Y. Safety and efficacy of remote ischemic conditioning in adult moyamoya disease patients undergoing revascularization surgery: a pilot study. Front Neurol 2023; 14:1200534. [PMID: 37576009 PMCID: PMC10419176 DOI: 10.3389/fneur.2023.1200534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
Background and purpose Revascularization surgery for patients with moyamoya disease (MMD) is very complicated and has a high rate of postoperative complications. This pilot study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) in adult MMD patients undergoing revascularization surgery. Methods A total of 44 patients with MMD were enrolled in this single-center, open-label, prospective, parallel randomized study, including 22 patients assigned to the sham group and 22 patients assigned to the RIC group. The primary outcome was the incidence of major neurologic complications during the perioperative period. Secondary outcomes were the modified Rankin Scale (mRS) score at discharge, at 90 days post-operation, and at 1 year after the operation. The outcome of safety was the incidence of adverse events associated with RIC. Blood samples were obtained to monitor the serum concentrations of cytokines (VEGF, IL-6). Results No subjects experienced adverse events during RIC intervention, and all patients could tolerate the RIC intervention in the perioperative period. The incidence of major neurologic complications was significantly lower in the RIC group compared with the control group (18.2% vs. 54.5%, P = 0.027). The mRS score at discharge in the RIC group was also lower than the control group (0.86 ± 0.99 vs. 1.18 ± 1.22, P = 0.035). In addition, the serum IL-6 level increased significantly at 7 days after bypass surgery in the control group and the serum level of VEGF at 7 days post-operation in the RIC group. Conclusion In conclusion, our study demonstrated the neuroprotective effect of RIC by reducing perioperative complications and improving cerebral blood flow in adult MMD patients undergoing revascularization surgery. Thus, RIC seems to be a potential treatment method for MMD. Clinical trial registration ClinicalTrials.gov, identifier: NCT05860946.
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Affiliation(s)
- Heng Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Zhenzhen Hu
- Department of Nursing, Huashan Hospital North, Fudan University, Shanghai, China
| | - Xinjie Gao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Jiabin Su
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hanqiang Jiang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaoxuan Yang
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Qing Zhang
- Department of Nursing, Huashan Hospital North, Fudan University, Shanghai, China
| | - Wei Ni
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
| | - Yuxiang Gu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
- Neurosurgical Institute, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Neurosurgery, Huashan Hospital North, Fudan University, Shanghai, China
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Yu W, Ren C, Ji X. A review of remote ischemic conditioning as a potential strategy for neural repair poststroke. CNS Neurosci Ther 2022; 29:516-524. [PMID: 36550592 PMCID: PMC9873528 DOI: 10.1111/cns.14064] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 11/17/2022] [Accepted: 12/01/2022] [Indexed: 12/24/2022] Open
Abstract
Ischemic stroke is one of the major disabling health-care problem and multiple different approaches are needed to enhance rehabilitation, in which neural repair is the structural basement. Remote ischemic conditioning (RIC) is a strategy to trigger endogenous protect. RIC has been reported to play neuroprotective role in acute stage of stroke, but the effect of RIC on repair process remaining unclear. Several studies have discovered some overlapped mechanisms RIC and neural repair performs. This review provides a hypothesis that RIC is a potential therapeutic strategy on stroke rehabilitation by evaluating the existing evidence and puts forward some remaining questions to clarify and future researches to be performed in the field.
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Affiliation(s)
- Wantong Yu
- Department of Neurology and Beijing Key Laboratory of Hypoxia Translational MedicineXuanwu Hospital, Capital Medical UniversityBeijingChina
| | - Changhong Ren
- Department of Neurology and Beijing Key Laboratory of Hypoxia Translational MedicineXuanwu Hospital, Capital Medical UniversityBeijingChina,Center of Stroke, Beijing Institute for Brain DisorderCapital Medical UniversityBeijingChina
| | - Xunming Ji
- Department of Neurology and Beijing Key Laboratory of Hypoxia Translational MedicineXuanwu Hospital, Capital Medical UniversityBeijingChina,Center of Stroke, Beijing Institute for Brain DisorderCapital Medical UniversityBeijingChina
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Ghori A, Prinz V, Nieminen-Kehlä M, Bayerl SH, Kremenetskaia I, Riecke J, Krechel H, Broggini T, Scherschinski L, Licht T, Keshet E, Vajkoczy P. Vascular Endothelial Growth Factor Augments the Tolerance Towards Cerebral Stroke by Enhancing Neurovascular Repair Mechanism. Transl Stroke Res 2022; 13:774-791. [PMID: 35175562 PMCID: PMC9391249 DOI: 10.1007/s12975-022-00991-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/05/2021] [Accepted: 01/26/2022] [Indexed: 11/30/2022]
Abstract
The breakdown of the blood-brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in containing the stroke-induced damage after cerebral ischemia. We report that the transgenic overexpression of VEGF (GOF) prior to the stroke stabilizes the vasculature and prevents blood-brain barrier disruption in young and aged animals after stroke. Whereas inhibition of signals for endogenous VEGF (LOF) prior to stroke results in bigger infarction with massive brain swelling and enhanced BBB permeability, furthermore, activating or blocking VEGF signaling after ischemic stroke onset had comparable effects on BBB repair and cerebral edema. VEGF can function as an anti-permeability factor, and a VEGF-based therapy in the context of stroke prevention and recovery has an enormous potential.
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Affiliation(s)
- Adnan Ghori
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Vincent Prinz
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | | | - Simon. H. Bayerl
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Irina Kremenetskaia
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Jana Riecke
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Hanna Krechel
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Thomas Broggini
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Lea Scherschinski
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Tamar Licht
- Department of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel
| | - Eli Keshet
- Department of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel
| | - Peter Vajkoczy
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
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Mei C, Ma T. Roles of isometric contraction training in promoting neuroprotection and angiogenesis after stroke in adult rats. Physiol Res 2022; 71:425-438. [PMID: 35616043 DOI: 10.33549/physiolres.934849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
100 rats were randomly divided into a sham-operated group and middle cerebral artery occlusion (MCAO) modeling groups. The sham group after surgery was observed for 14 days. After MCAO, some rats received isometric contraction training (ICT) which was as follows: an atraumatic tourniquet was placed around left or right hind limb to achieve hind limb ischemia for 5 min, followed by 5 min of reperfusion, 4 cycles for one time, once a day, and five days per week. The MCAO modeling groups included the following four groups: i) a group only received MCAO, and was observed for seven days (MCAO-7d), ii) a group only received MCAO, and was observed for 14 days (MCAO-14d), iii) a group, after MCAO, received ICT for seven days (ICT-7d), and iv) a group, after MCAO, received ICT for 14 days (ICT-14d). Brain infarct area, behavioral outcomes, the number of neurons, apoptosis, cerebral edema and cerebral water content were assessed, respectively. The mRNA expression of vascular endothelial growth factor (VEGF) was assayed with RT-PCR, and protein expression of VEGF was quantified with western blot. compared with MCAO controls, cerebral infarction, neurological deficits and neuronal apoptosis were reduced significantly in the ICT groups, while the number of neurons was increased. Moreover, the mRNA expression of VEGF and protein expression of VEGF were enhanced after 1 and 2 weeks of ICT. ICT may promote angiogenesis and neuroprotection after ischemic stroke and this new remodeling method provide a novel strategy for rehabilitation of stroke patients.
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Affiliation(s)
- C Mei
- Pukou Branch of Jiangsu People's Hospital, Nanjing City, Jiangsu Province, P. R. China.
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Wang Z, Dong H, Luan S, Liu J, Wang Q, Tao D, Cao H, Ji X. Distanct ischemic postconditioning in acute mild to moderate ischemic stroke: A randomized clinical study. J Clin Neurosci 2022; 100:89-93. [DOI: 10.1016/j.jocn.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 03/18/2022] [Accepted: 04/05/2022] [Indexed: 11/25/2022]
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The Role of Plasma Extracellular Vesicles in Remote Ischemic Conditioning and Exercise-Induced Ischemic Tolerance. Int J Mol Sci 2022; 23:ijms23063334. [PMID: 35328755 PMCID: PMC8951333 DOI: 10.3390/ijms23063334] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 02/04/2023] Open
Abstract
Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic conditioning (RIC), blood flow restricted resistance exercise (BFRRE), or high-load resistance exercise (HLRE). Blood samples were collected from human participants before and at serial time points after intervention. RIC and BFRRE plasma EVs released early after stimulation improved viability of endothelial cells subjected to oxygen-glucose deprivation. Furthermore, post-RIC EVs accumulated in the ischemic area of a stroke mouse model, and a mean decrease in infarct volume was observed for post-RIC EVs, although not reaching statistical significance. Thus, circulating EVs induced by RIC and BFRRE can mediate protection, but the in vivo and translational effects of conditioned EVs require further experimental verification.
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Torres-Querol C, Quintana-Luque M, Arque G, Purroy F. Preclinical evidence of remote ischemic conditioning in ischemic stroke, a metanalysis update. Sci Rep 2021; 11:23706. [PMID: 34887465 PMCID: PMC8660795 DOI: 10.1038/s41598-021-03003-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/12/2021] [Indexed: 01/13/2023] Open
Abstract
Remote ischemic conditioning (RIC) is a promising therapeutic approach for ischemic stroke patients. It has been proven that RIC reduces infarct size and improves functional outcomes. RIC can be applied either before ischemia (pre-conditioning; RIPreC), during ischemia (per-conditioning; RIPerC) or after ischemia (post-conditioning; RIPostC). Our aim was to systematically determine the efficacy of RIC in reducing infarct volumes and define the cellular pathways involved in preclinical animal models of ischemic stroke. A systematic search in three databases yielded 50 peer-review articles. Data were analyzed using random effects models and results expressed as percentage of reduction in infarct size (95% CI). A meta-regression was also performed to evaluate the effects of covariates on the pooled effect-size. 95.3% of analyzed experiments were carried out in rodents. Thirty-nine out of the 64 experiments studied RIPostC (61%), sixteen examined RIPreC (25%) and nine tested RIPerC (14%). In all studies, RIC was shown to reduce infarct volume (- 38.36%; CI - 42.09 to - 34.62%) when compared to controls. There was a significant interaction caused by species. Short cycles in mice significantly reduces infarct volume while in rats the opposite occurs. RIPreC was shown to be the most effective strategy in mice. The present meta-analysis suggests that RIC is more efficient in transient ischemia, using a smaller number of RIC cycles, applying larger length of limb occlusion, and employing barbiturates anesthetics. There is a preclinical evidence for RIC, it is safe and effective. However, the exact cellular pathways and underlying mechanisms are still not fully determined, and its definition will be crucial for the understanding of RIC mechanism of action.
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Affiliation(s)
- Coral Torres-Querol
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Manuel Quintana-Luque
- Epilepsy Unit, Neurology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Gloria Arque
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
- Experimental Medicine Department, Universitat de Lleida, Lleida, Spain
| | - Francisco Purroy
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain.
- Medicine Department, Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain.
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Clinical Neurosciences Group IRBLleida, Avda Rovira Roure 80, 25198, Lleida, Spain.
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Diamanti S, Beretta S, Tettamanti M, Sacco S, Sette G, Ornello R, Tiseo C, Caponnetto V, Beccia M, Alivernini D, Costanzo R, Ferrarese C. Multi-Center Randomized Phase II Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies (TRICS-9): Study Design and Protocol. Front Neurol 2021; 12:724050. [PMID: 34803872 PMCID: PMC8595400 DOI: 10.3389/fneur.2021.724050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 09/23/2021] [Indexed: 12/03/2022] Open
Abstract
Aim: To assess the efficacy of remote ischemic conditioning (RIC) in patients with ischemic stroke within 9 h of onset, that are not candidates for recanalization therapies. Sample Size Estimates: A sample size of 80 patients (40 in each arm) should yield 80% power to detect a 20% difference in early neurological improvement at 72 h at p = 0.05, two sided. Methods and Design: TRICS-9 is a phase II, multicenter, controlled, block randomized, open-label, interventional clinical trial. Patients recruited in Italian academic hospitals will be randomized 1:1 to either RIC plus standard medical therapy or standard medical therapy alone. After randomization, RIC will be applied manually by four alternating cycles of inflation/deflation 5 min each, using a blood pressure cuff around the non-paretic arm. Study Outcomes: The primary efficacy outcome is early neurological improvement, defined as the percent change in the National Institute of Health Stroke Scale (NIHSS) at 72 h in each arm. Secondary outcomes include early neurologic improvement at 24 and 48 h, disability at 3 months, rate of symptomatic intracerebral hemorrhage, feasibility (proportion of patients completing RIC), tolerability after RIC and at 72 h, blood levels of HIF-1α, and HSP27 at 24 h and 72 h. Discussion/Conclusion: RIC in combination with recanalization therapies appears to add no clinical benefit to patients, but whether it is beneficial to those that are not candidates for recanalization therapies is still to be demonstrated. TRICS-9 has been developed to elucidate this issue. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04400981.
