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Tsai MJ, Liou DY, Fay LY, Huang SL, Huang WC, Chern CM, Tsai SK, Cheng H, Huang SS. Targeting the Ischemic Core: A Therapeutic Microdialytic Approach to Prevent Neuronal Death and Restore Functional Behaviors. Int J Mol Sci 2025; 26:3821. [PMID: 40332503 PMCID: PMC12027531 DOI: 10.3390/ijms26083821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/08/2025] Open
Abstract
Ischemic stroke leads to cerebral ionic imbalance, increases acidosis, oxidative stress and release of glutamate and inflammatory mediators. Removing solute or stimulants from the ischemic core may block cell-damaging events and confer neuroprotection. In this study, we developed a minimally invasive therapeutic microdialysis (tMD) method, choosing to include serum albumin in the buffer because it is a multifunctional protein with osmotic properties. Aiming at the ischemic core, continuous perfusion of buffer supplemented with osmotic agents removes mediators of inflammation/cell damage/death from the lesion. This tMD treatment significantly removed the glutamate and zinc ions from the core, thereby reducing infarct volumes and affording high-grade neurobehavioral protection against ischemic stroke. The tMD treatment effectively protected neurons and reduced microglial activation. Furthermore, this tMD approach extended the therapeutic window to protect beyond 6 h after stroke onset. These findings support the potential clinical feasibility of applying tMD to patients with ischemic stroke, potentially without adverse effects.
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Affiliation(s)
- May-Jywan Tsai
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Dann-Ying Liou
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Li-Yu Fay
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan
| | - Shih-Ling Huang
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Wen-Cheng Huang
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan
| | - Chang-Ming Chern
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Neurology, En Chu Kong Hospital, New Taipei City 23702, Taiwan
| | - Shen-Kou Tsai
- Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 11283, Taiwan
| | - Henrich Cheng
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan
- Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan
| | - Shiang-Suo Huang
- Department of Pharmacology and Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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Toker D, Chiang JN, Vespa PM, Schnakers C, Monti MM. The Dipeptidyl Peptidase-4 Inhibitor Saxagliptin as a Candidate Treatment for Disorders of Consciousness: A Deep Learning and Retrospective Clinical Analysis. Neurocrit Care 2025:10.1007/s12028-025-02217-0. [PMID: 39904872 DOI: 10.1007/s12028-025-02217-0] [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: 07/30/2024] [Accepted: 01/13/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes. METHODS To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury. RESULTS Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage. CONCLUSIONS Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.
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Affiliation(s)
- Daniel Toker
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Jeffrey N Chiang
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Paul M Vespa
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Caroline Schnakers
- Research Institute, Casa Colina Hospital and Centers for Healthcare, Pomona, CA, USA
| | - Martin M Monti
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
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Lee AH, Tai SH, Huang SY, Chang LD, Chen LY, Chen YN, Hsu HH, Lee EJ. Melatonin Improves Vasogenic Edema via Inhibition to Water Channel Aquaporin-4 (AQP4) and Metalloproteinase-9 (MMP-9) Following Permanent Focal Cerebral Ischemia. Biomedicines 2024; 12:2184. [PMID: 39457496 PMCID: PMC11504272 DOI: 10.3390/biomedicines12102184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/10/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Background: The efficacy of melatonin in reducing vasogenic and cytotoxic edema was investigated using a model of permanent middle cerebral artery occlusion (pMCAO). Methods: Rats underwent pMCAO, followed by intravenous administration of either melatonin (5 mg/kg) or a vehicle 10 min post-insult. Brain infarction and edema were assessed, and Western blot analyses were conducted to examine the expression levels of aquaporin-4 (AQP4), metalloproteinase-9 (MMP-9), and the neurovascular tight-junction protein ZO-1 upon sacrifice. The permeability of the blood-brain barrier (BBB) was measured using spectrophotometric quantification of Evans blue dye leakage. Results: Compared to controls, melatonin-treated rats exhibited a significant reduction in infarct volume by 26.9% and showed improved neurobehavioral outcomes (p < 0.05 for both). Melatonin treatment also led to decreased Evans blue dye extravasation and brain edema (p < 0.05 for both), along with lower expression levels of AQP4 and MMP-9 proteins and better preservation of ZO-1 protein (p < 0.05 for all). Conclusions: Therefore, melatonin offers neuroprotection against brain swelling induced by ischemia, possibly through its modulation of AQP4 and MMP-9 activities in glial cells and the extracellular matrix (ECM) during the early phase of ischemic injury.
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Affiliation(s)
- Ai-Hua Lee
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Department of Occupational Safety and Health, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan
| | - Shih-Huang Tai
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Sheng-Yang Huang
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Li-Der Chang
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Liang-Yi Chen
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Yu-Ning Chen
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Hao-Hsiang Hsu
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - E-Jian Lee
- Neurophysiology Laboratory, Neurosurgical Service, Departments of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
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Owjfard M, Rahimian Z, Karimi F, Borhani-Haghighi A, Mallahzadeh A. A comprehensive review on the neuroprotective potential of resveratrol in ischemic stroke. Heliyon 2024; 10:e34121. [PMID: 39082038 PMCID: PMC11284444 DOI: 10.1016/j.heliyon.2024.e34121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 06/07/2024] [Accepted: 07/03/2024] [Indexed: 08/02/2024] Open
Abstract
Stroke is the second leading cause of death and the third leading cause of disability worldwide. Globally, 68 % of all strokes are ischemic, with 32 % being hemorrhagic. Ischemic stroke (IS) poses significant challenges globally, necessitating the development of effective therapeutic strategies. IS is among the deadliest illnesses. Major functions are played by neuroimmunity, inflammation, and oxidative stress in the multiple intricate pathways of IS. Secondary brain damage is specifically caused by the early pro-inflammatory activity that follows cerebral ischemia, which is brought on by excessive activation of local microglia and the infiltration of circulating monocytes and macrophages. Resveratrol, a natural polyphenol found in grapes and berries, has shown promise as a neuroprotective agent in IS. This review offers a comprehensive overview of resveratrol's neuroprotective role in IS, focusing on its mechanisms of action and therapeutic potential. Resveratrol exerts neuroprotective effects by activating nuclear factor erythroid 2-related factor 2 (NRF2) and sirtuin 1 (SIRT1) pathways. SIRT1 activation by resveratrol triggers the deacetylation and activation of downstream targets like peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and forkhead box protein O (FOXO), regulating mitochondrial biogenesis, antioxidant defense, and cellular stress response. Consequently, resveratrol promotes cellular survival and inhibits apoptosis in IS. Moreover, resveratrol activates the NRF2 pathway, a key mediator of the cellular antioxidant response. Activation of NRF2 through resveratrol enhances the expression of antioxidant enzymes, like heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), which neutralize reactive oxygen species and mitigate oxidative stress in the ischemic brain. Combined, the activation of SIRT1 and NRF2 pathways contributes to resveratrol's neuroprotective effects by reducing oxidative stress, inflammation, and apoptosis in IS. Preclinical studies demonstrate that resveratrol improves functional outcomes, reduces infarct size, regulates cerebral blood flow and preserves neuronal integrity. Gaining a comprehensive understanding of these mechanisms holds promise for the development of targeted therapeutic interventions aimed at promoting neuronal survival and facilitating functional recovery in IS patients and to aid future studies in this matter.
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Affiliation(s)
- Maryam Owjfard
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Rahimian
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Arashk Mallahzadeh
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Babkina I, Savinkova I, Molchanova T, Sidorova M, Surin A, Gorbacheva L. Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity. Int J Mol Sci 2024; 25:1221. [PMID: 38279219 PMCID: PMC10816171 DOI: 10.3390/ijms25021221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/28/2024] Open
Abstract
Serine proteases regulate cell functions through G protein-coupled protease-activated receptors (PARs). Cleavage of one peptide bond of the receptor amino terminus results in the formation of a new N-terminus ("tethered ligand") that can specifically interact with the second extracellular loop of the PAR receptor and activate it. Activation of PAR1 by thrombin (canonical agonist) and activated protein C (APC, noncanonical agonist) was described as a biased agonism. Here, we have supposed that synthetic peptide analogs to the PAR1 tethered ligand liberated by APC could have neuroprotective effects like APC. To verify this hypothesis, a model of the ischemic brain impairment based on glutamate (Glu) excitotoxicity in primary neuronal cultures of neonatal rats has been used. It was shown that the nanopeptide NPNDKYEPF-NH2 (AP9) effectively reduced the neuronal death induced by Glu. The influence of AP9 on cell survival was comparable to that of APC. Both APC and AP9 reduced the dysregulation of intracellular calcium homeostasis in cultured neurons induced by excitotoxic Glu (100 µM) or NMDA (200 µM) concentrations. PAR1 agonist synthetic peptides might be noncanonical PAR1 agonists and a basis for novel neuroprotective drugs for disorders related to Glu excitotoxicity such as brain ischemia, trauma and some neurodegenerative diseases.
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Affiliation(s)
- Irina Babkina
- Faculty of Medical Biology, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, 117997 Moscow, Russia; (I.B.); (I.S.)
| | - Irina Savinkova
- Faculty of Medical Biology, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, 117997 Moscow, Russia; (I.B.); (I.S.)
| | - Tatiana Molchanova
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;
| | - Maria Sidorova
- Chazov National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, 121552 Moscow, Russia;
| | - Alexander Surin
- Laboratory of Fundamental and Applied Problems of Pain, Institute of General Pathology and Pathophysiology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Liubov Gorbacheva
- Faculty of Medical Biology, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, 117997 Moscow, Russia; (I.B.); (I.S.)