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Affiliation(s)
- Susanna Diamanti
- Stroke Unit and Neurology Unit, Azienda Socio Sanitaria Territoriale (ASST)-Monza San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Simone Beretta
- Stroke Unit and Neurology Unit, Azienda Socio Sanitaria Territoriale (ASST)-Monza San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Mauro Tettamanti
- Dipartimento di Ricerca Neuroscienze, Istituto di Ricerche Farmacologiche Mario Negri Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Milano, Italy
| | - Simona Sacco
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Giuliano Sette
- NEuroscienze Salute Mentale e Organi di Senso (NESMOS) Department, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Roma, Italy
| | - Raffaele Ornello
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Cindy Tiseo
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Valeria Caponnetto
- Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Mario Beccia
- NEuroscienze Salute Mentale e Organi di Senso (NESMOS) Department, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Roma, Italy
| | - Diletta Alivernini
- NEuroscienze Salute Mentale e Organi di Senso (NESMOS) Department, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Roma, Italy
| | - Rocco Costanzo
- NEuroscienze Salute Mentale e Organi di Senso (NESMOS) Department, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Roma, Italy
| | - Carlo Ferrarese
- Stroke Unit and Neurology Unit, Azienda Socio Sanitaria Territoriale (ASST)-Monza San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
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12
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Poalelungi A, Tulbă D, Turiac E, Stoian D, Popescu BO. Remote Ischemic Conditioning May Improve Disability and Cognition After Acute Ischemic Stroke: A Pilot Randomized Clinical Trial. Front Neurol 2021; 12:663400. [PMID: 34526950 PMCID: PMC8435589 DOI: 10.3389/fneur.2021.663400] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/05/2021] [Indexed: 11/13/2022] Open
Abstract
Background and Aim: Remote ischemic conditioning is a procedure purported to reduce the ischemic injury of an organ. This study aimed to explore the efficiency and safety of remote ischemic conditioning in patients with acute ischemic stroke. We hypothesized that remote ischemic conditioning administered from the first day of hospital admission would improve the infarct volume and clinical outcome at 180 days. Material and Methods: We performed a unicentric double-blind randomized controlled trial. We included all patients consecutively admitted to an Emergency Neurology Department with acute ischemic stroke, ineligible for reperfusion treatment, up to 24 hours from onset. All subjects were assigned to receive secondary stroke prevention treatment along with remote ischemic conditioning on the non-paretic upper limb during the first 5 days of hospitalization, twice daily - a blood pressure cuff placed around the arm was inflated to 20 mmHg above the systolic blood pressure (up to 180 mmHg) in the experimental group and 30 mmHg in the sham group. The primary outcome was the difference in infarct volume (measured on brain CT scan) at 180 days compared to baseline, whereas the secondary outcomes included differences in clinical scores (NIHSS, mRS, IADL, ADL) and cognitive/mood changes (MoCA, PHQ-9) at 180 days compared to baseline. Results: We enrolled 40 patients; the mean age was 65 years and 60% were men. Subjects in the interventional group had slightly better recovery in terms of disability, as demonstrated by the differences in disability scores between admission and 6 months (e.g., the median difference score for Barthel was -10 in the sham group and -17.5 in the interventional group, for ADL -2 in the sham group and -2.5 in the interventional group), as well as cognitive performance (the median difference score for MoCA was -2 in the sham group and -3 in the interventional group), but none of these differences reached statistical significance. The severity of symptoms (median difference score for NIHSS = 5 for both groups) and depression rate (median difference score for PHQ-9 = 0 for both groups) were similar in the two groups. The median difference between baseline infarct volume and final infarct volume at 6 months was slightly larger in the sham group compared to the interventional group (p = 0.4), probably due to an initial larger infarct volume in the former. Conclusion: Our results suggest that remote ischemic conditioning might improve disability and cognition. The difference between baseline infarct volume and final infarct volume at 180 days was slightly larger in the sham group.
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Affiliation(s)
- Alina Poalelungi
- Department of Neurology, Emergency Clinical Hospital, Bucharest, Romania.,Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Delia Tulbă
- Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of Neurology, Colentina Clinical Hospital, Bucharest, Romania.,Colentina-Research and Development Center, Colentina Clinical Hospital, Bucharest, Romania
| | - Elena Turiac
- Department of Radiology, Emergency Clinical Hospital, Bucharest, Romania
| | - Diana Stoian
- Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Bogdan Ovidiu Popescu
- Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of Neurology, Colentina Clinical Hospital, Bucharest, Romania.,Laboratory of Cell Biology, Neurosciences and Experimental Myology, "Victor Babeş" National Institute of Pathology, Bucharest, Romania
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13
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Sheng R, Chen JL, Qin ZH. Cerebral conditioning: Mechanisms and potential clinical implications. BRAIN HEMORRHAGES 2021. [DOI: 10.1016/j.hest.2021.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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14
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Hansen LF, Nielsen NSK, Christoffersen LC, Kruuse C. Translational challenges of remote ischemic conditioning in ischemic stroke - a systematic review. Ann Clin Transl Neurol 2021; 8:1720-1729. [PMID: 34133841 PMCID: PMC8351389 DOI: 10.1002/acn3.51405] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/20/2021] [Accepted: 05/19/2021] [Indexed: 12/27/2022] Open
Abstract
Remote ischemic conditioning (RIC) has well‐established cardioprotective effects in preclinical studies and promising results in preclinical stroke research. Effective translation from preclinical studies to clinical trials has yet to be accomplished, perhaps because of the use of multiple applications of RIC (e.g., pre‐, per‐, or post‐conditioning) in preclinical studies by both invasive and non‐invasive protocols, some of which not clinically applicable. Our systematic review conformed to PRISMA guidelines and addressed differences in clinically relevant RIC applications and outcomes between preclinical and clinical studies. We retrieved a total of 30 studies (8 human; 22 animal) that met the inclusion criteria of testing clinically relevant procedures; namely, non‐invasive and per‐ or post‐conditioning protocols. Per‐conditioning was applied in 6 animal and 3 human studies, post‐conditioning was applied in 16 animal and 5 human studies, and both conditioning methods were applied in 2 animal studies. Application of RIC varied between human and animal studies regarding initiation, duration, repetition, and number of limbs included. Study designs did not systematically apply blinding, randomization, or placebo controls. On only a few occasions did preclinical studies include animals with clinically relevant comorbidities. Clinical trials were challenged by not completing the intended number of RIC cycles or addressing this deficit in the data analysis. Consistency and transferability of methods used for positive animal studies and subsequent human studies are essential for the optimal translation of results. Consensus on preclinical and clinical RIC procedures should be reached for a full understanding of the possible beneficial effects of RIC treatment in stroke.
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Affiliation(s)
- Line Fuglsang Hansen
- Department of Neurology, Neurovascular Research Unit, Herlev Gentofte Hospital, Copenhagen, Denmark.,Department of Anesthesiology and Intensive Care, Holbaek Hospital, Holbaek, Denmark
| | - Nicholine S K Nielsen
- Department of Neurology, Neurovascular Research Unit, Herlev Gentofte Hospital, Copenhagen, Denmark
| | | | - Christina Kruuse
- Department of Neurology, Neurovascular Research Unit, Herlev Gentofte Hospital, Copenhagen, Denmark.,Department. of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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15
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Nizari S, Basalay M, Chapman P, Korte N, Korsak A, Christie IN, Theparambil SM, Davidson SM, Reimann F, Trapp S, Yellon DM, Gourine AV. Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke. Basic Res Cardiol 2021; 116:32. [PMID: 33942194 PMCID: PMC8093159 DOI: 10.1007/s00395-021-00873-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 04/22/2021] [Indexed: 12/12/2022]
Abstract
Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9-39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.
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Affiliation(s)
- Shereen Nizari
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Marina Basalay
- The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Philippa Chapman
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Nils Korte
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Alla Korsak
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Isabel N Christie
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Shefeeq M Theparambil
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Frank Reimann
- Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Stefan Trapp
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Alexander V Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
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16
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Pico F, Lapergue B, Ferrigno M, Rosso C, Meseguer E, Chadenat ML, Bourdain F, Obadia M, Hirel C, Duong DL, Deltour S, Aegerter P, Labreuche J, Cattenoy A, Smadja D, Hosseini H, Guillon B, Wolff V, Samson Y, Cordonnier C, Amarenco P. Effect of In-Hospital Remote Ischemic Perconditioning on Brain Infarction Growth and Clinical Outcomes in Patients With Acute Ischemic Stroke: The RESCUE BRAIN Randomized Clinical Trial. JAMA Neurol 2021; 77:725-734. [PMID: 32227157 DOI: 10.1001/jamaneurol.2020.0326] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Importance Treatment with remote ischemic perconditioning has been reported to reduce brain infarction volume in animal models of stroke. Whether this neuroprotective effect was observed in patients with acute ischemic stroke remains unknown. Objective To determine whether treatment with remote ischemic perconditioning administered to the leg of patients with acute ischemic stroke can reduce brain infarction volume growth. Design, Setting, and Participants This proof-of-concept multicenter prospective randomized open-label with blinded end point clinical trial was performed from January 12, 2015, to May 2, 2018. Patients were recruited from 11 stroke centers in France. Of the 188 patients who received magnetic resonance imaging within 6 hours of symptom onset and were confirmed to have carotid ischemic stroke, 93 were randomized to receive treatment with lower-limb remote ischemic perconditioning in addition to standard care (the intervention group), and 95 were randomized to receive standard care alone (the control group). Interventions Randomization on a 1:1 ratio to receive treatment with remote ischemic perconditioning (4 cycles of 5-minute inflations and 5-minute deflations to the thigh to 110 mm Hg above systolic blood pressure) in addition to standard care or standard care alone. Main Outcomes and Measures The change in brain infarction volume growth between baseline and 24 hours, measured by a diffusion-weighted sequence of magnetic resonance imaging scans of the brain. Results A total of 188 patients (mean [SD] age, 67.2 [15.7] years; 98 men [52.1%]) were included in this intention-to-treat analysis. At hospital admission, the median National Institutes of Health Stroke Scale score was 10 (interquartile range [IQR], 6-16) and the median brain infarction volume was 11.4 cm3 (IQR, 3.6-35.8 cm3); 164 patients (87.2%) received intravenous thrombolysis, and 64 patients (34.0%) underwent mechanical thrombectomy. The median increase in brain infarction growth was 0.30 cm3 (IQR, 0.11-0.48 cm3) in the intervention group and 0.37 cm3 (IQR, 0.19-0.55 cm3) in the control group (mean between-group difference on loge-transformed change, -0.07; 95% CI, -0.33 to 0.18; P = .57). An excellent outcome (defined as a score of 0-1 on the 90-day modified Rankin Scale or a score equal to the prestroke modified Rankin Scale score) was observed in 46 of 90 patients (51.1%) in the intervention group and 37 of 91 patients (40.7%) in the control group (P = .12). No significant differences in 90-day mortality were observed between the intervention and control groups (14 of 90 patients; Kaplan-Meier estimate, 15.8% vs 10 of 91 patients; Kaplan-Meier estimate, 10.4%, respectively; P = .45) or with symptomatic intracerebral hemorrhage (4 of 88 patients [4.5%] in both groups; P = .97). Conclusions and Relevance In this study, treatment with remote ischemic perconditioning, during or after reperfusion therapies, had no significant effect on brain infarction volume growth at 24 hours after symptom onset. Trial Registration ClinicalTrials.gov Identifier: NCT02189928.
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Affiliation(s)
- Fernando Pico
- Department of Neurology and Stroke Center, Versailles Mignot Hospital, Versailles, France.,University of Versailles Saint-Quentin-en-Yvelines and Paris-Saclay University, Saint-Aubin, France.,Laboratoire de Recherche Vasculaire Translationnelle, Inserm U1148, Paris, France
| | - Bertrand Lapergue
- University of Versailles Saint-Quentin-en-Yvelines and Paris-Saclay University, Saint-Aubin, France.,Neurology and Stroke Center, Hôpital Foch, Suresnes, France
| | - Marc Ferrigno
- Department of Degenerative and Vascular Cognitive Disorders, Inserm U1171, Université de Lille, Lille, France.,Department of Neurology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Charlotte Rosso
- Assistance Publique-Hopitaux de Paris, Service des Urgences Cerebro-Vasculaires, Hôpital Pitié-Salpêtrière, Paris, France.,Centre National de la Recherche Scientifique, Inserm U1127, Unite Mixte de Recherche 7225, Institut du Cerveau et de la Moelle Epiniere, Sorbonne Universite, Paris, France
| | - Elena Meseguer
- Assistance Publique-Hôpitaux de Paris, Department of Neurology and Stroke Center, Bichat University Hospital, Universite Paris Diderot, Sorbonne Cite, Paris, France
| | - Marie-Laure Chadenat
- Department of Neurology and Stroke Center, Versailles Mignot Hospital, Versailles, France
| | | | - Michael Obadia
- Neurology and Stroke Center, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
| | - Catherine Hirel
- Department of Neurology and Stroke Center, Versailles Mignot Hospital, Versailles, France.,University of Versailles Saint-Quentin-en-Yvelines and Paris-Saclay University, Saint-Aubin, France
| | - Duc Long Duong
- Department of Neurology and Stroke Center, Versailles Mignot Hospital, Versailles, France
| | - Sandrine Deltour
- Assistance Publique-Hopitaux de Paris, Service des Urgences Cerebro-Vasculaires, Hôpital Pitié-Salpêtrière, Paris, France
| | - Philippe Aegerter
- Assistance Publique-Hôpitaux de Paris, Vieillissement et Maladies Chroniques, IndianaSERM, Unité Mixte de Recherche 1168, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France.,Department of Biostatistics, Université de Lille, Lille, France
| | - Julien Labreuche
- Unité de Recherche EA 2694-Sante Publique: Epidemiologie et Qualite des Soins, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Amina Cattenoy
- Délégation à la Recherche Clinique, Versailles Mignot Hospital, Versailles, France
| | - Didier Smadja
- Stroke Unit, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
| | - Hassan Hosseini
- Assistance Publique-Hopitaux de Paris, Stroke Center, Henri Mondor Hospital, Université Paris-Est Créteil, Creteil, France
| | - Benoit Guillon
- Department of Neurology, University Hospital of Nantes, Nantes, France
| | - Valérie Wolff
- Stroke Unit, Strasbourg University Hospital, Strasbourg, France
| | - Yves Samson
- Assistance Publique-Hopitaux de Paris, Service des Urgences Cerebro-Vasculaires, Hôpital Pitié-Salpêtrière, Paris, France
| | - Charlotte Cordonnier
- Department of Degenerative and Vascular Cognitive Disorders, Inserm U1171, Université de Lille, Lille, France.,Department of Neurology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Pierre Amarenco
- Laboratoire de Recherche Vasculaire Translationnelle, Inserm U1148, Paris, France.,Assistance Publique-Hôpitaux de Paris, Department of Neurology and Stroke Center, Bichat University Hospital, Universite Paris Diderot, Sorbonne Cite, Paris, France
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17
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Purroy F, Arque G, Mauri G, García-Vázquez C, Vicente-Pascual M, Pereira C, Vazquez-Justes D, Torres-Querol C, Vena A, Abilleira S, Cardona P, Forné C, Jiménez-Fàbrega X, Pagola J, Portero-Otin M, Rodríguez-Campello A, Rovira À, Martí-Fàbregas J. REMOTE Ischemic Perconditioning Among Acute Ischemic Stroke Patients in Catalonia: REMOTE-CAT PROJECT. Front Neurol 2020; 11:569696. [PMID: 33101178 PMCID: PMC7546310 DOI: 10.3389/fneur.2020.569696] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/27/2020] [Indexed: 01/24/2023] Open
Abstract
Rationale: Remote ischemic perconditioning during cerebral ischemia (RIPerC) refers to the application of brief episodes of transient limb ischemia commonly to a limb, it represents a new safe, simple and low-cost paradigm in neuroprotection. Aim and/or Hypothesis: To evaluate the effects of RIPerC on acute ischemic stroke (AIS) patients, applied in the ambulance, to improve functional outcomes compared with standard of care. Sample Size Estimates: A sample size of 286 patients in each arm achieves 80% power to detect treatment differences of 14% in the outcome, using a two-sided binomial test at significance level of 0.05, assuming that 40% of the control patients will experience good outcome and an initial misdiagnosis rate of 29%. Methods and Design: We aim to conduct a multicentre study of pre-hospital RIPerC application in AIS patients. A total of 572 adult patients diagnosed of suspected clinical stroke within 8 h of symptom onset and clinical deficit >0 according to prehospital rapid arterial occlusion evaluation (RACE) scale score will be randomized, in blocks of size 4, to RIPerC or sham. Patients will be stratified by RACE score scale. RIPerC will be started in the ambulance before hospital admission and continued in the hospital if necessary. It will consist of five cycles of electronic tourniquet inflation and deflation (5 min each). The cuff pressure for RIPerC will be 200 mmHg during inflation. Sham will only simulate vibration of the device. Study Outcome(s): The primary outcome will be the difference in the proportion of patients with good outcomes as defined by a mRS score of 2 or less at 90 days. Secondary outcomes to be monitored will include early neurological improvement rate, treatment related serious adverse event rates, size of the infarct volume, symptomatic intracranial hemorrhage, metabolomic and lipidomic response to RIPerC and Neuropsychological evaluation at 90 days. Discussion: Neuroprotective therapies could not only increase the benefits of available reperfusion therapies among AIS patients but also provide an option for patients who are not candidates for these treatments. REMOTE-CAT will investigate the clinical benefit of RIC as a new neuroprotective strategy in AIS. Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03375762.
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Affiliation(s)
- Francisco Purroy
- Stroke Unit, Department of Neurology, Hospital Universitari Arnau de Vilanova de Lleida, Lleida, Spain.,Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Gloria Arque
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Gerard Mauri
- Stroke Unit, Department of Neurology, Hospital Universitari Arnau de Vilanova de Lleida, Lleida, Spain.,Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Cristina García-Vázquez
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Mikel Vicente-Pascual
- Stroke Unit, Department of Neurology, Hospital Universitari Arnau de Vilanova de Lleida, Lleida, Spain.,Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Cristina Pereira
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Daniel Vazquez-Justes
- Stroke Unit, Department of Neurology, Hospital Universitari Arnau de Vilanova de Lleida, Lleida, Spain.,Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Coral Torres-Querol
- Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Ana Vena
- Stroke Unit, Department of Neurology, Hospital Universitari Arnau de Vilanova de Lleida, Lleida, Spain.,Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Sònia Abilleira
- Stroke Programme, Agency for Health Quality and Assessment of Catalonia, CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Pere Cardona
- Stroke Unit, Hospital de Bellvitge, Hospitalet de Llobregat, Spain
| | - Carles Forné
- Department of Basic Medical Sciences, Universitat de Lleida, Lleida, Spain
| | | | - Jorge Pagola
- Stroke Unit, Neurology Department, Vall d'Hebron Hospital, Barcelona, Spain
| | - Manuel Portero-Otin
- Department of Experimental Medicine, NUTREN-Nutrigenomics, Biomedical Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain
| | - Ana Rodríguez-Campello
- Neurovascular Research Group, Neurology Department, Institut Hospital del Mar d'Investigacions Mèdiques-Hospital del Mar, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Àlex Rovira
- Section of Neuroradiology and MRI Unit, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
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Neuroprotection by remote ischemic conditioning in the setting of acute ischemic stroke: a preclinical two-centre study. Sci Rep 2020; 10:16874. [PMID: 33037284 PMCID: PMC7547701 DOI: 10.1038/s41598-020-74046-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 09/22/2020] [Indexed: 01/01/2023] Open
Abstract
Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.
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19
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RiPerC Attenuates Cerebral Ischemia Injury through Regulation of miR-98/PIK3IP1/PI3K/AKT Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6454281. [PMID: 33082912 PMCID: PMC7559836 DOI: 10.1155/2020/6454281] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/11/2020] [Accepted: 09/19/2020] [Indexed: 02/06/2023]
Abstract
Background Cerebral ischemic stroke is a refractory disease which seriously endangers human health. Remote ischemic perconditioning (RiPerC) by which the sublethal ischemic stimulus is administered during the ischemic event is beneficial after an acute stroke. However, the regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear. Methods In the present study, we investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). Forty-eight adult male Sprague-Dawley (SD) rats were injected intracerebroventricularly with miR-98 agomir, miR-98 antagomir, or their negative controls (agomir-NC, antagomir-NC) 2 h before MCAO or MCAO+RiPerC followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. The expression of miR-98, PIK3IP1, and tight junction proteins in rat hippocampus and cerebral cortex tissues was detected by quantitative polymerase chain reaction (qPCR) and Western blot (WB). Enzyme-linked immunosorbent assay (ELISA) was used to assess the IL-1β, IL-6, and TNF-α levels in the rat serum. Results The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Then, we found that PIK3IP1 was a potential target of miR-98. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. But treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled. Conclusion Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, thus reducing the cerebral ischemia-reperfusion injury.
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20
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Mishra RK, Pandia MP, Kumar S, Singh GP, Kalaivani M. The effect of anaesthetic exposure in presurgical period on delayed cerebral ischaemia and neurological outcome in patients with aneurysmal subarachnoid haemorrhage undergoing clipping of aneurysm: A retrospective analysis. Indian J Anaesth 2020; 64:495-500. [PMID: 32792714 PMCID: PMC7398020 DOI: 10.4103/ija.ija_958_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/13/2020] [Accepted: 04/19/2020] [Indexed: 11/21/2022] Open
Abstract
Background and Aims: Delayed cerebral ischaemia is one of the major contributors to morbidity in aneurysmal subarachnoid haemorrhage (aSAH). General anaesthesia (GA) in the presurgical period may have a preconditioning effect. The primary aim was to assess the effect of preoperative exposure to GA during digital subtraction angiography (DSA) on neurological outcome in patients presenting with aSAH. Methods: After Ethical Committee approval, we conducted a retrospective analysis of the data of patients with aSAH treated surgically. Patients, admitted to neurosurgical ICU (June 2014 and December 2017) with a computed tomography (CT) diagnosis of aSAH and underwent DSA, were included. DSA, done with or without exposure to a general anaesthetic, was classified to GA group and LA group, respectively. Propensity score matching was done on the baseline variables. Appropriate statistical methods were applied. Results: Of the 278 patients, 116 (41.7%) patients had received GA during DSA. Propensity matching yielded 114 (57 in each group) matched patients. In a logistic regression model, the odds ratio (OR) for poor outcome at discharge in GA group as compared to LA group was 4.4 (CI: 2.7–7.4), P = 0.001, whereas, in the matched data, the OR for poor outcome at discharge in GA group as compared to LA group was 1.2 (CI: 0.6–2.6), P = 0.57. Conclusion: The presurgical exposure to GA did not offer any neuroprotection and the odds of poor outcome were higher compare to non-exposure to GA group.