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;
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Modi JP, Shen W, Menzie-Suderam J, Xu H, Lin CH, Tao R, Prentice HM, Schloss J, Wu JY. The Role of NMDA Receptor Partial Antagonist, Carbamathione, as a Therapeutic Agent for Transient Global Ischemia. Biomedicines 2023; 11:1885. [PMID: 37509524 PMCID: PMC10377037 DOI: 10.3390/biomedicines11071885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023] Open
Abstract
Carbamathione (Carb), an NMDA glutamate receptor partial antagonist, has potent neuroprotective functions against hypoxia- or ischemia-induced neuronal injury in cell- or animal-based stroke models. We used PC-12 cell cultures as a cell-based model and bilateral carotid artery occlusion (BCAO) for stroke. Whole-cell patch clamp recording in the mouse retinal ganglion cells was performed. Key proteins involved in apoptosis, endoplasmic reticulum (ER) stress, and heat shock proteins were analyzed using immunoblotting. Carb is effective in protecting PC12 cells against glutamate- or hypoxia-induced cell injury. Electrophysiological results show that Carb attenuates NMDA-mediated glutamate currents in the retinal ganglion cells, which results in activation of the AKT signaling pathway and increased expression of pro-cell survival biomarkers, e.g., Hsp 27, P-AKT, and Bcl2 and decreased expression of pro-cell death markers, e.g., Beclin 1, Bax, and Cleaved caspase 3, and ER stress markers, e.g., CHOP, IRE1, XBP1, ATF 4, and eIF2α. Using the BCAO animal stroke model, we found that Carb reduced the brain infarct volume and decreased levels of ER stress markers, GRP 78, CHOP, and at the behavioral level, e.g., a decrease in asymmetric turns and an increase in locomotor activity. These findings for Carb provide promising and rational strategies for stroke therapy.
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Affiliation(s)
- Jigar Pravinchandra Modi
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Wen Shen
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Janet Menzie-Suderam
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Hongyuan Xu
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Chun-Hua Lin
- Department of Nursing, Kang-Ning University, Taipei 11485, Taiwan
| | - Rui Tao
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Howard M Prentice
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - John Schloss
- Department of Pharmaceutical Science, American University of Health Sciences, Signal Hill, CA 90755, USA
| | - Jang-Yen Wu
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
- Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA
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Chavda V, Lu B. Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases. Antioxidants (Basel) 2023; 12:895. [PMID: 37107270 PMCID: PMC10135819 DOI: 10.3390/antiox12040895] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 03/28/2023] [Accepted: 03/31/2023] [Indexed: 04/09/2023] Open
Abstract
Stroke is one of the leading causes of morbidity and mortality worldwide. A main cause of brain damage by stroke is ischemia-reperfusion (IR) injury due to the increased production of reactive oxygen species (ROS) and energy failure caused by changes in mitochondrial metabolism. Ischemia causes a build-up of succinate in tissues and changes in the mitochondrial NADH: ubiquinone oxidoreductase (complex I) activity that promote reverse electron transfer (RET), in which a portion of the electrons derived from succinate are redirected from ubiquinol along complex I to reach the NADH dehydrogenase module of complex I, where matrix NAD+ is converted to NADH and excessive ROS is produced. RET has been shown to play a role in macrophage activation in response to bacterial infection, electron transport chain reorganization in response to changes in the energy supply, and carotid body adaptation to changes in the oxygen levels. In addition to stroke, deregulated RET and RET-generated ROS (RET-ROS) have been implicated in tissue damage during organ transplantation, whereas an RET-induced NAD+/NADH ratio decrease has been implicated in aging, age-related neurodegeneration, and cancer. In this review, we provide a historical account of the roles of ROS and oxidative damage in the pathogenesis of ischemic stroke, summarize the latest developments in our understanding of RET biology and RET-associated pathological conditions, and discuss new ways to target ischemic stroke, cancer, aging, and age-related neurodegenerative diseases by modulating RET.
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Affiliation(s)
| | - Bingwei Lu
- Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA
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Snider S, Albano L, Gagliardi F, Comai S, Roncelli F, De Domenico P, Pompeo E, Panni P, Bens N, Calvi MR, Mortini P, Ruban A. Substantially elevated serum glutamate and CSF GOT-1 levels associated with cerebral ischemia and poor neurological outcomes in subarachnoid hemorrhage patients. Sci Rep 2023; 13:5246. [PMID: 37002262 PMCID: PMC10066256 DOI: 10.1038/s41598-023-32302-3] [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: 08/24/2022] [Accepted: 03/25/2023] [Indexed: 04/03/2023] Open
Abstract
Brain injury and cerebral vasospasm during the 14 days after the subarachnoid hemorrhage (SAH) are considered the leading causes of poor outcomes. The primary injury induces a cascade of events, including increased intracranial pressure, cerebral vasospasm and ischemia, glutamate excitotoxicity, and neuronal cell death. The objective of this study was to monitor the time course of glutamate, and associated enzymes, such as glutamate-oxaloacetate transaminase (GOT1), glutamate-pyruvate transaminase (GPT) in cerebrospinal fluid (CSF) and serum, shortly after SAH, and to assess their prognostic value. A total of 74 participants participated in this study: 45 participants with SAH and 29 controls. Serum and CSF were sampled up to 14 days after SAH. SAH participants' clinical and neurological status were assessed at hospitalization, at discharge from the hospital, and 3 months after SAH. Furthermore, a logistic regression analysis was carried out to evaluate the ability of GOT1 and glutamate levels to predict neurological outcomes. Our results demonstrated consistently elevated serum and CSF glutamate levels after SAH. Furthermore, serum glutamate level was significantly higher in patients with cerebral ischemia and poor neurological outcome. CSF GOT1 was significantly higher in patients with uncontrolled intracranial hypertension and cerebral ischemia post-SAH, and independently predicted poor neurological outcomes.
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Affiliation(s)
- Silvia Snider
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Albano
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Filippo Gagliardi
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Comai
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Francesca Roncelli
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Pierfrancesco De Domenico
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Edoardo Pompeo
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Pietro Panni
- Department of Neuroradiology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy
| | - Nicole Bens
- Behavioral Neuroscience, Human Movement Science, Mathematics, Pre-Medicine, Northeastern University COS, Boston, MA, USA
| | - Maria Rosa Calvi
- Department of Neurocritical Care, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy
| | - Pietro Mortini
- Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angela Ruban
- Sackler Faculty of Medicine, Steyer School of Health Professions, Tel Aviv University, P.O. Box 39040, 6997801, Tel-Aviv, Israel.
- Sagol School of Neuroscience, Tel-Aviv University, P.O. Box 39040, 6997801, Tel-Aviv, Israel.
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Jiao Y, Wu G. Optimizing the Time Window of Minimally Invasive Stereotactic Surgery for Intracerebral Hemorrhage Evacuation Combined with Rosiglitazone Infusion Therapy in Rabbits. World Neurosurg 2022; 165:e265-e275. [PMID: 35697232 DOI: 10.1016/j.wneu.2022.06.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/04/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This study aimed to explore the effects of minimally invasive surgery (MIS) in combination with rosiglitazone (RSG) on intracerebral hemorrhage (ICH) and determine the optimal time window. METHODS An ICH rabbit model was constructed using the injection of autologous arterial blood and then treated with RSG, MIS, and MIS combined with RSG at 6, 12, 18, and 24 hours. Thereafter, rabbits that underwent different treatments were used to measure the neurological deficit score, brain water content, and glutamate content. Expression of peroxisome proliferator-activated receptor γ (PPARγ) and CD36 in the different groups was detected using real-time quantitative polymerase chain reaction and Western blotting. In addition, oxidative stress-related and inflammation-related genes were examined. RESULTS Brain computed tomography indicated that an ICH rabbit model was successfully established. Compared to those in the control rabbits, the neurological deficit scores, brain water content, and glutamate content in the ICH rabbits were significantly increased at each time window (P < 0.05), while they were decreased at each time window after MIS combined with RSG treatment and declined to the lowest at 6 hours. Additionally, ICH significantly upregulated PPARγ and CD36 expression (P < 0.05). Moreover, superoxide dismutase content decreased after ICH, and nitric oxide synthase 2, tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta mRNA expression was upregulated, whereas MIS combined with RSG treatment reversed the levels caused by ICH. CONCLUSIONS Evacuation of MIS hematoma combined with RSG infusion at an early stage (6 hours) may attenuate secondary brain damage caused by ICH by regulating the PPARγ/CD36 pathway.
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Affiliation(s)
- Yu Jiao
- Department of Emergency Neurology, Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Guofeng Wu
- Department of Emergency Neurology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
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Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies. Int J Mol Sci 2022; 23:ijms23169381. [PMID: 36012647 PMCID: PMC9409263 DOI: 10.3390/ijms23169381] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 01/01/2023] Open
Abstract
Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).