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Affiliation(s)
- Rajeeb K Mishra
- Department of Neuroanaesthesia and Neurocritical Care, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
| | - Mihir P Pandia
- Department of Neuroanaesthesia and Critical Care, All India Institute of Medical Sciences, New Delhi, India
| | - Subodh Kumar
- Department of Anaesthesia and Intensive care, Government Medical College and Hospital, Chandigarh, India
| | - Gyaninder P Singh
- Department of Neuroanaesthesia and Critical Care, All India Institute of Medical Sciences, New Delhi, India
| | - M Kalaivani
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
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21
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Costa FLDS, Teixeira RKC, Yamaki VN, Valente AL, Percário S, Brito MVH. Remote ischemic conditioning enhances heart and brain antioxidant defense. J Vasc Bras 2020; 19:e20190129. [PMID: 34178069 PMCID: PMC8202165 DOI: 10.1590/1677-5449.190129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background Ischemia-reperfusion injury contributes to morbidity after revascularization
procedures. Along with early reperfusion, tissue conditioning by alternating
intervals of brief ischemia-reperfusion episodes is considered the best approach
to limit tissue damage. Remote ischemic conditioning is conducted remotely, in
tissues other than those under ischemia. Despite this, remote ischemic
conditioning protection mechanisms are poorly understood, which can lead to
misapplication. Objectives To assess whether remote ischemic conditioning works in the heart and brain
through enhancement of cells’ antioxidant defenses and whether the response is
sustained or temporary. Methods Twenty-one male Wistar rats were assigned to three groups (n = 7): SHAM: same
procedure as the other groups, but no remote ischemic conditioning was carried
out. RIC 10: heart and brain were harvested 10 minutes after the remote ischemic
conditioning protocol. RIC 60: heart and brain were harvested 60 minutes after the
remote ischemic conditioning protocol. The remote ischemic conditioning protocol
consisted of 3 cycles of 5 min left hindlimb ischemia followed by 5 min left
hindlimb perfusion, lasting 30 min in total. Heart and brain samples were used to
measure the tissue antioxidant capacity. Results Remote ischemic conditioning increased heart and brain antioxidant capacity after
10 minutes (0.746 ± 0.160/0.801 ± 0.227 mM/L) when compared to SHAM (0.523 ±
0.078/0.404 ± 0.124 mM/L). No enhancement of heart or brain antioxidant capacity
was detected 60 minutes after remote ischemic conditioning (0.551 ± 0.073/0.455 ±
0.107 mM/L). Conclusions Remote ischemic conditioning temporarily enhances heart and brain antioxidant
defenses in male Wistar rats.
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Affiliation(s)
| | | | - Vitor Nagai Yamaki
- Universidade do Estado do Pará - UEPA, Laboratório de Cirurgia Experimental, Belém, PA, Brasil
| | - André Lopes Valente
- Universidade do Estado do Pará - UEPA, Laboratório de Cirurgia Experimental, Belém, PA, Brasil
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22
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Just J, Yan Y, Farup J, Sieljacks P, Sloth M, Venø M, Gu T, de Paoli FV, Nyengaard JR, Bæk R, Jørgensen MM, Kjems J, Vissing K, Drasbek KR. Blood flow-restricted resistance exercise alters the surface profile, miRNA cargo and functional impact of circulating extracellular vesicles. Sci Rep 2020; 10:5835. [PMID: 32245988 PMCID: PMC7125173 DOI: 10.1038/s41598-020-62456-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 03/10/2020] [Indexed: 01/12/2023] Open
Abstract
Ischemic exercise conducted as low-load blood flow restricted resistance exercise (BFRE) can lead to muscle remodelling and promote muscle growth, possibly through activation of muscle precursor cells. Cell activation can be triggered by blood borne extracellular vesicles (EVs) as these nano-sized particles are involved in long distance signalling. In this study, EVs isolated from plasma of healthy human subjects performing a single bout of BFRE were investigated for their change in EV surface profiles and miRNA cargos as well as their impact on skeletal muscle precursor cell proliferation. We found that after BFRE, five EV surface markers and 12 miRNAs were significantly altered. Furthermore, target prediction and functional enrichment analysis of the miRNAs revealed several target genes that are associated to biological pathways involved in skeletal muscle protein turnover. Interestingly, EVs from BFRE plasma increased the proliferation of muscle precursor cells. In addition, alterations in surface markers and miRNAs indicated that the combination of exercise and ischemic conditioning during BFRE can stimulate blood cells to release EVs. These results support that BFRE promotes EV release to engage in muscle remodelling and/or growth processes.
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Affiliation(s)
- Jesper Just
- Center of Functionally Integrative Neuroscience, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Yan Yan
- Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark
| | - Jean Farup
- Research laboratory for Biochemical Pathology, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Dept of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Peter Sieljacks
- Section for Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Mette Sloth
- Center of Functionally Integrative Neuroscience, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Morten Venø
- Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark
| | - Tingting Gu
- Center of Functionally Integrative Neuroscience, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Jens Randel Nyengaard
- Dept of Clinical Medicine, Core Center for Molecular Morphology, Section for Stereology and Microscopy, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Aarhus, Denmark
| | - Rikke Bæk
- Dept of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
| | - Malene Møller Jørgensen
- Dept of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.,Dept of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark.,Dept of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Kristian Vissing
- Section for Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Kim Ryun Drasbek
- Center of Functionally Integrative Neuroscience, Dept of Clinical Medicine, Aarhus University, Aarhus, Denmark.
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23
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RIPC provides neuroprotection against ischemic stroke by suppressing apoptosis via the mitochondrial pathway. Sci Rep 2020; 10:5361. [PMID: 32210331 PMCID: PMC7093414 DOI: 10.1038/s41598-020-62336-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/10/2020] [Indexed: 12/18/2022] Open
Abstract
Ischemic stroke is a common disease with high morbidity and mortality. Remote ischemic preconditioning (RIPC) can stimulate endogenous protection mechanisms by inducing ischemic tolerance to reduce subsequent damage caused by severe or fatal ischemia to non-ischemic organs. This study was designed to assess the therapeutic properties of RIPC in ischemic stroke and to elucidate their underlying mechanisms. Neurobehavioral function was evaluated with the modified neurological severity score (mNSS) test and gait analysis. PET/CT was used to detect the ischemic volume and level of glucose metabolism. The protein levels of cytochrome c oxidase-IV (COX-IV) and heat shock protein 60 (HSP60) were tested by Western blotting. TUNEL and immunofluorescence staining were used to analyze apoptosis and to observe the nuclear translocation and colocalization of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in apoptotic cells. Transmission electron microscopy (TEM) was used to detect mitochondrial-derived vesicle (MDV) production and to assess mitochondrial ultrastructure. The experimental results showed that RIPC exerted significant neuroprotective effects, as indicated by improvements in neurological dysfunction, reductions in ischemic volume, increases in glucose metabolism, inhibition of apoptosis, decreased nuclear translocation of AIF and EndoG from mitochondria and improved MDV formation. In conclusion, RIPC alleviates ischemia/reperfusion injury after ischemic stroke by inhibiting apoptosis via the endogenous mitochondrial pathway.
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24
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Mohammad Seyedsaadat S, Kallmes DF, Brinjikji W. Remote ischemic conditioning approach for the treatment of ischemic stroke. Neural Regen Res 2020; 15:1033-1034. [PMID: 31823878 PMCID: PMC7034284 DOI: 10.4103/1673-5374.270303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
| | - David F Kallmes
- Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN, USA
| | - Waleed Brinjikji
- Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN, USA
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25
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Qin C, Yan X, Jin H, Zhang R, He Y, Sun X, Zhang Y, Guo ZN, Yang Y. Effects of Remote Ischemic Conditioning on Cerebral Hemodynamics in Ischemic Stroke. Neuropsychiatr Dis Treat 2020; 16:283-299. [PMID: 32021218 PMCID: PMC6988382 DOI: 10.2147/ndt.s231944] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 12/16/2019] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is one of the most common cerebrovascular diseases and is the leading cause of disability all over the world. It is well known that cerebral blood flow (CBF) is disturbed or even disrupted when ischemic stroke happens. The imbalance between demand and shortage of blood supply makes ischemic stroke take place or worsen. The search for treatments that can preserve CBF, especially during the acute phase of ischemic stroke, has become a research hotspot. Animal and clinical experiments have proven that remote ischemic conditioning (RIC) is a beneficial therapeutic strategy for the treatment of ischemic stroke. However, the mechanism by which RIC affects CBF has not been fully understood. This review aims to discuss several possible mechanisms of RIC on the cerebral hemodynamics in ischemic stroke, such as the improvement of cardiac function and collateral circulation of cerebral vessels, the protection of neurovascular units, the formation of gas molecules, the effect on the function of vascular endothelial cells and the nervous system. RIC has the potential to become a therapeutic treatment to improve CBF in ischemic stroke. Future studies are needed to highlight our understanding of RIC as well as accelerate its clinical translation.
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Affiliation(s)
- Chen Qin
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Xiuli Yan
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Hang Jin
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Ruyi Zhang
- Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yaode He
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Xin Sun
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yihe Zhang
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Zhen-Ni Guo
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China.,Clinical Trial and Research Center for Stroke, Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yi Yang
- Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China.,Clinical Trial and Research Center for Stroke, Department of Neurology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
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26
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England TJ, Hedstrom A, O'Sullivan SE, Woodhouse L, Jackson B, Sprigg N, Bath PM. Remote Ischemic Conditioning After Stroke Trial 2: A Phase IIb Randomized Controlled Trial in Hyperacute Stroke. J Am Heart Assoc 2019; 8:e013572. [PMID: 31747864 PMCID: PMC6912955 DOI: 10.1161/jaha.119.013572] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/23/2019] [Indexed: 11/16/2022]
Abstract
Background Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may protect the brain from ischemic reperfusion injury. Methods and Results We performed a phase IIb blinded dose-escalation sham-controlled trial in patients with hyperacute stroke, randomized 1:1 to receive RIC (four 5-minute cycles) or sham to the nonparetic upper limb, in 3 blocks of increasing dose, starting within 6 hours of ictus. The primary outcome was trial feasibility (recruitment, attrition). Secondary outcomes included adherence, tolerability, safety (serious adverse events), plasma biomarkers at days 1 and 4 (S100-ß protein, matrix metalloproteinase-9, and neuron-specific enolase), and functional outcome. Sixty participants were recruited from 2 centers (3 per month) with no loss to follow-up: time to randomization 4 hours 5 minutes (SD 72 minutes), age 72 years (12), men 60%, blood pressure 154/80 mm Hg (25/12), National Institutes of Health Stroke Scale 8.4 (6.9), and 55% thrombolyzed. RIC was well tolerated with adherence not differing between RIC and sham, falling in both groups on day 3 (P=0.001, repeated measures ANOVA) because of discharge or transfer. S100ß increased in the sham group (mean rise 111 pg/mL [302], P=0.041, repeated measures ANCOVA) but not the RIC group. There were no differences in matrix metalloproteinase-9, neuron-specific enolase, number with serious adverse events (RIC 10 versus sham 10, P=0.81), deaths (2 versus 4, P=0.36), or modified Rankin Scale score (2 [interquartile range 1-4], 2 [interquartile range, 1-3]; P=0.85). Conclusions RIC in hyperacute stroke is feasible when given twice daily for 2 days and appears safe in a small population with hyperacute stroke. A larger phase III trial is warranted. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02779712.