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Synaptic Secretion and Beyond: Targeting Synapse and Neurotransmitters to Treat Neurodegenerative Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9176923. [PMID: 35923862 PMCID: PMC9343216 DOI: 10.1155/2022/9176923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/16/2022] [Accepted: 06/04/2022] [Indexed: 11/17/2022]
Abstract
The nervous system is important, because it regulates the physiological function of the body. Neurons are the most basic structural and functional unit of the nervous system. The synapse is an asymmetric structure that is important for neuronal function. The chemical transmission mode of the synapse is realized through neurotransmitters and electrical processes. Based on vesicle transport, the abnormal information transmission process in the synapse can lead to a series of neurorelated diseases. Numerous proteins and complexes that regulate the process of vesicle transport, such as SNARE proteins, Munc18-1, and Synaptotagmin-1, have been identified. Their regulation of synaptic vesicle secretion is complicated and delicate, and their defects can lead to a series of neurodegenerative diseases. This review will discuss the structure and functions of vesicle-based synapses and their roles in neurons. Furthermore, we will analyze neurotransmitter and synaptic functions in neurodegenerative diseases and discuss the potential of using related drugs in their treatment.
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Sasaki-Hamada S, Sanai E, Kanemaru M, Kamanaka G, Oka JI. Long-term exposure to high glucose induces changes in the expression of AMPA receptor subunits and glutamate transmission in primary cultured cortical neurons. Biochem Biophys Res Commun 2022; 589:48-54. [PMID: 34891041 DOI: 10.1016/j.bbrc.2021.11.108] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/25/2021] [Accepted: 11/30/2021] [Indexed: 12/14/2022]
Abstract
Hyperglycemia, which occurs under the diabetic conditions, induces serious diabetic complications. Diabetic encephalopathy has been defined as one of the major complications of diabetes, and is characterized by neurochemical and neurodegenerative changes. However, little is known about the effect of long-term exposure to high glucose on neuronal cells. In the present study, we showed that exposure to glutamate (100 mM) for 7 days induced toxicity in primary cortical neurons using the MTT assay. Additionally, high glucose increased the sensitivity of AMPA- or NMDA-induced neurotoxicity, and decreased extracellular glutamate levels in primary cortical neurons. In Western blot analyses, the protein levels of the GluA1 and GluA2 subunits of the AMPA receptor as well as synaptophysin in neurons treated with high glucose were significantly increased compared with the control (25 mM glucose). Therefore, long-term exposure to high glucose induced neuronal death through the disruption of glutamate homeostasis.
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Affiliation(s)
- Sachie Sasaki-Hamada
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan; Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, 252-0373, Japan.
| | - Emi Sanai
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan
| | - Mariko Kanemaru
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan
| | - Gaku Kamanaka
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan
| | - Jun-Ichiro Oka
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan.
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Falcone J, Chen JW. Early Minimally Invasive Parafascicular Surgery for Evacuation of Spontaneous Intracerebral Hemorrhage in the Setting of Computed Tomography Angiography Spot Sign: A Case Series. Oper Neurosurg (Hagerstown) 2022; 22:123-130. [PMID: 35030111 DOI: 10.1227/ons.0000000000000078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/03/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Spontaneous intracerebral hemorrhage (sICH) is associated with high morbidity and mortality, and the role of surgery is uncertain. Spot sign on computed tomography angiography (CTA) has previously been seen as a contraindication for minimally invasive techniques. OBJECTIVE To demonstrate the use of minimally invasive parafascicular surgery (MIPS) for early evacuation of sICH in patients with spot sign on CTA. METHODS Retrospective review of patients presenting to a US tertiary academic medical center from 2018 to 2020 with sICH and CTA spot sign who were treated with MIPS within 6 h of arrival. RESULTS Seven patients (6 men and 1 woman, mean age 54.4 yr) were included in this study. There was a significant decrease between preoperative and postoperative intracerebral hemorrhage volumes (75.03 ± 39.00 cm3 vs 19.48 ± 17.81 cm3, P = .005) and intracerebral hemorrhage score (3.1 ± 0.9 vs 1.9 ± 0.9, P = .020). The mean time from arrival to surgery was 3.72 h (±1.22 h). The mean percentage of hematoma evacuation was 73.78% (±21.11%). The in-hospital mortality was 14.29%, and the mean modified Rankin score at discharge was 4.6 (±1.3). No complications related to the surgery were encountered in any of the cases, with no abnormal intraoperative bleeding and no pathology demonstrating occult vascular lesion. CONCLUSION Early intervention with MIPS appears to be a safe and effective means of hematoma evacuation despite the presence of CTA spot sign, and this finding should not delay early intervention when indicated. Intraoperative hemostasis may be facilitated by the direct visualization provided by a tubular retractor system.
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Affiliation(s)
- Joseph Falcone
- Department of Neurosurgery, University of California Irvine, Orange, California, USA
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Abstract
Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF-1α is the main molecule that responds to hypoxia. HIF-1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF-1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF-1α target, including biological factors, non-coding RNA, hypoxic-ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF-1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.
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Affiliation(s)
- Peiliang Dong
- Institute of Traditional Chinese Medicine, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Qingna Li
- College of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Hua Han
- College of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
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Chen L, Hu J, Mu J, Li C, Wu GY, He C, Xie Y, Ye JN. Specific stimulation of PV + neurons at early stage ameliorates prefrontal ischemia-induced spatial working memory impairment. Behav Brain Res 2021; 414:113511. [PMID: 34358569 DOI: 10.1016/j.bbr.2021.113511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 11/16/2022]
Abstract
Prefrontal ischemia can cause impairments in learning and memory, executive functions and cognitive flexibility. However, the related cellular mechanisms at the early stage are still elusive. The present study used ischemic stroke in medial prefrontal cortex and systemically investigated the electrophysiological changes of the parvalbumin (PV+) interneurons 12 h post ischemia. We found that Ih and the related voltage sags in PV+ interneurons are downregulated post ischemia, which correlates with hyperpolarization of the membrane potentials and increased input resistance in these interneurons. Consistent with the suppression of Ih, postischemic PV+ interneurons exhibited a reduction in excitability and exerted a less inhibitory control over the neighboring pyramidal excitatory neurons. Moreover, we found that specifically chemogenetic activation of PV+ neurons at early stage ameliorated prefrontal ischemia-induced spatial working memory dysfunction in T-maze without effects on the locomotor coordination and balance. In contrast, suppression of PV+ neurons by blockade of Ih leaded to further aggravate the damage of spatial memory. These findings indicate that dysfunctional Ih in the PV+ neuron postischemia induces the imbalance of excitation and inhibition, which might represent a novel mechanism underlying the prefrontal ischemia-induced cognitive impairment.
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Affiliation(s)
- Lin Chen
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, PR China
| | - Jun Hu
- Department of Neurology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Jiankun Mu
- The Affiliated Rehabilitation Hospital of Chongqing Medical University, Chongqing 400036, PR China
| | - Chao Li
- Department of Neurology, The General Hospital of Western Theater Command, No.270 Rongdu Avenue, Jinniu District, Chengdu 610083, Sichuan Province, PR China
| | - Guang-Yan Wu
- Experimental Center of Basic Medicine, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, PR China
| | - Chao He
- Department of Physiology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400037, PR China
| | - Youhong Xie
- The Affiliated Rehabilitation Hospital of Chongqing Medical University, Chongqing 400036, PR China
| | - Jian-Ning Ye
- Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, PR China.
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Chojnowski K, Opielka M, Nazar W, Kowianski P, Smolenski RT. Neuroprotective Effects of Guanosine in Ischemic Stroke-Small Steps towards Effective Therapy. Int J Mol Sci 2021; 22:6898. [PMID: 34199004 PMCID: PMC8268871 DOI: 10.3390/ijms22136898] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.
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Affiliation(s)
- Karol Chojnowski
- Faculty of Medicine, Medical University of Gdańsk, Marii Skłodowskiej-Curie 3a, 80-210 Gdańsk, Poland; (K.C.); (W.N.)
| | - Mikolaj Opielka
- Department of Biochemistry, Medical University of Gdansk, 1 Debinki St., 80-211 Gdansk, Poland
- International Research Agenda 3P—Medicine Laboratory, Medical University of Gdańsk, 3A Sklodowskiej-Curie Street, 80-210 Gdansk, Poland
| | - Wojciech Nazar
- Faculty of Medicine, Medical University of Gdańsk, Marii Skłodowskiej-Curie 3a, 80-210 Gdańsk, Poland; (K.C.); (W.N.)
| | - Przemyslaw Kowianski
- Department of Anatomy and Neurobiology, Medical University of Gdansk, 1 Debinki Street, 80-211 Gdańsk, Poland;
- Institute of Health Sciences, Pomeranian University of Słupsk, Bohaterów Westerplatte 64, 76-200 Słupsk, Poland
| | - Ryszard T. Smolenski
- Department of Biochemistry, Medical University of Gdansk, 1 Debinki St., 80-211 Gdansk, Poland
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Amina M, Bhat RS, Al-Dbass AM, Musayeib NM, Fahmy R, Alhadlaq L, El-Ansary A. The protective effect of Moringa oleifera plant extract against glutamate-induced DNA damage and reduced cell viability in a primary retinal ganglion cell line. PeerJ 2021; 9:e11569. [PMID: 34221717 PMCID: PMC8231317 DOI: 10.7717/peerj.11569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 05/16/2021] [Indexed: 12/22/2022] Open
Abstract
Background Glutamate excitotoxicity can cause DNA damage and is linked to many retinal and neurological disorders. In mammals, the visual signal from the eyes to the brain is conducted only by retinal ganglion cells (RGCs), which can be damaged by overstimulation of glutamate receptors. Methodology We examined the protective effects of Moringa oleifera seed extract against glutamate-induced DNA damage in RGCs. RGCs cells were treated with 5, 10, 50, or 100 µg/ml of M. oleifera seed extract and glutamate separately and then assessed for DNA damage using the comet assay. We also evaluated the viability of the RGCs after both treatments using the MTT test. Additionally, RGCs were pretreated with M. oleifera seed extract (50 or 100 µg/ml) for 2 h before glutamate treatment (100 µg/ml) to determine the potential protective effects of M. oleifera. We performed a phytochemical analysis of the M. oleifera seed extract using standard reactions. Results The M. oleifera seed extract was found to be rich in many phytochemicals. We observed a significant dose-dependent elevation in all comet assay variables in glutamate-treated RGCs, whereas M. oleifera seed extract treatments did not show any significant change in DNA integrity. Conclusion M. oleifera seed extract demonstrates neuroprotective effects, which suggests it may help to prevent the development of many neurodegenerative disorders.
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Affiliation(s)
- Musarat Amina
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ramesa Shafi Bhat
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Abeer M Al-Dbass
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Nawal M Musayeib
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Rania Fahmy
- Department of Optometry, College of Applied Medical Sciences, King Saud University, Riyadh, r, Saudi Arabia.,Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Leen Alhadlaq
- College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Afaf El-Ansary
- Central Laboratory, King Saud University, Riyadh, Saudi Arabia
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Moteki Y, Kobayashi T, Kawamata T. Clinical Significance of Cytotoxic Lesions of the Corpus Callosum in Subarachnoid Hemorrhage Patients: A Retrospective Analysis. Cerebrovasc Dis 2021; 50:405-411. [PMID: 33774621 DOI: 10.1159/000514383] [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: 08/12/2020] [Accepted: 01/07/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Cytotoxic lesions of the corpus callosum are secondary lesions induced by significant increases in cytokine levels in the brain and are associated with subarachnoid hemorrhage (SAH). However, their clinical significance in SAH patients remains unclear. METHODS We retrospectively analyzed SAH patients who were treated in our hospital and evaluated between-group differences in the backgrounds, clinical findings, and outcomes between SAH patients who developed cytotoxic lesions of the corpus callosum and those who did not. We further compared patients who achieved good outcomes with those who had poor outcomes. Multivariate logistic regression analysis was used to identify risk factors for poor clinical outcomes. RESULTS We analyzed 159 SAH patients; 17 patients (10.7%) had cytotoxic lesions of the corpus callosum. Patients with cytotoxic lesions of the corpus callosum were more likely to be in a severe condition (World Federation of Neurosurgical Societies grading IV-V: odds ratio [OR], 4.53; 95% confidence interval [95% CI]: 1.60-12.84; p = 0.0042) and have an intraventricular (OR, 5.98; 95% CI: 1.32-27.13; p = 0.0054) or an intraparenchymal hematoma (OR, 3.62; 95% CI: 1.25-10.45; p = 0.023). Patients with cytotoxic lesions of the corpus callosum had a greater propensity of a poor outcome 3 months after onset (modified Rankin Scale score 0-2: OR, 0.22; 95% CI: 0.07-0.66; p = 0.0043). Multivariate analysis confirmed that cytotoxic lesions of the corpus callosum increased the risk of a poor outcome (OR, 4.39; 95% CI: 1.06-18.1; p = 0.037). DISCUSSION/CONCLUSIONS The development of cytotoxic lesions of the corpus callosum may be related to the extent of hematomas in SAH patients. Although they are usually reversible lesions, the development of cytotoxic lesions of the corpus callosum may be a predictor of poor outcomes in SAH patients.
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Affiliation(s)
- Yosuke Moteki
- Department of Neurosurgery, Ebina General Hospital, Kanagawa, Japan
| | | | - Takakazu Kawamata
- Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan
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Ye N, Qin W, Tian S, Xu Q, Wold EA, Zhou J, Zhen XC. Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases. J Med Chem 2020; 63:15187-15217. [PMID: 33111525 DOI: 10.1021/acs.jmedchem.0c01192] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The sigma-1 (σ1) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ1 receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ1 receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ1 receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ1 selective orthosteric ligands or allosteric modulators.
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Affiliation(s)
- Na Ye
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Wangzhi Qin
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Sheng Tian
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Qingfeng Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Eric A Wold
- Chemical Biology Program, Department of Pharmacology and Toxicology, and Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, and Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Xue-Chu Zhen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
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Mostafa MM, Awad EM, Hazzou AM, Elewa MKA, Aziz TTA, Samy DM. Biochemical and structural magnetic resonance imaging in chronic stroke and the relationship with upper extremity motor function. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2020. [DOI: 10.1186/s41983-020-00183-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Recovery of upper extremity (UE) motor function after stroke is variable from one to another due to heterogeneity of stroke pathology. Structural and biochemical magnetic resonance imaging of the primary motor cortex (M1) have been used to document reorganization of neural activity after stroke.
Objective
To assess cortical biochemical and structural causes of delayed recovery of UE motor function impairment in chronic subcortical ischemic stroke patients.
Methodology
A cross-sectional study with fifty patients were enrolled: thirty patients with chronic (> 6 months) subcortical ischemic stroke suffering from persistent UE motor function impairment (not improved group) and twenty patients with chronic subcortical ischemic stroke and improved UE motor function (improved group). We recruited a group of (16) age-matched healthy subjects. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed to measure n-acetylaspartate (NAA) and glutamate+glutamine (Glx) ratios relative to creatine (Cr) in the precentral gyrus which represent M1of hand area in both ipsilesional and contralesional hemispheres. Brain magnetic resonance imaging (MRI) to measure precentral gyral thickness is representing the M1of hand area. UE motor function assessment is using the Fugl Meyer Assessment (FMA-UE) Scale.
Results
The current study found that ipslesional cortical thickness was significantly lower than contralesional cortical thickness among all stroke patients. Our study found that ipsilesional NAA/Cr ratio was lower than contralesional NAA/Cr among stroke patients. UE and hand motor function by FMA-UE showed highly statistically significant correlation with ipsilesional cortical thickness and ipsilesional NAA/Cr ratio, more powerful with NAA/Cr ratio.
Conclusion
We concluded that persistent motor impairment in individuals with chronic subcortical stroke may be at least in part related to ipsilesional structural and biochemical changes in motor areas remote from infarction in form of decreased cortical thickness and NAA/Cr ratio which had the strongest relationship with that impairment.
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Hao Y, Xin M, Feng L, Wang X, Wang X, Ma D, Feng J. Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges. Front Neurol 2020; 11:812. [PMID: 33071923 PMCID: PMC7530891 DOI: 10.3389/fneur.2020.00812] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 06/29/2020] [Indexed: 12/13/2022] Open
Abstract
Stroke is one of the leading causes of morbidity and mortality worldwide, and it is increasing in prevalence. The limited therapeutic window and potential severe side effects prevent the widespread clinical application of the venous injection of thrombolytic tissue plasminogen activator and thrombectomy, which are regarded as the only approved treatments for acute ischemic stroke. Triggered by various types of mild stressors or stimuli, ischemic preconditioning (IPreC) induces adaptive endogenous tolerance to ischemia/reperfusion (I/R) injury by activating a multitude cascade of biomolecules, for example, proteins, enzymes, receptors, transcription factors, and others, which eventually lead to transcriptional regulation and epigenetic and genomic reprogramming. During the past 30 years, IPreC has been widely studied to confirm its neuroprotection against subsequent I/R injury, mainly including local ischemic preconditioning (LIPreC), remote ischemic preconditioning (RIPreC), and cross preconditioning. Although LIPreC has a strong neuroprotective effect, the clinical application of IPreC for subsequent cerebral ischemia is difficult. There are two main reasons for the above result: Cerebral ischemia is unpredictable, and LIPreC is also capable of inducing unexpected injury with only minor differences to durations or intensity. RIPreC and pharmacological preconditioning, an easy-to-use and non-invasive therapy, can be performed in a variety of clinical settings and appear to be more suitable for the clinical management of ischemic stroke. Hoping to advance our understanding of IPreC, this review mainly focuses on recent advances in IPreC in stroke management, its challenges, and the potential study directions.
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Affiliation(s)
| | | | | | | | | | - Di Ma
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Jiachun Feng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
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Therapeutic time window of minimally invasive surgery for intracerebral hemorrhage. BRAIN HEMORRHAGES 2020. [DOI: 10.1016/j.hest.2020.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Transport rate of EAAT2 is regulated by amino acid located at the interface between the scaffolding and substrate transport domains. Neurochem Int 2020; 139:104792. [PMID: 32668264 DOI: 10.1016/j.neuint.2020.104792] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/19/2020] [Accepted: 06/21/2020] [Indexed: 01/24/2023]
Abstract
Excitatory Amino Acid Transporters (EAATs) are plasma membrane proteins responsible for maintenance of low extracellular concentrations of glutamate in the CNS. Dysfunction in their activity is implicated in various neurological disorders. Glutamate transport by EAATs occurs through the movement of the central transport domain relative to the scaffold domain in the EAAT membrane protein. Previous studies suggested that residues located within the interface of these two domains in EAAT2, the main subtype of glutamate transporter in the brain, are involved in regulating transport rates. We used mutagenesis, structure-function relationship, surface protein expression and electrophysiology studies, in transfected COS-7 cells and oocytes, to examine residue glycine at position 298, which is located within this interface. Mutation G298A results in increased transport rate without changes in surface expression, suggesting a more hydrophobic and larger alanine results in facilitated transport movement. The increased transport rate does not involve changes in sodium affinity. Electrophysiological currents show that G298A increase both transport and anion currents, suggesting faster transitions through the transport cycle. This work identifies a region critically involved in setting the glutamate transport rate.