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Affiliation(s)
- Timothy J. England
- Vascular MedicineDivision of Medical Sciences and GEMSchool of MedicineUniversity of NottinghamDerbyUnited Kingdom
- StrokeRoyal Derby HospitalUniversity Hospitals of Derby and BurtonNHS Foundation TrustDerbyUnited Kingdom
| | - Amanda Hedstrom
- Vascular MedicineDivision of Medical Sciences and GEMSchool of MedicineUniversity of NottinghamDerbyUnited Kingdom
| | - Saoirse E. O'Sullivan
- Vascular MedicineDivision of Medical Sciences and GEMSchool of MedicineUniversity of NottinghamDerbyUnited Kingdom
| | - Lisa Woodhouse
- Stroke Trials UnitDivision of Clinical NeuroscienceCity Hospital CampusUniversity of NottinghamNottinghamUnited Kingdom
| | - Ben Jackson
- Stroke Trials UnitDivision of Clinical NeuroscienceCity Hospital CampusUniversity of NottinghamNottinghamUnited Kingdom
| | - Nikola Sprigg
- Stroke Trials UnitDivision of Clinical NeuroscienceCity Hospital CampusUniversity of NottinghamNottinghamUnited Kingdom
- StrokeNottingham University Hospitals NHS TrustCity Hospital CampusNottinghamUnited Kingdom
| | - Philip M. Bath
- Stroke Trials UnitDivision of Clinical NeuroscienceCity Hospital CampusUniversity of NottinghamNottinghamUnited Kingdom
- StrokeNottingham University Hospitals NHS TrustCity Hospital CampusNottinghamUnited Kingdom
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27
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Blauenfeldt RA, Hjort N, Gude MF, Behrndtz AB, Fisher M, Valentin JB, Kirkegaard H, Johnsen SP, Hess DC, Andersen G. A multicentre, randomised, sham-controlled trial on REmote iSchemic conditioning In patients with acute STroke (RESIST) - Rationale and study design. Eur Stroke J 2019; 5:94-101. [PMID: 32232175 DOI: 10.1177/2396987319884408] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/03/2019] [Indexed: 12/20/2022] Open
Abstract
Rationale Remote ischaemic conditioning, applied in the prehospital setting and continued in-hospital, may improve functional outcome in patients with acute ischaemic stroke and intracerebral haemorrhage. Aims To evaluate whether combined remote ischaemic per- and postconditioning can improve long-term functional outcome in acute ischaemic stroke and intracerebral haemorrhage patients. Methods and design Danish multicentre, prospective, randomised, patient-assessor blinded, sham-controlled study. Adult patients with a putative stroke identified prehospital with symptom duration <4 h, who are independent in daily activities will be randomised 1:1 to remote ischaemic conditioning or Sham-remote ischaemic conditioning. The treatment protocol will be five cycles, each consisting of 5 min with a blood pressure cuff inflation and 5 min with a deflated cuff placed on the upper extremity. The cuff pressure for remote ischaemic conditioning will be 200 mmHg-285 mmHg according to the individual systolic blood pressure and 20 mmHg sham-remote ischaemic conditioning during inflation. The study is approved as an acute study and consent is waived in the acute phase.Sample size estimation: For a 7% increased odds for a beneficial shift on the modified Rankin Scale at a significance level of 5% and power of 90%, 1000 patients with a target diagnosis of acute ischaemic stroke and intracerebral haemorrhage and a total of 1500 patients with a prehospital presumed stroke will be included.Study outcomes: The primary outcome will be the modified Rankin Scale score measured at three-month follow-up (analysed using ordinal logistic regression). ClinicalTrials.gov Identifier: NCT03481777.
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Affiliation(s)
- Rolf A Blauenfeldt
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Hjort
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark
| | - Martin F Gude
- Department of Research and Development, Emergency Medical Services, Central Denmark Region and Aarhus University, Aarhus, Denmark
| | - Anne B Behrndtz
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark.,Department of Neurology, Regional Hospital of West Jutland, Holstebro, Denmark
| | - Marc Fisher
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jan B Valentin
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University and Aalborg University Hospital, Aalborg, Denmark
| | - Hans Kirkegaard
- Department of Research and Development, Emergency Medical Services, Central Denmark Region and Aarhus University, Aarhus, Denmark
| | - Søren P Johnsen
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University and Aalborg University Hospital, Aalborg, Denmark
| | - David C Hess
- Department of Neurology, Medical College Georgia & Augusta University, Augusta, GA, USA
| | - Grethe Andersen
- Neurology & Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark
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28
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Kate M, Brar S, George U, Rathore S, Butcher K, Pandian J, Hess D. Self- or caregiver-delivered manual remote ischemic conditioning therapy in acute ischemic stroke is feasible: the Early Remote Ischemic Conditioning in Stroke (ERICS) trial. Wellcome Open Res 2019. [DOI: 10.12688/wellcomeopenres.15490.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background: Infarct growth and recurrent stroke may be responsible for early morbidity and mortality in patients with acute ischemic stroke. Remote ischemic conditioning (RIC) may reduce infarct growth and prevent recurrent stroke; however, the exact dose remains to be investigated. We hypothesized that self- or caregiver-delivered six cycles of RIC intervention in acute ischaemic stroke for the first 12 weeks is feasible and safe compared to the four cycles RIC intervention. Methods: Adult ischemic stroke patients presenting within the first 48 h of symptom onset were screened. Patients with magnetic resonance imaging (MRI) evidence of acute infarct were randomized (1:1) to receive either four or six cycles of RIC therapy sessions two times daily in both arms for 12 weeks. All patients underwent MRI for infarct volume assessment and endothelial-dependent flow-mediated dilation (EDFMD) testing at baseline, 7 days and 12 weeks. Results: A total of 57 patients with mean±SD age of 59.4±12.4 years and median National Institute of Stroke Scale, 4 (IQR, 3-7) were randomised at a median of 23 h 30 min (IQR, 10 h 20 min to 30 h) after symptom onset to either the four-cycle (n=27) or six-cycle group (n=30). A total of 18 (66%) patients completed ≥50% sessions in 12 weeks in the four-cycles group; 21 (69.7%) patients completed ≥50% sessions in 12 weeks in the six-cycle group (p=0.4). There was no between-group differences in infarct growth, early neurological deterioration, recurrent stroke, and EDFMD at 7 days and 90 days. Conclusion: Both four and six cycles of short-term self- or caregiver-delivered RIC therapy is safe and may be feasible in acute ischaemic stroke patients. Randomised clinical trials are needed to assess efficacy to decrease infarct growth and prevent early neurological deterioration. Registration: Clinical Trial Registry - India: CTRI/2016/11/007495; registered on 25/11/2016.
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29
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Li XQ, Tao L, Zhou ZH, Cui Y, Chen HS. Remote ischemic conditioning for acute moderate ischemic stroke (RICAMIS): Rationale and design. Int J Stroke 2019; 15:454-460. [PMID: 31581929 DOI: 10.1177/1747493019879651] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
RATIONALE A large number of basic and clinical studies have proved that remote ischemic conditioning has neuroprotective effect. For example, remote ischemic conditioning showed a neuroprotective role in cerebral ischemia-reperfusion injury model. Recent clinical studies suggested that remote ischemic conditioning may improve neurological function and reduce the risk of recurrence in ischemic stroke patients. However, there is a lack of convincing evidence for the neuroprotective effect of remote ischemic conditioning on ischemic stroke, which deserves further study. AIM To explore the efficacy and safety of remote ischemic conditioning for acute moderate ischemic stroke. SAMPLE SIZE ESTIMATES A maximum of 1800 subjects are required to test the superiority hypothesis with 80% power according to a one-sided 0.025 level of significance, stratified by gender, age, time from onset to treatment, National Institutes of Health Stroke Scale (6-10 vs. 11-16), degree of responsible vessel stenosis, location of stenosis, and stroke etiology. METHODS AND DESIGN Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke is a prospective, random, open label, blinded endpoint and multi-center study. The subjects are divided into experimental group and control group randomly. The experimental group was treated with remote ischemic conditioning twice daily with 200 mmHg pressure for 10-14 days besides guideline-based therapy. The control group was treated according to the guidelines. STUDY OUTCOME The primary efficacy endpoint is favorable functional outcome, defined as modified Rankin Scale 0-1 at 90 days post-randomization.
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Affiliation(s)
- Xiao-Qiu Li
- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, P.R. China
| | - Lin Tao
- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, P.R. China
| | - Zhong-He Zhou
- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, P.R. China
| | - Yu Cui
- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, P.R. China
| | - Hui-Sheng Chen
- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, P.R. China
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- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, P.R. China
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30
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Yang Q, Huang Q, Hu Z, Tang X. Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation. Front Neurosci 2019; 13:1036. [PMID: 31611768 PMCID: PMC6777147 DOI: 10.3389/fnins.2019.01036] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 09/12/2019] [Indexed: 01/08/2023] Open
Abstract
Stroke is a major cause of death and adult disability. However, therapeutic options remain limited. Numerous pathways underlie acute responses of brain tissue to stroke. Early events following ischemic damage include reactive oxygen species (ROS)-mediated oxidative stress and glutamate-induced excitotoxicity, both of which contribute to rapid cell death within the infarct core. A subsequent cascade of inflammatory events escalates damage progression. This review explores potential neuroprotective strategies for targeting key steps in the cascade of ischemia–reperfusion (I/R) injury. NADPH oxidase (NOX) inhibitors and several drugs currently approved by the U.S. Food and Drug Administration including glucose-lowering agents, antibiotics, and immunomodulators, have shown promise in the treatment of stroke in both animal experiments and clinical trials. Ischemic conditioning, a phenomenon by which one or more cycles of a short period of sublethal ischemia to an organ or tissue protects against subsequent ischemic events in another organ, may be another potential neuroprotective strategy for the treatment of stroke by targeting key steps in the I/R injury cascade.
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Affiliation(s)
- Qianwen Yang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qianyi Huang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiangqi Tang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, China
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Liang W, Lin C, Yuan L, Chen L, Guo P, Li P, Wang W, Zhang X. Preactivation of Notch1 in remote ischemic preconditioning reduces cerebral ischemia-reperfusion injury through crosstalk with the NF-κB pathway. J Neuroinflammation 2019; 16:181. [PMID: 31526384 PMCID: PMC6747758 DOI: 10.1186/s12974-019-1570-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 08/29/2019] [Indexed: 12/21/2022] Open
Abstract
Background Remote ischemic preconditioning (RIPC) initiates endogenous protective pathways in the brain from a distance and represents a new, promising paradigm in neuroprotection against cerebral ischemia-reperfusion (I/R) injury. However, the underlying mechanism of RIPC-mediated cerebral ischemia tolerance is complicated and not well understood. We reported previously that preactivation of Notch1 mediated the neuroprotective effects of cerebral ischemic preconditioning in rats subjected to cerebral I/R injury. The present study seeks to further explore the role of crosstalk between the Notch1 and NF-κB signaling pathways in the process of RIPC-induced neuroprotection. Methods Middle cerebral artery occlusion and reperfusion (MCAO/R) in adult male rats and oxygen-glucose deprivation and reoxygenation (OGD/R) in primary hippocampal neurons were used as models of I/R injury in vivo and in vitro, respectively. RIPC was induced by a 3-day procedure with 4 cycles of 5 min of left hind limb ischemia followed by 5 min of reperfusion each day before MCAO/R. Intracerebroventricular DAPT injection and sh-Notch1 lentivirus interference were used to inhibit the Notch1 signaling pathway in vivo and in vitro, respectively. After 24 h of reperfusion, neurological deficit scores, infarct volume, neuronal apoptosis, and cell viability were assessed. The protein expression levels of NICD, Hes1, Phospho-IKKα/β (p-IKK α/β), Phospho-NF-κB p65 (p-NF-κB p65), Bcl-2, and Bax were assessed by Western blotting. Results RIPC significantly improved neurological scores and reduced infarct volume and neuronal apoptosis in rats subjected to I/R injury. OGD preconditioning significantly reduced neuronal apoptosis and improved cell viability after I/R injury on days 3 and 7 after OGD/R. However, the neuroprotective effect was reversed by DAPT in vivo and attenuated by Notch1-RNAi in vitro. RIPC significantly upregulated the expression of proteins related to the Notch1 and NF-κB pathways. NF-κB signaling pathway activity was suppressed by a Notch1 signaling pathway inhibitor and Notch1-RNAi. Conclusions The neuroprotective effect of RIPC against cerebral I/R injury was associated with preactivation of the Notch1 and NF-κB pathways in neurons. The NF-κB pathway is a downstream target of the Notch1 pathway in RIPC and helps protect focal cerebral I/R injury.
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Affiliation(s)
- Weidong Liang
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.,The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Chunshui Lin
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Liuqing Yuan
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Li Chen
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Peipei Guo
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ping Li
- Department of Anesthesia, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Wei Wang
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xin Zhang
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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Baron JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nat Rev Neurol 2019; 14:325-337. [PMID: 29674752 DOI: 10.1038/s41582-018-0002-2] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
After ischaemic stroke, brain damage can be curtailed by rescuing the 'ischaemic penumbra' - that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Current evidence-based treatments involve restoration of blood flow so as to salvage the penumbra before it evolves into irreversibly damaged tissue, termed the 'core'. Intravenous thrombolysis (IVT) can salvage the penumbra if given within 4.5 h after stroke onset; however, the early recanalization rate is only ~30%. Direct removal of the occluding clot by mechanical thrombectomy considerably improves outcomes over IVT alone, but despite early recanalization in > 80% of cases, ~50% of patients who receive this treatment do not enjoy functional independence, usually because the core is already too large at the time of recanalization. Novel therapies aiming to 'freeze' the penumbra - that is, prevent core growth until recanalization is complete - hold potential as adjuncts to mechanical thrombectomy. This Review focuses on nonpharmacological approaches that aim to restore the physiological balance between oxygen delivery to and oxygen demand of the penumbra. Particular emphasis is placed on normobaric oxygen therapy, hypothermia and sensory stimulation. Preclinical evidence and early pilot clinical trials are critically reviewed, and future directions, including clinical translation and trial design issues, are discussed.