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Forster YM, Green JL, Khatiwada A, Liberato JL, Narayana Reddy PA, Salvino JM, Bienz S, Bigler L, dos Santos WF, Karklin Fontana AC. Elucidation of the Structure and Synthesis of Neuroprotective Low Molecular Mass Components of the Parawixia bistriata Spider Venom. ACS Chem Neurosci 2020; 11:1573-1596. [PMID: 32343555 DOI: 10.1021/acschemneuro.0c00007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The South American social spider Parawixia bistriata produces a venom containing complex organic compounds with intriguing biological activities. The crude venom leads to paralysis in termites and stimulates l-glutamate uptake and inhibits GABA uptake in rat brain synaptosomes. Glutamate is the major neurotransmitter at the insect neuromuscular junction and at the mammalian central nervous system, suggesting a modulation of the glutamatergic system by the venom. Parawixin1, 2, and 10 (Pwx1, 2 and 10) are HPLC fractions that demonstrate this bioactivity. Pwx1 stimulates l-glutamate uptake through the main transporter in the brain, EAAT2, and is neuroprotective in in vivo glaucoma models. Pxw2 inhibits GABA and glycine uptake in synaptosomes and inhibits seizures and neurodegeneration, and Pwx10 increases l-glutamate uptake in synaptosomes and is neuroprotective and anticonvulsant, shown in in vivo epilepsy models. Herein, we investigated the low molecular mass compounds in this venom and have found over 20 small compounds and 36 unique acylpolyamines with and without amino acid linkers. The active substances in fractions Pwx1 and Pwx2 require further investigation. We elucidated and confirmed the structure of the active acylpolyamine in Pwx10. Both fraction Pwx10 and the synthesized component enhance the activity of transporters EAAT1 and EAAT2, and, importantly, offer in vitro neuroprotection against excitotoxicity in primary cultures. These data suggest that compounds with this mechanism could be developed into therapies for disorders in which l-glutamate excitotoxicity is involved.
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Affiliation(s)
- Yvonne M. Forster
- Department of Chemistry, University of Zurich, Zurich, CH 8057, Switzerland
| | - Jennifer Leigh Green
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Apeksha Khatiwada
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - José Luiz Liberato
- Department of Biology, University of São Paulo, Ribeirão Preto, SP 14040-900, Brazil
| | | | - Joseph M. Salvino
- The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Stefan Bienz
- Department of Chemistry, University of Zurich, Zurich, CH 8057, Switzerland
| | - Laurent Bigler
- Department of Chemistry, University of Zurich, Zurich, CH 8057, Switzerland
| | | | - Andréia Cristina Karklin Fontana
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
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Liddle L, Reinders R, South S, Blacker D, Knuckey N, Colbourne F, Meloni B. Poly-arginine-18 peptides do not exacerbate bleeding, or improve functional outcomes following collagenase-induced intracerebral hemorrhage in the rat. PLoS One 2019; 14:e0224870. [PMID: 31697775 PMCID: PMC6837498 DOI: 10.1371/journal.pone.0224870] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 10/23/2019] [Indexed: 12/23/2022] Open
Abstract
Background Cationic arginine-rich peptides (CARPs) have demonstrated neuroprotective and/or behavioural efficacy in ischemic and hemorrhagic stroke and traumatic brain injury models. Therefore, in this study we investigated the safety and neuroprotective efficacy of the CARPs poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer R18D given in the acute bleeding phase in an intracerebral hemorrhage (ICH) model. Methods One hundred and fifty-eight male Sprague-Dawley rats received collagenase-induced ICH. Study 1 examined various doses of R18D (30, 100, 300, or 1000 nmol/kg) or R18 (100, 300, 1000 nmol/kg) administered intravenously 30 minutes post-collagenase injection on hemorrhage volume 24 hours after ICH. Study 2 examined R18D (single intravenous dose) or R18 (single intravenous dose, plus 6 daily intraperitoneal doses) at 300 or 1000 nmol/kg commencing 30 minutes post-collagenase injection on behavioural outcomes (Montoya staircase test, and horizontal ladder test) in the chronic post-ICH period. A histological assessment of tissue loss was assessed using a Nissl stain at 28 days after ICH. Results When administered during ongoing bleeding, neither R18 or R18D exacerbated hematoma volume or worsened functional deficits. Lesion volume assessment at 28 days post-ICH was not reduced by the peptides; however, animals treated with the lower R18D 300 nmol/kg dose, but not with the higher 1000 nmol/kg dose, demonstrated a statistically increased lesion size compared to saline treated animals. Conclusion Overall, both R18 and R18D appeared to be safe when administered during a period of ongoing bleeding following ICH. Neither peptide appears to have any statistically significant effect in reducing lesion volume or improving functional recovery after ICH. Additional studies are required to further assess dose efficacy and safety in pre-clinical ICH studies.
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Affiliation(s)
- Lane Liddle
- Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
| | - Ryan Reinders
- Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
| | - Samantha South
- Office of Research Enterprise, The University of Western Australia, Western Australia, Australia
| | - David Blacker
- Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, Western Australia, Australia
- Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Neville Knuckey
- Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, Western Australia, Australia
- Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Frederick Colbourne
- Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Bruno Meloni
- Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, Western Australia, Australia
- Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
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Falcucci RM, Wertz R, Green JL, Meucci O, Salvino J, Fontana ACK. Novel Positive Allosteric Modulators of Glutamate Transport Have Neuroprotective Properties in an in Vitro Excitotoxic Model. ACS Chem Neurosci 2019; 10:3437-3453. [PMID: 31257852 DOI: 10.1021/acschemneuro.9b00061] [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: 12/13/2022] Open
Abstract
Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsy, and several neurodegenerative disorders. EAAT2 is the main transporter subtype responsible for glutamate clearance in the brain, and plays a key role in regulating neurotransmission and preventing excitotoxicity. Therefore, compounds that increase the activity of EAAT2 have therapeutic potential for neuroprotection. In previous studies, we used virtual screening approaches to identify novel positive allosteric modulators (PAMs) of EAAT2. These compounds were shown to selectively increase the activity of EAAT2 and increase Vmax of transport, without changing substrate affinity. In this work, our major effort was to investigate whether increasing the activity of EAAT2 by allosteric modulation would translate to neuroprotection in in vitro primary culture models of excitotoxicity. To investigate potential neuroprotective effects of one EAAT2 PAM, GT949, we subjected cultures to acute and prolonged excitotoxic insults by exogenous application of glutamate, or oxidative stress by application of hydrogen peroxide. GT949 administration did not result in neuroprotection in the oxidative stress model, likely due to damage of the glutamate transporters. However, GT949 displayed neuroprotective properties after acute and prolonged glutamate-mediated excitotoxicity. We propose that this compound prevents excess glutamate signaling by increasing the rate of glutamate clearance by EAAT2, thereby preventing excitotoxic damage and cell death. This novel class of compounds is therefore an innovative approach for neuroprotection with potential for translation in in vivo animal models of excitotoxicity.
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Affiliation(s)
- Romulo Martelli Falcucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Ryan Wertz
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Jennifer Leigh Green
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Olimpia Meucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Joseph Salvino
- The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Andréia Cristina Karklin Fontana
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
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27
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Sun Y, Yang J, Hu X, Gao X, Li Y, Yu M, Liu S, Lu Y, Wang J, Huang L, Lu X, Jin C, Wu S, Cai Y. Conditioned medium from overly excitatory primary astrocytes induced by La 3+ increases apoptosis in primary neurons via upregulating the expression of NMDA receptors. Metallomics 2019; 10:1016-1028. [PMID: 29989126 DOI: 10.1039/c8mt00056e] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Lanthanum (La) can accumulate in the brain and impair learning and memory. However, the underlying mechanism of La-induced neurotoxicity has remained elusive. Under physiological conditions, it has been reported that moderately excitatory astrocytes play an important role in the regulation of neuronal signals and synaptic plasticity. However, under pathological conditions, overly excitatory astrocytes can release excess excitatory transmitters, such as glutamate (Glu) and d-serine, and induce the over-activation of NMDA receptors (NMDAR) in neurons, ultimately leading to neuronal excitotoxicity. To date, limited work has been performed with respect to whether La can induce neuronal excitotoxicity by inducing astrocytes to become overexcited. In this study, in vitro models of primary culture rat cortical astrocytes and neurons were established. First, the astrocytes were treated with 0.125 mM, 0.25 mM and 0.5 mM lanthanum chloride (LaCl3) for 24 h, and the supernatants were collected as a conditioned medium (CM) which is denoted as CM (La3+); then, the neurons were treated with CM (La3+) for 48 h. The results illustrate that LaCl3 treatment significantly upregulated the mRNA and protein expression levels of metabotropic glutamate receptor 5 (mGLUR5), phospholipase C (PLC), connexin 43 (Cx43) and Cx30, increased the concentrations of inositol trisphosphate (IP3) and [Ca2+]i, and promoted the synthesis and release of Glu and d-serine in astrocytes. Moreover, the CM (La3+) could increase the mRNA and protein expression levels of NMDAR subunits (NR1, NR2A, NR2B), the concentration of [Ca2+]i and the rate of apoptosis in neurons. Furthermore, after removal of La, CM (La-free) had a similar effect on neurons which could be antagonized by MK-801, DCKA and DAAO. These results suggest that the neuron apoptosis induced by La is closely related to the excessive release of Glu and d-serine from overly excitatory astrocytes.
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Affiliation(s)
- Yaling Sun
- Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.