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Affiliation(s)
- Jean-Claude Baron
- Department of Neurology, Hôpital Sainte-Anne, Université Paris 5, INSERM U894, Paris, France.
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Mohammad Seyedsaadat S, Rangel Castilla L, Lanzino G, Cloft HJ, Blezek DJ, Theiler A, Kadirvel R, Brinjikji W, Kallmes DF. Remote ischemic preconditioning for elective endovascular intracranial aneurysm repair: a feasibility study. Neuroradiol J 2019; 32:166-172. [PMID: 30942660 DOI: 10.1177/1971400919842059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES Remote ischemic preconditioning has been proposed as a possible potential treatment for ischemic stroke. However, neuroprotective benefits of the pre-procedural administration of remote ischemic preconditioning have not been investigated in patients undergoing an elective endovascular intracranial aneurysm repair procedure. This study investigated the safety and feasibility of remote ischemic preconditioning in patients with an unruptured intracranial aneurysm who undergo elective endovascular treatment. METHODS In this single-center prospective study, patients with an unruptured intracranial aneurysm undergoing elective endovascular treatment with flow diverters or coiling were recruited. Patients received three intermittent cycles of 5 minutes arm ischemia followed by reperfusion using manual blood cuff inflation/deflation less than 5 hours prior to endovascular treatment. Patients were monitored and followed up for remote ischemic preconditioning-related adverse events and ischemic brain lesions by diffusion -weighted magnetic resonance imaging within 48 hours following endovascular treatment. RESULTS A total of seven patients aged 60 ± 5 years with an unruptured intracranial aneurysm successfully completed a total of 21 sessions of remote ischemic preconditioning and the required procedures. Except for two patients who developed skin petechiae over their arms, no other serious procedure-related adverse events were observed as a result of the remote ischemic preconditioning procedure. On follow-up diffusion -weighted magnetic resonance imaging, a total of 19 ischemic brain lesions with a median (interquartile range) volume of 245 (61-466) mm3 were found in four out of seven patients. CONCLUSIONS The application of remote ischemic preconditioning prior to endovascular intracranial aneurysm repair was well tolerated, safe and clinically feasible. Larger sham-controlled clinical trials are required to determine the safety and efficacy of this therapeutic strategy in mitigating ischemic damage following endovascular treatment of intracranial aneurysms.
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Affiliation(s)
| | - Leonardo Rangel Castilla
- 1 Department of Radiology, Mayo Clinic, Rochester, MN, USA.,2 Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
| | - Giuseppe Lanzino
- 1 Department of Radiology, Mayo Clinic, Rochester, MN, USA.,2 Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
| | - Harry J Cloft
- 1 Department of Radiology, Mayo Clinic, Rochester, MN, USA.,2 Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
| | | | - Amy Theiler
- 1 Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | | | - Waleed Brinjikji
- 1 Department of Radiology, Mayo Clinic, Rochester, MN, USA.,2 Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
| | - David F Kallmes
- 1 Department of Radiology, Mayo Clinic, Rochester, MN, USA.,2 Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
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Landman T, Schoon Y, Warlé M, De Leeuw FE, Thijssen D. The effect of repeated remote ischemic postconditioning on infarct size in patients with an ischemic stroke (REPOST): study protocol for a randomized clinical trial. Trials 2019; 20:167. [PMID: 30876432 PMCID: PMC6419836 DOI: 10.1186/s13063-019-3264-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 02/27/2019] [Indexed: 01/28/2023] Open
Abstract
Background Remote ischemic postconditioning (rIPostC) refers to the observation that repeated, short periods of ischemia protect remote areas against tissue damage during and after prolonged ischemia. Based on previous observations of a potential neuroprotective effect of rIPostC, the aim of this study is to evaluate whether repeated rIPostC after an ischemic stroke can reduce infarct size, which could be translated to an improvement in clinical outcomes. Methods/design We will enroll 200 ischemic stroke patients to daily rIPostC or sham conditioning during hospitalization into a randomized single-blind placebo-controlled trial. The intervention consists of twice daily exposure to four cycles of 5-min cuff inflation around the upper arm to > 20 mmHg above systolic blood pressure (i.e., rIPostC) or 50 mmHg (i.e., control), followed by 5 minutes of deflation. The primary outcome is infarct size, measured using an MRI diffusion-weighted image at the end of hospitalization. Secondary outcomes include the Modified Rankin Scale, National Institutes of Health Stroke Scale, quality of life, and cardiovascular and cerebrovascular morbidity and mortality. To explore possible underlying mechanisms of rIPostC, venous blood will be sampled to assess biomarkers of inflammation and vascular health. Discussion Previous studies in animals and humans, using a single bout of remote ischemic conditioning, report a potential effect of rIPostC in attenuating neural damage. Although repeated rIPostC has been investigated for cardiovascular disease patients and preclinical stroke models, no previous study has explored the potential physiological and clinical effects of repeatedly applying rIPostC during the hospitalization phase after a stroke. Trial registration Netherlands Trial Register, NTR6880. Registered on 8 December 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3264-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Thijs Landman
- Department of Physiology, Radboud University Medical Centre, Radboud Institute for Health Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, Gelderland, Netherlands.
| | - Yvonne Schoon
- Department of Geriatric Medicine, Radboud University Medical Centre, Radboud Institute for Health Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, Gelderland, Netherlands
| | - Michiel Warlé
- Department of Surgery, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, Gelderland, Netherlands
| | - Frank-Erik De Leeuw
- Centre for Cognitive Neuroscience, Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, Gelderland, Netherlands
| | - Dick Thijssen
- Department of Physiology, Radboud University Medical Centre, Radboud Institute for Health Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, Gelderland, Netherlands
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Limb Remote Ischemic Preconditioning Reduces Repeated Ketamine Exposure-Induced Adverse Effects in the Developing Brain of Rats. J Mol Neurosci 2019; 68:58-65. [DOI: 10.1007/s12031-019-01282-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 02/18/2019] [Indexed: 11/26/2022]
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Choi JH, Pile-Spellman J. Reperfusion Changes After Stroke and Practical Approaches for Neuroprotection. Neuroimaging Clin N Am 2019; 28:663-682. [PMID: 30322601 DOI: 10.1016/j.nic.2018.06.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Reperfusion is the first line of care in a growing number of eligible acute ischemic stroke patients. Early reperfusion with thrombolytic drugs and endovascular mechanical devices is associated with improved outcome and lower mortality rates compared with natural history. Reperfusion is not without risk, however, and may result in reperfusion injury, which manifests in hemorrhagic transformation, brain edema, infarct progression, and neurologic worsening. In this article, the functional and structural changes and underlying molecular mechanisms of ischemia and reperfusion are reviewed. The pathways that lead to reperfusion injury and novel neuroprotective strategies with endogenous properties are discussed.
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Affiliation(s)
- Jae H Choi
- Center for Unruptured Brain Aneurysms, Neurological Surgery PC, 1991 Marcus Avenue, Suite 108, Lake Success, NY 11042, USA; Department of Neurology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Hybernia Medical LLC, 626 RexCorp Plaza, Uniondale, NY 11556, USA.
| | - John Pile-Spellman
- Center for Unruptured Brain Aneurysms, Neurological Surgery PC, 1991 Marcus Avenue, Suite 108, Lake Success, NY 11042, USA; Hybernia Medical LLC, 626 RexCorp Plaza, Uniondale, NY 11556, USA
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Yakovlev A, Lyzhin A, Aleksandrova O, Khaspekov L, Gulyaeva N. Exosomes secretion and autophagy in long-term protection of neurons from excitotoxic damage. ACTA ACUST UNITED AC 2019; 65:361-365. [DOI: 10.18097/pbmc20196505361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In the model of induced neuronal resistance to the toxic effect of glutamate (deprivation of trophic factors), exosome secretion is demonstrated. Exosomes are secreted at the development of resistance during deprivation and at the first 24 h after preconditioning, as was shown by dot blot of extracellular fluid using anti-CD63 antibody. The autophagy inhibitor bafilomycin (0.01 μM) significantly reduces the quantity of the secreted exosomes at the stage of autophagy induction and at 24 h after induction. At the same time, inhibition of autophagy during the deprivation of trophic factors prevents the development of resistance, but inhibition of autophagy during the first 24 h after deprivation does not affect the development of resistance. We suggest that the long-term effects of preconditioning may be mediated by exosome secretion.
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Affiliation(s)
- A.A. Yakovlev
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia; Soloviev Moscow Research and Clinical Center for Neuropsychiatry, Moscow, Russia
| | - A.A. Lyzhin
- Brain Research Center at Research Center of Neurology, Moscow, Russia
| | - O.P. Aleksandrova
- Brain Research Center at Research Center of Neurology, Moscow, Russia
| | - L.G. Khaspekov
- Brain Research Center at Research Center of Neurology, Moscow, Russia
| | - N.V. Gulyaeva
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia; Soloviev Moscow Research and Clinical Center for Neuropsychiatry, Moscow, Russia
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Zhao W, Zhang J, Sadowsky MG, Meng R, Ding Y, Ji X, Cochrane Stroke Group. Remote ischaemic conditioning for preventing and treating ischaemic stroke. Cochrane Database Syst Rev 2018; 7:CD012503. [PMID: 29974450 PMCID: PMC6513257 DOI: 10.1002/14651858.cd012503.pub2] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Remote ischaemic conditioning (RIC) has been developed as a neuroprotective strategy to prevent and treat ischaemic stroke. It usually involves restricting blood flow to limbs and then releasing the ischaemic blood to promote a neuroprotective effect. Preclinical studies have suggested that RIC may have beneficial effects in ischaemic stroke patients and those at risk of ischaemic stroke. However, existing evidence is insufficient to demonstrate the efficacy and safety of RIC in preventing and treating ischaemic stroke. OBJECTIVES To assess the benefits and harms of RIC for preventing ischaemic stroke and for treating people with ischaemic stroke and those at risk for ischaemic stroke. SEARCH METHODS We searched the Cochrane Stroke Group Trials Register (16 January 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (January 2018), MEDLINE Ovid (1946 to January 2018), Embase Ovid (1974 to January 2018), Web of Science Core Collection (1950 to January 2018) and three Chinese databases (January 2018). We also searched four ongoing trials registers, reference lists, and conference proceedings. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing RIC with sham RIC or medical management in people with ischaemic stroke or at risk of ischaemic stroke. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies, assessed trial quality and risk of bias, and extracted data. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS We included seven trials, involving 735 participants, in this review. We analysed the effects of RIC on preventing and treating ischaemic stroke respectively.We evaluated risk of bias and judged it to be low for generation of allocation sequence in six studies and unclear in one study; unclear for allocation concealment in four studies and low in three studies; high for incomplete outcome data (attrition bias) in five studies and low in two studies; high for blinding in three studies and low in four studies; low for selective reporting; and high for other sources of bias in six studies and low in one study.We included three trials (involving 371 participants) in the analysis of the effects of RIC on ischaemic stroke prevention. In people with symptomatic intracerebral artery stenosis, recurrent stroke was significantly reduced by RIC (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.83; 2 trials, 182 participants, low-quality evidence). In people with carotid stenosis undergoing carotid stenting, there was no significant difference in the incidence of ischaemic stroke between participants treated with RIC and non-RIC (RR 0.22, 95% CI 0.01 to 4.03; 1 trial, 189 participants, low-quality evidence); however the stroke severity (assessed by infarct volume) was significantly lower in participants treated with RIC (mean difference (MD) -0.17 mL, 95% CI -0.23 to -0.11; 1 trial, 189 participants, low-quality evidence). Adverse events associated with RIC were significantly higher in participants treated with RIC (RR 10.91; 95% CI 2.01 to 59.28; 3 trials, 371 participants, low-quality evidence), but no severe adverse event was attributable to RIC treatment. No participants experienced death or cardiovascular events during the period of the studies; and no trial reported haemorrhagic stroke or improvement in neurological, phycological or cognitive impairment.We included four trials (involving 364 participants) in the analysis of the effects of RIC on ischaemic stroke treatment. In acute ischaemic stroke, for people receiving intravenous thrombolysis, the rate of death or dependency was significantly increased by RIC treatment compared with non-RIC treatment (RR 2.34; 95% 1.19 to 4.61; 1 trial, 285 participants, low-quality evidence). In people with acute ischaemic stroke, there was no significant difference between RIC and non-RIC for reducing stroke severity as assessed by the National Institutes of Health Stroke Scale score and the final infarct volume (standardised mean difference (SMD) -0.24 mL, 95% CI -1.02 to 0.54; 2 trials, 175 participants, very low quality evidence). There was no significant difference between RIC and non-RIC for improving the psychological impairment (SMD -0.37 points, 95% CI -1.15 to 0.41; 1 trial, 26 participants, very low quality evidence) and the cognitive impairment (SMD -0.26 points; 95% CI -0.72 to 0.21; 3 trials, 79 participants, low-quality evidence) in people with acute ischaemic stroke and cerebral small vessel disease. No trial reported ischaemic stroke, recurrent ischaemic stroke, improvement in neurological impairment, hemorrhagic stroke, cardiovascular events, and RIC associated adverse events. AUTHORS' CONCLUSIONS We found low-quality evidence that RIC may reduce the risk of recurrent stroke in participants with intracerebral artery stenosis and reduce stroke severity in participants undergoing carotid stenting, but it may increase death or dependence in participants with acute ischaemic stroke who are undergoing intravenous thrombolysis. However, there is considerable uncertainty about these conclusions because of the small number of studies and low quality of the evidence.