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28
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Yin A, Guo H, Tao L, Cai G, Wang Y, Yao L, Xiong L, Zhang J, Li Y. NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake. Transl Stroke Res 2019; 11:214-227. [PMID: 31250377 PMCID: PMC7067740 DOI: 10.1007/s12975-019-00708-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 04/22/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023]
Abstract
Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2-/-) mice exhibited an increase in cerebral interstitial glutamate and a reduction in glutamate uptake into astrocytes. The ability of NDRG2 to control EAAT-mediated glutamate uptake into astrocytes required NDRG2 to interact with and promote the function of Na+/K+-ATPase β1, which could be disrupted by a Na+/K+-ATPase β1 peptide. The deletion of NDRG2 or treatment with the Na+/K+-ATPase β1 peptide significantly increased neuronal death upon a glutamate challenge and aggravated brain damage after ischemia. Our findings demonstrate that NDRG2 plays a pivotal role in promoting astroglial glutamate uptake from the interstitial space and protecting the brain from glutamate excitotoxicity.
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Affiliation(s)
- Anqi Yin
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hang Guo
- Department of Anesthesiology, PLA Army General Hospital, Beijing, 100700, China
| | - Liang Tao
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Guohong Cai
- Institute of Neuroscience, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yazhou Wang
- Institute of Neuroscience, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Libo Yao
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China
| | - Lize Xiong
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jian Zhang
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
| | - Yan Li
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China.
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29
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4-Imidazo[2,1-b]thiazole-1,4-DHPs and neuroprotection: preliminary study in hits searching. Eur J Med Chem 2019; 169:89-102. [PMID: 30861492 DOI: 10.1016/j.ejmech.2019.02.075] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 02/21/2019] [Accepted: 02/27/2019] [Indexed: 12/25/2022]
Abstract
In the present work we describe the synthesis, characterization and evaluation of neuroprotective effects of a focused library of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines. Furthermore, the new dihydropyridines were subjected to functional in vitro assays in cardiac tissues and vascular smooth muscle to determine their possible selectivity in counteracting the effects of neurodegeneration. In particular the strategy adopted for designing the compounds involves the imidazo[2,1-b]thiazole nucleus. The observed properties show that substituents at C2 and C6 of the bicyclic scaffold are able to influence the cardiovascular parameters and the neuroprotective activity. In comparison to nifedipine, a set of derivatives such as compound 6, showed a neuroprotective profile of particular interest.
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30
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Bieri G, Lucin KM, O'Brien CE, Zhang H, Villeda SA, Wyss-Coray T. Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration. Mol Neurodegener 2018; 13:68. [PMID: 30594228 PMCID: PMC6310967 DOI: 10.1186/s13024-018-0302-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 12/05/2018] [Indexed: 12/12/2022] Open
Abstract
Background Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer’s disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo. Methods Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus. Results We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo. Conclusions Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration. Electronic supplementary material The online version of this article (10.1186/s13024-018-0302-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Gregor Bieri
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.,Neurosciences PhD Program, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Kurt M Lucin
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Caitlin E O'Brien
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Hui Zhang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Saul A Villeda
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Tony Wyss-Coray
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA. .,Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, 3801 Miranda Avenue, 154W, Palo Alto, CA, 94304, USA.
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31
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Beneficial Effects of Resveratrol Administration-Focus on Potential Biochemical Mechanisms in Cardiovascular Conditions. Nutrients 2018; 10:nu10111813. [PMID: 30469326 PMCID: PMC6266814 DOI: 10.3390/nu10111813] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/08/2018] [Accepted: 11/14/2018] [Indexed: 12/15/2022] Open
Abstract
Resveratrol (RV) is a natural non-flavonoid polyphenol and phytoalexin produced by a number of plants such as peanuts, grapes, red wine and berries. Numerous in vitro studies have shown promising results of resveratrol usage as antioxidant, antiplatelet or anti-inflammatory agent. Beneficial effects of resveratrol activity probably result from its ability to purify the body from ROS (reactive oxygen species), inhibition of COX (cyclooxygenase) and activation of many anti-inflammatory pathways. Administration of the polyphenol has a potential to slow down the development of CVD (cardiovascular disease) by influencing on certain risk factors such as development of diabetes or atherosclerosis. Resveratrol induced an increase in Sirtuin-1 level, which by disrupting the TLR4/NF-κB/STAT signal cascade (toll-like receptor 4/nuclear factor κ-light-chain enhancer of activated B cells/signal transducer and activator of transcription) reduces production of cytokines in activated microglia. Resveratrol caused an attenuation of macrophage/mast cell-derived pro-inflammatory factors such as PAF (platelet-activating factor), TNF-α (tumour necrosis factor-α and histamine. Endothelial and anti-oxidative effect of resveratrol may contribute to better outcomes in stroke management. By increasing BDNF (brain-derived neurotrophic factor) serum concentration and inducing NOS-3 (nitric oxide synthase-3) activity resveratrol may have possible therapeutical effects on cognitive impairments and dementias especially in those characterized by defective cerebrovascular blood flow.
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Shimauchi-Ohtaki H, Kurachi M, Naruse M, Shibasaki K, Sugio S, Matsumoto K, Ema M, Yoshimoto Y, Ishizaki Y. The dynamics of revascularization after white matter infarction monitored in Flt1-tdsRed and Flk1-GFP mice. Neurosci Lett 2018; 692:70-76. [PMID: 30389418 DOI: 10.1016/j.neulet.2018.10.057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/11/2018] [Accepted: 10/30/2018] [Indexed: 12/18/2022]
Abstract
Subcortical white matter infarction causes ischemic demyelination and loss of brain functions, as the result of disturbances of the blood flow. Although angiogenesis is one of the recovery processes after cerebral infarction, the dynamics of revascularization after white matter infarction still remains unclear. We induced white matter infarction in the internal capsule of Flk1-GFP::Flt1-tdsRed double transgenic mice by injection of endothelin-1 (ET-1), a vasoconstrictor peptide, together with N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and followed the changes in Flk1 and Flt1 expression in the vascular system in the infarct area. Reduction of Flt1-tdsRed-positive blood vessels 1 day after the injection and increase of Flk1-GFP-strongly-positive blood vessels 3 days after the injection were apparent. PDGFRβ-strongly-positive (PDGFRβ+) cells appeared in the infarct area 3 days after the injection and increased their number thereafter. Three days after the injection, most of these cells were in close contact with Flk1-GFP-positive endothelial cells, indicating these cells are bona fide pericytes. Seven days after the injection, the number of PDGFRβ+ cells increased dramatically, and the vast majority of these cells were not in close contact with Flk1-GFP-positive endothelial cells. Taken together, our results suggest revascularization begins early after the ischemic insult, and the emerging pericytes first ensheath blood vessels and then produce fibroblast-like cells not directly associated with blood vessels.
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Affiliation(s)
- Hiroya Shimauchi-Ohtaki
- Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Masashi Kurachi
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Masae Naruse
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Koji Shibasaki
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Shouta Sugio
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Ken Matsumoto
- Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Masatsugu Ema
- Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yuhei Yoshimoto
- Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yasuki Ishizaki
- Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
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Davidson SM, Arjun S, Basalay MV, Bell RM, Bromage DI, Bøtker HE, Carr RD, Cunningham J, Ghosh AK, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Maddock H, Ovize M, Walker M, Wiart M, Yellon DM. The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology. Basic Res Cardiol 2018; 113:43. [PMID: 30310998 PMCID: PMC6182684 DOI: 10.1007/s00395-018-0704-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 12/13/2022]
Abstract
Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.
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Affiliation(s)
- Sean M Davidson
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Sapna Arjun
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Maryna V Basalay
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Robert M Bell
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Daniel I Bromage
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Richard D Carr
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
- MSD A/S, Copenhagen, Denmark
| | - John Cunningham
- Centre for Nephrology, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Arjun K Ghosh
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Gerd Heusch
- West German Heart and Vascular Center, Institute for Pathophysiology, University of Essen Medical School, Essen, Germany
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER de Enfermedades CardioVasculares, Madrid, Spain
- IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Petra Kleinbongard
- West German Heart and Vascular Center, Institute for Pathophysiology, University of Essen Medical School, Essen, Germany
| | - Sandrine Lecour
- Cardioprotection Group, Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa
| | - Helen Maddock
- Centre for Sport, Exercise and Life Sciences, Faculty of Health and Life Sciences, Coventry University, Priory Street, Coventry, CV1 5FB, UK
| | - Michel Ovize
- INSERM U1060, CarMeN Laboratory, Université de Lyon and Service d'explorations Fonctionnelles Cardiovasculaires Groupement Hospitalier Est, 59 Boulevard Pinel, 69500, Bron, France
| | - Malcolm Walker
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Marlene Wiart
- INSERM U1060, CarMeN Laboratory, Université de Lyon and Service d'explorations Fonctionnelles Cardiovasculaires Groupement Hospitalier Est, 59 Boulevard Pinel, 69500, Bron, France
- CNRS, Lyon, France
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
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Lu C, Meng Z, He Y, Xiao D, Cai H, Xu Y, Liu X, Wang X, Mo L, Liang Z, Wei X, Ao Q, Liang B, Li X, Tang S, Guo S. Involvement of gap junctions in astrocyte impairment induced by manganese exposure. Brain Res Bull 2018; 140:107-113. [DOI: 10.1016/j.brainresbull.2018.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 03/16/2018] [Accepted: 04/13/2018] [Indexed: 11/28/2022]
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Sirh S, Park HR. Optimal Surgical Timing of Aspiration for Spontaneous Supratentorial Intracerebral Hemorrhage. J Cerebrovasc Endovasc Neurosurg 2018; 20:96-105. [PMID: 30370243 PMCID: PMC6196143 DOI: 10.7461/jcen.2018.20.2.96] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 05/05/2018] [Accepted: 06/11/2018] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Minimally invasive techniques such as stereotactic aspiration have been regarded as promising alternative methods to replace craniotomy in the treatment of intracerebral hemorrhage (ICH). The aim of this study was to identify the optimal timing of stereotactic aspiration and analyze the factors affecting the clinical outcome. MATERIALS AND METHODS This retrospective study included 81 patients who underwent stereotactic aspiration for spontaneous supratentorial ICH at single institution. Volume of hematoma was calculated based on computed tomography scan at admission, just before aspiration, immediately after aspiration, and after continuous drainage. The neurologic outcome was compared with Glasgow outcome scale (GOS) score. RESULTS The mean volume ratio of residual hematoma was 59.5% and 17.6% immediately after aspiration and after continuous drainage for an average of 2.3 days, respectively. Delayed aspiration group showed significantly lower residual volume ratio immediately after aspiration. However, there was no significant difference in the residual volume ratio after continuous drainage. The favorable outcome of 1-month GOS 4 or 5 was significantly better in the group with delayed aspiration after more than 7 days (p = 0.029), despite no significant difference in postoperative 6-months GOS score. A factor which has significant correlation with postoperative 6-months favorable outcome was the final hematoma volume ratio after drainage (p = 0.028). CONCLUSION There is no difference in final residual volume of hematoma or 6-months neurologic outcome according to the surgical timing of hematoma aspiration. The only factor affecting the postoperative 6-months neurologic outcome is the final volume of remaining hematoma after drainage.