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Affiliation(s)
- Wenbo Zhao
- Xuanwu Hospital, Capital Medical UniversityDepartment of NeurologyBeijingChina100053
| | - Jing Zhang
- Xuanwu Hospital, Capital Medical UniversityDepartment of NeurologyBeijingChina100053
| | - Mordechai G Sadowsky
- Wayne State University School of MedicineDepartment of Neurological SurgeryDetroit, MichiganUSA
| | - Ran Meng
- Xuanwu Hospital, Capital Medical UniversityDepartment of NeurologyBeijingChina100053
| | - Yuchuan Ding
- Wayne State University School of MedicineDepartment of Neurological SurgeryDetroit, MichiganUSA
| | - Xunming Ji
- Xuanwu Hospital, Capital Medical UniversityDepartment of NeurosurgeryBeijingChina100053
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Leak RK, Calabrese EJ, Kozumbo WJ, Gidday JM, Johnson TE, Mitchell JR, Ozaki CK, Wetzker R, Bast A, Belz RG, Bøtker HE, Koch S, Mattson MP, Simon RP, Jirtle RL, Andersen ME. Enhancing and Extending Biological Performance and Resilience. Dose Response 2018; 16:1559325818784501. [PMID: 30140178 PMCID: PMC6096685 DOI: 10.1177/1559325818784501] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 05/15/2018] [Indexed: 12/17/2022] Open
Abstract
Human performance, endurance, and resilience have biological limits that are genetically and epigenetically predetermined but perhaps not yet optimized. There are few systematic, rigorous studies on how to raise these limits and reach the true maxima. Achieving this goal might accelerate translation of the theoretical concepts of conditioning, hormesis, and stress adaptation into technological advancements. In 2017, an Air Force-sponsored conference was held at the University of Massachusetts for discipline experts to display data showing that the amplitude and duration of biological performance might be magnified and to discuss whether there might be harmful consequences of exceeding typical maxima. The charge of the workshop was "to examine and discuss and, if possible, recommend approaches to control and exploit endogenous defense mechanisms to enhance the structure and function of biological tissues." The goal of this white paper is to fulfill and extend this workshop charge. First, a few of the established methods to exploit endogenous defense mechanisms are described, based on workshop presentations. Next, the white paper accomplishes the following goals to provide: (1) synthesis and critical analysis of concepts across some of the published work on endogenous defenses, (2) generation of new ideas on augmenting biological performance and resilience, and (3) specific recommendations for researchers to not only examine a wider range of stimulus doses but to also systematically modify the temporal dimension in stimulus inputs (timing, number, frequency, and duration of exposures) and in measurement outputs (interval until assay end point, and lifespan). Thus, a path forward is proposed for researchers hoping to optimize protocols that support human health and longevity, whether in civilians, soldiers, athletes, or the elderly patients. The long-term goal of these specific recommendations is to accelerate the discovery of practical methods to conquer what were once considered intractable constraints on performance maxima.
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Affiliation(s)
- Rehana K. Leak
- Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA
| | - Edward J. Calabrese
- School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA
| | | | - Jeffrey M. Gidday
- Departments of Ophthalmology, Neuroscience, and Physiology, Louisiana State University School of Medicine, New Orleans, LA, USA
| | - Thomas E. Johnson
- Department of Integrative Physiology, University of Colorado, Boulder, CO, USA
| | - James R. Mitchell
- Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - C. Keith Ozaki
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Reinhard Wetzker
- Institute for Molecular Cell Biology, University of Jena, Jena, Germany
| | - Aalt Bast
- Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands
| | - Regina G. Belz
- Hans-Ruthenberg-Institute, Agroecology Unit, University of Hohenheim, Stuttgart, Germany
| | - Hans E. Bøtker
- Department of Clinical Medicine, Aarhus University Hospital Skejby, Aarhus, Denmark
| | - Sebastian Koch
- Department of Neurology, University of Miami, Miller School of Medicine, FL, USA
| | - Mark P. Mattson
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA
| | - Roger P. Simon
- Departments of Medicine and Neurobiology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Randy L. Jirtle
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
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Wang H, He Z, Zhang Y, Zhang J. 1 H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning. Neurochem Int 2018; 116:95-103. [DOI: 10.1016/j.neuint.2018.02.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/03/2018] [Accepted: 02/19/2018] [Indexed: 12/14/2022]
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Liang D, He X, Wang Z, Li C, Gao B, Wu J, Bai Y. Remote limb ischemic postconditioning promotes motor function recovery in a rat model of ischemic stroke via the up-regulation of endogenous tissue kallikrein. CNS Neurosci Ther 2018; 24:519-527. [PMID: 29399973 PMCID: PMC6489769 DOI: 10.1111/cns.12813] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 01/16/2023] Open
Abstract
AIMS Remote ischemic conditionings, such as pre- and per-conditioning, are known to provide cardioprotection in animal models of ischemia. However, little is known about the neuroprotection effect of postconditioning after cerebral ischemia. In this study, we aim to evaluate the motor function rescuing effect of remote limb ischemic postconditioning (RIPostC) in a rat model of acute cerebral stroke. METHODS Left middle cerebral artery occlusion (MCAO) was performed to generate the rat model of ischemic stroke, followed by daily RIPostC treatment for maximum 21 days. The motor function after RIPostC was assessed with foot fault test and balance beam test. Local infarct volume was measured through MRI scanning. Neuronal status was evaluated with Nissl's, HE, and MAP2 immunostaining. Lectin immunostaining was performed to evaluate the microvessel density and area. RESULTS Daily RIPostC for more than 21 days promoted motor function recovery and provided long-lasting neuroprotection after MCAO. Reduced infarct volume, rescued neuronal loss, and enhanced microvessel density and size in the injured areas were observed. In addition, the RIPostC effect was associated with the up-regulation of endogenous tissue kallikrein (TK) level in circulating blood and local ischemic brain regions. A TK receptor antagonist HOE-140 partially reversed RIPostC-induced improvements, indicating the specificity of endogenous TK mediating the neuroprotection effect of RIPostC. CONCLUSION Our study demonstrates RIPostC treatment as an effective rehabilitation therapy to provide motor function recovery and alleviate brain impairment in a rat model of acute cerebral ischemia. We also for the first time provide evidence showing that the up-regulation of endogenous TK from remote conditioning regions underlies the observed effects of RIPostC.
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Affiliation(s)
- Dan Liang
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Xi‐Biao He
- Shanghai University of Medicine & Health SciencesShanghaiChina
| | - Zheng Wang
- Department of NeurologyHuashan HospitalState Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina
| | - Ce Li
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Bei‐Yao Gao
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Jun‐Fa Wu
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
| | - Yu‐Long Bai
- Department of Rehabilitation MedicineHuashan HospitalFudan UniversityShanghaiChina
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Zhou G, Li MH, Tudor G, Lu HT, Kadirvel R, Kallmes D. Remote Ischemic Conditioning in Cerebral Diseases and Neurointerventional Procedures: Recent Research Progress. Front Neurol 2018; 9:339. [PMID: 29867745 PMCID: PMC5964135 DOI: 10.3389/fneur.2018.00339] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/30/2018] [Indexed: 12/11/2022] Open
Abstract
Cerebral ischemia and stroke are increasing in prevalence and are among the leading causes of morbidity and mortality in both developed and developing countries. Despite the progress in endovascular treatment, ischemia/reperfusion (IR) injury is an important contributor to post-surgical mortality and morbidity affecting a wide range of neurointerventional procedures. However, pharmacological recruitment of effective cerebral protective signaling has been largely disappointing to date. In remote ischemic conditioning (RIC), repetitive transient mechanical obstruction of vessels at a limb remote from the IR injury site protects vital organs from IR injury and confers infarction size reduction following prolonged arterial occlusion. Results of pharmacologic agents appear to be species specific, while RIC is based on the neuroprotective influences of phosphorylated protein kinase B, signaling proteins, nitric oxide, and transcriptional activators, the benefits of which have been confirmed in many species. Inducing RIC protection in patients undergoing cerebral vascular surgery or those who are at high risk of brain injury has been the subject of research and has been enacted in clinical settings. Its simplicity and non-invasive nature, as well as the flexibility of the timing of RIC stimulus, also makes it feasible to apply alongside neurointerventional procedures. Furthermore, despite nonuniform RIC protocols, emerging literature demonstrates improved clinical outcomes. The aims of this article are to summarize the potential mechanisms underlying different forms of conditioning, to explore the current translation of this paradigm from laboratory to neurovascular diseases, and to outline applications for patient care.
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Affiliation(s)
- Geng Zhou
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Mayo Clinic, Rochester, MN, United States
| | - Ming Hua Li
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | | | - Hai Tao Lu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Meybohm P, Kohlhaas M, Stoppe C, Gruenewald M, Renner J, Bein B, Albrecht M, Cremer J, Coburn M, Schaelte G, Boening A, Niemann B, Sander M, Roesner J, Kletzin F, Mutlak H, Westphal S, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schoen J, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Bogatsch H, Brosteanu O, Hasenclever D, Zacharowski K. RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up. J Am Heart Assoc 2018; 7:e008077. [PMID: 29581218 PMCID: PMC5907591 DOI: 10.1161/jaha.117.008077] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 01/26/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. METHODS AND RESULTS In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. CONCLUSIONS Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703.
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Affiliation(s)
- Patrick Meybohm
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Madeline Kohlhaas
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christian Stoppe
- Department of Anesthesiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Matthias Gruenewald
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Germany
| | - Jochen Renner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Germany
| | - Berthold Bein
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Germany
- Department of Anesthesiology and Intensive Care Medicine, Asklepios Hospital St. Georg Hamburg, Germany
| | - Martin Albrecht
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Germany
| | - Jochen Cremer
- Department of Cardiovascular Surgery, University Hospital Schleswig-Holstein, Germany
| | - Mark Coburn
- Department of Anesthesiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Gereon Schaelte
- Department of Anesthesiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Andreas Boening
- Department of Cardiovascular Surgery, University of Giessen, Germany
| | - Bernd Niemann
- Department of Cardiovascular Surgery, University of Giessen, Germany
| | - Michael Sander
- Department of Anesthesiology and Intensive Care, University of Giessen, Germany
- Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Jan Roesner
- Department of Anesthesiology and Intensive Care, Suedstadt Hospital Rostock, Germany
- Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Rostock, Germany
| | - Frank Kletzin
- Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Rostock, Germany
| | - Haitham Mutlak
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sabine Westphal
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | | | - Marion Ferner
- Department of Anesthesiology, Medical Center of Johannes Gutenberg-University, Mainz, Germany
| | - Ivo F Brandes
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Goettingen, Germany
| | - Martin Bauer
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Goettingen, Germany
- Department of Anesthesiology and Intensive Care, Klinikum Region Hannover, Germany
| | - Sebastian N Stehr
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Germany
| | - Andreas Kortgen
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Maria Wittmann
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany
| | - Georg Baumgarten
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany
- Department of Anesthesiology and Intensive Care Medicine, Johanniter Hospital Bonn, Germany
| | - Tanja Meyer-Treschan
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Duesseldorf, Germany
| | - Peter Kienbaum
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Duesseldorf, Germany
| | - Matthias Heringlake
- Department of Anesthesiology and Intensive Care Medicine, University Luebeck, Germany
| | - Julika Schoen
- Department of Anesthesiology and Intensive Care Medicine, University Luebeck, Germany
- Department of Anesthesiology and Intensive Care Medicine, Hospital Neuruppin, Germany
| | - Sascha Treskatsch
- Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
| | - Thorsten Smul
- Department of Anesthesiology, University Hospital Wuerzburg, Germany
| | - Ewa Wolwender
- Department of Anesthesiology, University Hospital Wuerzburg, Germany
| | - Thomas Schilling
- Department of Anesthesiology, University Hospital Magdeburg, Germany
| | - Georg Fuernau
- University Heart Luebeck Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine) University Hospital Schleswig-Holstein, Luebeck, Germany
| | | | | | - Dirk Hasenclever
- Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Germany
| | - Kai Zacharowski
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany
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Abstract
Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes.
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Affiliation(s)
- Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark
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Chen G, Thakkar M, Robinson C, Doré S. Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options. Front Neurol 2018; 9:40. [PMID: 29467715 PMCID: PMC5808199 DOI: 10.3389/fneur.2018.00040] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/17/2018] [Indexed: 12/23/2022] Open
Abstract
Novel and innovative approaches are essential in developing new treatments and improving clinical outcomes in patients with ischemic stroke. Remote ischemic conditioning (RIC) is a series of mechanical interruptions in blood flow of a distal organ, following end organ reperfusion, shown to significantly reduce infarct size through inhibition of oxidation and inflammation. Ischemia/reperfusion (I/R) is what ultimately leads to the irreversible brain damage and clinical picture seen in stroke patients. There have been several reports and reviews about the potential of RIC in acute ischemic stroke; however, the focus here is a comprehensive look at the differences in the three types of RIC (remote pre-, per-, and postconditioning). There are some limited uses of preconditioning in acute ischemic stroke due to the unpredictability of the ischemic event; however, it does provide the identification of biomarkers for clinical studies. Remote limb per- and postconditioning offer a more promising treatment during patient care as they can be harnessed during or after the initial ischemic insult. Though further research is needed, it is imperative to discuss the importance of preclinical data in understanding the methods and mechanisms involved in RIC. This understanding will facilitate translation to a clinically feasible paradigm for use in the hospital setting.
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Affiliation(s)
- Gangling Chen
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States.,Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Mrugesh Thakkar
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States
| | - Christopher Robinson
- McKnight Brain Institute, University of Florida, Gainesville, FL, United States.,Department of Neurology, University of Florida, Gainesville, FL, United States
| | - Sylvain Doré
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States.,McKnight Brain Institute, University of Florida, Gainesville, FL, United States.,Department of Neurology, University of Florida, Gainesville, FL, United States.,Department of Psychiatry, University of Florida, Gainesville, FL, United States.,Department of Pharmaceutics, University of Florida, Gainesville, FL, United States.,Department of Psychology, University of Florida, Gainesville, FL, United States.,Department of Neuroscience, University of Florida, Gainesville, FL, United States
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Remote Limb Ischemic Conditioning during Cerebral Ischemia Reduces Infarct Size through Enhanced Collateral Circulation in Murine Focal Cerebral Ischemia. J Stroke Cerebrovasc Dis 2018; 27:831-838. [PMID: 29395650 DOI: 10.1016/j.jstrokecerebrovasdis.2017.09.068] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/21/2017] [Accepted: 09/24/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Remote ischemic conditioning (RIC) induces protection in focal cerebral ischemia. The conditioning is divided into pre-, per-, and postconditioning. However, the mechanisms of RIC remain unknown. OBJECTIVES This study aimed to determine the most effective subtype of RIC. We also examined involvement of collateral circulation on RIC. METHODS Transient middle cerebral artery occlusion (MCAO) was performed with nylon sutures in adult C57BL/6 mice under the monitoring of cerebral blood flow (CBF). Fifty mice were divided into 5 groups: MCAO control group, delayed pre-RIC group (RIC 24 hours before MCAO), early pre-RIC group (RIC 5 minutes before MCAO), per-RIC group (RIC during MCAO), and post-RIC group (RIC 5 minutes after MCAO). In other middle cerebral artery (MCA) control and per-RIC groups, collateral circulation was visualized with latex compound perfusion. RESULTS After MCAO, CBF was reduced by 80% in all groups. At the end of MCAO, relative increase in CBF in per-RIC group was significantly greater than that in MCA control, whereas the infarct volume in per-RIC group was significantly smaller than that in other groups. The diameter of leptomeningeal anastomosis was larger in the per-RIC group than that in the control group. CONCLUSIONS Among the 4 RIC procedures, only the per-RIC group showed clear brain protection. Enhancement of collateral circulation could play a role in the protective effect of per-RIC.
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Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3804979. [PMID: 29770166 PMCID: PMC5892600 DOI: 10.1155/2018/3804979] [Citation(s) in RCA: 318] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 12/07/2017] [Indexed: 12/16/2022]
Abstract
Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.
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Pan J, Li X, Peng Y. Remote ischemic conditioning for acute ischemic stroke: dawn in the darkness. Rev Neurosci 2018; 27:501-10. [PMID: 26812782 DOI: 10.1515/revneuro-2015-0043] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 12/03/2015] [Indexed: 02/07/2023]
Abstract
Stroke is a leading cause of disability with high morbidity and mortality worldwide. Of all strokes, 87% are ischemic. The only approved treatments for acute ischemic stroke are intravenous thrombolysis with alteplase within 4.5 h and thrombectomy within 8 h after symptom onset, which can be applied to just a few patients. During the past decades, ischemic preconditioning has been widely studied to confirm its neuroprotection against subsequent ischemia/reperfusion injury in the brain, including preconditioning in situ or in a remote organ (such as a limb) before onset of brain ischemia, the latter of which is termed as remote ischemic preconditioning. Because acute stroke is unpredicted, ischemic preconditioning is actually not suitable for clinical application. So remote ischemic conditioning performed during or after the ischemic duration of the brain was then designed to study its neuroprotection alone or in combination with alteplase in animals and patients, which is named as remote ischemic perconditioning or remote ischemic postconditioning. As expected, animal experiments and clinical trials both showed exciting results, indicating that an evolution in the treatment for acute ischemic stroke may not be far away. However, some problems or disputes still exist. This review summarizes the research progress and unresolved issues of remote ischemic conditioning (pre-, per-, and post-conditioning) in treating acute ischemic stroke, with the hope of advancing our understanding of this promising neuroprotective strategy for ischemic stroke in the near future.
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Costa FLDS, Yamaki VN, Teixeira RKC, Feijó DH, Valente AL, Carvalho LTFD, Yasojima EY, Brito MVH. Perconditioning combined with postconditioning on kidney ischemia and reperfusion. Acta Cir Bras 2017; 32:599-606. [PMID: 28902935 DOI: 10.1590/s0102-865020170080000001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 07/17/2017] [Indexed: 11/22/2022] Open
Abstract
Purpose: To evaluate if combination of perconditioning and postconditioning provides improved renal protection compared to perconditioning alone in a model of renal reperfusion injury. Methods: Thirty rats were assigned into 6 groups: normality; sham; ischemia and reperfusion; postconditioning; perconditioning; perconditioning + postconditioning. Animals were subjected to right nephrectomy and left renal ischemia for 30 minutes. Postconditioning consisted of 3 cycles of 5 min renal perfusion followed by 5 min of renal ischemia after major ischemic period. Perconditioning consisted of 3 cycles of 5 min hindlimb ischemia followed by 5 min of hindlimb perfusion contemporaneously to renal major ischemic period. After 24 hours, kidney was harvested and blood collected to measure urea and creatinine. Results: Perconditioning obtained better values for creatinine and urea level than only postconditioning (p<0.01); performing both techniques contemporaneously had no increased results (p>0.05). Regarding tissue structure, perconditioning was the only technique to protect the glomerulus and tubules (p<0.05), while postconditioning protected only the glomerulus (p<0.05). Combination of both techniques shows no effect on glomerulus or tubules (p>0.05). Conclusions: Perconditioning had promising results on ischemia and reperfusion induced kidney injury, enhanced kidney function and protected glomerulus and tubules. There was no additive protection when postconditioning and perconditioning were combined.
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Affiliation(s)
- Felipe Lobato da Silva Costa
- MD, Department of Experimental Surgery, School of Medicine, Universidade do Estado do Pará (UEPA), Belem-PA, Brazil. Conception, design, intellectual and scientific content of the study; interpretation of data; manuscript writing
| | - Vitor Nagai Yamaki
- MD, School of Medicine, UEPA, Belem-PA, Brazil. Acquisition and interpretation of data, statistical analysis
| | - Renan Kleber Costa Teixeira
- Fellow Master degree, Department of Experimental Surgery, UEPA, Belem-PA, Brazil. Interpretation of data, manuscript writing, critical revision
| | - Daniel Haber Feijó
- Graduate student, School of Medicine, UEPA, Belem-PA, Brazil. Interpretation of data, manuscript preparation
| | - André Lopes Valente
- Graduate student, School of Medicine, UEPA, Belem-PA, Brazil. Acquisition and interpretation of data, manuscript preparation
| | - Luan Teles Ferreira de Carvalho
- Graduate student, School of Medicine, UEPA, Belem-PA, Brazil. Acquisition and interpretation of data, manuscript preparation
| | - Edson Yuzur Yasojima
- PhD, Associate Professor, Department of Experimental Surgery, School of Medicine, UEPA, Belem-PA, Brazil. Conception, design, intellectual and scientific content of the study; critical revision
| | - Marcus Vinicius Henriques Brito
- PhD, Full Professor, Department of Experimental Surgery, School of Medicine, UEPA, Belem-PA, Brazil. Conception, design, intellectual and scientific content of the study; critical revision
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Yunoki M, Kanda T, Suzuki K, Uneda A, Hirashita K, Yoshino K. Ischemic Tolerance of the Brain and Spinal Cord: A Review. Neurol Med Chir (Tokyo) 2017; 57:590-600. [PMID: 28954945 PMCID: PMC5709712 DOI: 10.2176/nmc.ra.2017-0062] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ischemic tolerance is an endogenous neuroprotective phenomenon induced by sublethal ischemia. Ischemic preconditioning (IPC), the first discovered form of ischemic tolerance, is widely seen in many species and in various organs including the brain and the spinal cord. Ischemic tolerance of the spinal cord is less familiar among neurosurgeons, although it has been reported from the viewpoint of preventing ischemic spinal cord injury during aortic surgery. It is important for neurosurgeons to have opportunities to see patients with spinal cord ischemia, and to understand ischemic tolerance of the spinal cord as well as the brain. IPC has a strong neuroprotective effect in animal models of ischemia; however, clinical application of IPC for ischemic brain and spinal diseases is difficult because they cannot be predicted. In addition, one drawback of preconditioning stimuli is that they are also capable of producing injury with only minor changes to their intensity or duration. Numerous methods to induce ischemic tolerance have been discovered that vary in their timing and the site at which short-term ischemia occurs. These methods include ischemic postconditioning (IPoC), remote ischemic preconditioning (RIPC), remote ischemic perconditioning (RIPerC) and remote ischemic postconditioning (RIPoC), which has had a great impact on clinical approaches to treatment of ischemic brain and spinal cord injury. Especially RIPerC and RIPoC to induce spinal cord tolerance are considered clinically useful, however the evidence supporting these methods is currently insufficient; further experimental or clinical research in this area is thus necessary.
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Affiliation(s)
| | | | - Kenta Suzuki
- Department of Neurosurgery, Kagawa Rosai Hospital
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