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Affiliation(s)
- Sooji Sirh
- Department of Neurosurgery, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Hye Ran Park
- Department of Neurosurgery, Soonchunhyang University Seoul Hospital, Seoul, Korea
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Laskowitz DT, Bennett ER, Durham RJ, Volpi JJ, Wiese JR, Frankel M, Shpall E, Wilson JM, Troy J, Kurtzberg J. Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase I Safety Study. Stem Cells Transl Med 2018; 7:521-529. [PMID: 29752869 PMCID: PMC6052613 DOI: 10.1002/sctm.18-0008] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/21/2018] [Indexed: 12/16/2022] Open
Abstract
Stroke is a major cause of death and long‐term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase I open‐label trial to assess the safety and feasibility of a single IV infusion of non‐human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3–9 days post‐stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well‐tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post‐treatment, all participants had improved by at least one grade in mRS (mean 2.8 ± 0.9) and by at least 4 points in NIHSS (mean 5.9 ± 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non‐HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo‐controlled phase 2 study. stemcellstranslationalmedicine2018;7:521–529
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Affiliation(s)
| | | | - Rebecca J. Durham
- Robertson Clinical and Translational Cell Therapy Program, Duke Translational Research Institute/Duke UniversityDurhamNorth CarolinaUSA
| | - John J. Volpi
- Eddy Scurlock Stroke Center, Houston Methodist Neurological InstituteHoustonTexasUSA
| | - Jonathan R. Wiese
- Eddy Scurlock Stroke Center, Houston Methodist Neurological InstituteHoustonTexasUSA
| | - Michael Frankel
- Department of NeurologyEmory University School of MedicineAtlantaGeorgiaUSA
| | - Elizabeth Shpall
- MD Anderson Cancer Center, The University of TexasHoustonTexasUSA
| | - Jeffry M. Wilson
- MD Anderson Cancer Center, The University of TexasHoustonTexasUSA
| | - Jesse Troy
- Robertson Clinical and Translational Cell Therapy Program, Duke Translational Research Institute/Duke UniversityDurhamNorth CarolinaUSA
| | - Joanne Kurtzberg
- Robertson Clinical and Translational Cell Therapy Program, Duke Translational Research Institute/Duke UniversityDurhamNorth CarolinaUSA
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Khan S, Yuldasheva NY, Batten TFC, Pickles AR, Kellett KAB, Saha S. Tau pathology and neurochemical changes associated with memory dysfunction in an optimised murine model of global cerebral ischaemia - A potential model for vascular dementia? Neurochem Int 2018; 118:134-144. [PMID: 29649504 DOI: 10.1016/j.neuint.2018.04.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 12/15/2022]
Abstract
Cerebral ischemia is known to be a major cause of death and the later development of Alzheimer's disease and vascular dementia. However, ischemia induced cellular damage that initiates these diseases remain poorly understood. This is primarily due to lack of clinically relevant models that are highly reproducible. Here, we have optimised a murine model of global cerebral ischaemia with multiple markers to determine brain pathology, neurochemistry and correlated memory deficits in these animals. Cerebral ischaemia in mice was induced by bilateral common carotid artery occlusion. Following reperfusion, the mice were either fixed with 4% paraformaldehyde or decapitated under anaesthesia. Brains were processed for Western blotting or immunohistochemistry for glial (GLT1) and vesicular (VGLUT1, VGLUT2) glutamate transporters and paired helical filament (PHF1) tau. The PHF1 tau is the main component of neurofibrillary tangle, which is the pathological hallmark of Alzheimer's disease and vascular dementia. The novel object recognition behavioural assay was used to investigate the functional cognitive consequences in these mice. The results show consistent and selective neuronal and glial cell changes in the hippocampus and the cortex together with significant reductions in GLT1 (***P < 0.001), VGLUT1 (**P < 0.01) and VGLUT2 (***P < 0.001) expressions in the hippocampus in occluded mice as compared to sham-operated animals. These changes are associated with increased PHF1 (***P < 0.0001) protein and a significant impairment of performance (*p < 0.0006, N = 6/group) in the novel object recognition test. This model represents a useful tool for investigating cellular, biochemical and molecular mechanisms of global cerebral ischaemia and may be an ideal preclinical model for vascular dementia.
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Affiliation(s)
- Sabah Khan
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - Nadira Y Yuldasheva
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - Trevor F C Batten
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK; Leeds Trinity University, Brownberrie Lane, Horsforth, Leeds, LS18 5HD, UK
| | | | - Katherine A B Kellett
- Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - Sikha Saha
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Kortagere S, Mortensen OV, Xia J, Lester W, Fang Y, Srikanth Y, Salvino JM, Fontana ACK. Identification of Novel Allosteric Modulators of Glutamate Transporter EAAT2. ACS Chem Neurosci 2018; 9:522-534. [PMID: 29140675 DOI: 10.1021/acschemneuro.7b00308] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsy, and neurodegenerative diseases, among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain. In this work, a hybrid structure based approach was applied, based on this molecular domain, to create a high-resolution pharmacophore. Subsequently, virtual screening of a library of small molecules was performed, identifying 10 hit molecules that interact at the proposed domain. Among these, three compounds were determined to be activators, four were inhibitors, and three had no effect on EAAT2-mediated transport in vitro. Further characterization of the two best ranking EAAT2 activators for efficacy, potency, and selectivity for glutamate over monoamine transporters subtypes and NMDA receptors and for efficacy in cultured astrocytes is demonstrated. Mutagenesis studies suggest that the EAAT2 activators interact with residues forming the interface between the trimerization and transport domains. These compounds enhance the glutamate translocation rate, with no effect on substrate interaction, suggesting an allosteric mechanism. The identification of these novel positive allosteric modulators of EAAT2 offers an innovative approach for the development of therapies based on glutamate transport enhancement.
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Affiliation(s)
- Sandhya Kortagere
- Department of Microbiology and Immunology, Centers for Molecular Parasitology, Virology and Translational Neuroscience, Institute for Molecular Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, United States
| | - Ole V. Mortensen
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Jingsheng Xia
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - William Lester
- Analytical Chemistry, Division of Pre-Clinical Innovation (DPI), NCATS, National Institutes of Health, Rockville, Maryland 20850, United States
| | - Yuhong Fang
- Analytical Chemistry, Division of Pre-Clinical Innovation (DPI), NCATS, National Institutes of Health, Rockville, Maryland 20850, United States
| | - Yellamelli Srikanth
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Joseph M. Salvino
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Andréia C. K. Fontana
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States
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Hu X, Yang J, Sun Y, Gao X, Zhang L, Li Y, Yu M, Liu S, Lu X, Jin C, Wu S, Cai Y. Lanthanum chloride impairs memory in rats by disturbing the glutamate-glutamine cycle and over-activating NMDA receptors. Food Chem Toxicol 2018; 113:1-13. [DOI: 10.1016/j.fct.2018.01.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 01/12/2018] [Accepted: 01/14/2018] [Indexed: 02/06/2023]
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Koizumi S, Hirayama Y, Morizawa YM. New roles of reactive astrocytes in the brain; an organizer of cerebral ischemia. Neurochem Int 2018; 119:107-114. [PMID: 29360494 DOI: 10.1016/j.neuint.2018.01.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 12/18/2017] [Accepted: 01/16/2018] [Indexed: 01/16/2023]
Abstract
The brain consists of neurons and much higher number of glial cells. They communicate each other, by which they control brain functions. The brain is highly vulnerable to several insults such as ischemia, but has a self-protective and self-repairing mechanisms against these. Ischemic tolerance or preconditioning is an endogenous neuroprotective phenomenon, where a mild non-lethal ischemic episode can induce resistance to a subsequent severe ischemic injury in the brain. Because of its neuroprotective effects against cerebral ischemia or stroke, ischemic tolerance has been widely studied. However, almost all studies have been performed from the viewpoint of neurons. Glial cells are structurally in close association with synapses. Recent studies have uncovered the active roles of astrocytes in modulating synaptic connectivity, such as synapse formation, elimination and maturation, during development or pathology. However, glia-mediated ischemic tolerance and/or neuronal repairing have received only limited attention. We and others have demonstrated that glial cells, especially astrocytes, play a pivotal role in regulation of induction of ischemic tolerance as well as repairing/remodeling of neuronal networks by phagocytosis. Here, we review our current understanding of (1) glial-mediated ischemic tolerance and (2) glia-mediated repairing/remodeling of the penumbra neuronal networks, and highlight their mechanisms as well as their potential benefits, problems, and therapeutic application.
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Affiliation(s)
- Schuichi Koizumi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
| | - Yuri Hirayama
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
| | - Yosuke M Morizawa
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
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Jones PW, Borich MR, Vavsour I, Mackay A, Boyd LA. Cortical thickness and metabolite concentration in chronic stroke and the relationship with motor function. Restor Neurol Neurosci 2018; 34:733-46. [PMID: 27258945 DOI: 10.3233/rnn-150623] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Hemiparesis is one of the most prevalent chronic disabilities after stroke. Biochemical and structural magnetic resonance imaging approaches may be employed to study the neural substrates underpinning upper-extremity (UE) recovery after chronic stroke. OBJECTIVE The purposes of this study were to 1) quantify anatomical and metabolic differences in the precentral gyrus, and 2) test the relationships between anatomical and metabolic differences, and hemiparetic arm function in individuals in the chronic stage of stroke recovery. Our hypotheses were: 1) the Stroke group would exhibit reduced precentral gyrus cortical thickness and lower concentrations of total N-acetylaspartate (tNAA) and glutamate+glutamine (Glx) in the ipsilesional motor cortex; and 2) that each of these measures would be associated with UE motor function after stroke. METHODS Seventeen individuals with chronic (>6 months) subcortical ischemic stroke and eleven neurologically healthy controls were recruited. Single voxel proton magnetic resonance spectroscopy (H1MRS) was performed to measure metabolite concentrations of tNAA and Glx in the precentral gyrus in both ipsilesional and contralesional hemispheres. Surface-based cortical morphometry was used to quantify precentral gyral thickness. Upper-extremity motor function was assessed using the Wolf Motor Function Test (WMFT). RESULTS Results demonstrated significantly lower ipsilesional tNAA and Glx concentrations and precentral gyrus thickness in the Stroke group. Ipsilesional tNAA and Glx concentration and precentral gyrus thickness was significantly lower in the ipsilesional hemisphere in the Stroke group. Parametric correlation analyses revealed a significant positive relationship between precentral gyrus thickness and tNAA concentration bilaterally. Multivariate regression analyses revealed that ipsilesional concentrations of tNAA and Glx predicted the largest amount of variance in WMFT scores. Cortical thickness measures alone did not predict a significant amount of variance in WMFT scores. CONCLUSION While stroke impairs both structure and biochemistry in the ipsilesional hemisphere our data suggest that tNAA has the strongest relationship with motor function.
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Affiliation(s)
- Paul W Jones
- Graduate Program in Neuroscience, University of British Columbia, Wesbrook Mall, Vancouver, Canada
| | - Michael R Borich
- Division of Physical Therapy, Department of Rehabilitation Medicine, Emory University School of Medicine, Clifton Road NE, Atlanta, Georgia, USA
| | - Irene Vavsour
- Department of Radiology, University of British Columbia, Vancouver, Canada
| | - Alex Mackay
- Department of Physics, University of British Columbia, Agricultural Road, Vancouver, Canada
| | - Lara A Boyd
- Department of Physical Therapy, University of British Columbia, Wesbrook Mall, Vancouver, Canada.,Centre for Brain Health, University of British Columbia, Wesbrook Mall, Vancouver, Canada
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Duris K, Splichal Z, Jurajda M. The Role of Inflammatory Response in Stroke Associated Programmed Cell Death. Curr Neuropharmacol 2018; 16:1365-1374. [PMID: 29473512 PMCID: PMC6251044 DOI: 10.2174/1570159x16666180222155833] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/17/2017] [Accepted: 02/22/2018] [Indexed: 01/13/2023] Open
Abstract
Stroke represents devastating pathology which is associated with a high morbidity and mortality. Initial damage caused directly by the onset of stroke, primary injury, may be eclipsed by secondary injury which may have a much more devastating effect on the brain. Primary injury is predominantly associated with necrotic cell death due to fatal insufficiency of oxygen and glucose. Secondary injury may on the contrary, lead apoptotic cell death due to structural damage which is not compatible with cellular functions or which may even represent the danger of malign transformation. The immune system is responsible for surveillance, defense and healing processes and the immune system plays a major role in triggering programmed cell death. Severe pathologies, such as stroke, are often associated with deregulation of the immune system, resulting in aggravation of secondary brain injury. The goal of this article is to overview the current knowledge about the role of immune system in the pathophysiology of stroke with respect to programmed neuronal cell death as well as to discuss current therapeutic strategies targeting inflammation after stroke.
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Affiliation(s)
| | | | - M. Jurajda
- Address correspondence to this author at the Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic; E-mail:
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Penke B, Fülöp L, Szűcs M, Frecska E. The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases. Curr Neuropharmacol 2018; 16:97-116. [PMID: 28554311 PMCID: PMC5771390 DOI: 10.2174/1570159x15666170529104323] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 04/15/2017] [Accepted: 05/25/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. METHODS Research articles on Sigma-1 receptor were reviewed. RESULTS ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. CONCLUSION Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity.
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Affiliation(s)
- Botond Penke
- University of Szeged, Department of Medical Chemistry, Faculty of Medicine, Szeged, Hungary
| | - Lívia Fülöp
- University of Szeged, Department of Medical Chemistry, Faculty of Medicine, Szeged, Hungary
| | - Mária Szűcs
- University of Szeged, Department of Medical Chemistry, Faculty of Medicine, Szeged, Hungary
| | - Ede Frecska
- University of Debrecen, Department of Psychiatry, Faculty of Medicine, Debrecen, Hungary
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Collina S, Rui M, Stotani S, Bignardi E, Rossi D, Curti D, Giordanetto F, Malacrida A, Scuteri A, Cavaletti G. Are sigma receptor modulators a weapon against multiple sclerosis disease? Future Med Chem 2017; 9:2029-2051. [PMID: 29076758 DOI: 10.4155/fmc-2017-0122] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5 million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS. A pilot study was performed, evaluating the effect of the S1R agonist (R)-RC33 on rat dorsal root ganglia experimental model. The encouraging results support the potential of S1R agonists for MS treatment.
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Affiliation(s)
- Simona Collina
- Department of Drug Sciences, Medicinal Chemistry & Pharmaceutical Technology Section, Centre for Health Technologies (CHT), University of Pavia, Viale Taramelli 12, Pavia 27100, Italy
| | - Marta Rui
- Department of Drug Sciences, Medicinal Chemistry & Pharmaceutical Technology Section, Centre for Health Technologies (CHT), University of Pavia, Viale Taramelli 12, Pavia 27100, Italy
| | - Silvia Stotani
- Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, Dortmund 44227, Germany
| | - Emanuele Bignardi
- Department of Drug Sciences, Medicinal Chemistry & Pharmaceutical Technology Section, Centre for Health Technologies (CHT), University of Pavia, Viale Taramelli 12, Pavia 27100, Italy
| | - Daniela Rossi
- Department of Drug Sciences, Medicinal Chemistry & Pharmaceutical Technology Section, Centre for Health Technologies (CHT), University of Pavia, Viale Taramelli 12, Pavia 27100, Italy
| | - Daniela Curti
- Department of Biology & Biotechnology 'L. Spallanzani', Laboratory of Cellular & Molecular Neuropharmacology, University of Pavia, Via Ferrata 9, Pavia 27100, Italy
| | | | - Alessio Malacrida
- Experimental Neurology Unit, Department of Medicine & Surgery & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, Monza 20900, Italy
| | - Arianna Scuteri
- Experimental Neurology Unit, Department of Medicine & Surgery & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, Monza 20900, Italy
| | - Guido Cavaletti
- Experimental Neurology Unit, Department of Medicine & Surgery & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, Monza 20900, Italy
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Rivera-Carvantes MC, Jarero-Basulto JJ, Feria-Velasco AI, Beas-Zárate C, Navarro-Meza M, González-López MB, Gudiño-Cabrera G, García-Rodríguez JC. Changes in the expression level of MAPK pathway components induced by monosodium glutamate-administration produce neuronal death in the hippocampus from neonatal rats. Neuroscience 2017; 365:57-69. [PMID: 28954212 DOI: 10.1016/j.neuroscience.2017.09.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 09/12/2017] [Accepted: 09/17/2017] [Indexed: 11/18/2022]
Abstract
Excessive Glutamate (Glu) release may trigger excitotoxic cellular death by the activation of intracellular signaling pathways that transduce extracellular signals to the cell nucleus, which determines the onset of a death program. One such signaling pathway is the mitogen-activated protein kinases (MAPK), which is involved in both survival and cell death. Experimental evidences from the use of specific inhibitors supports the participation of some MAPK pathway components in the excitotoxicity mechanism, but the complete process of this activation, which terminates in cell damage and death, is not clearly understood. The present work, we investigated the changes in the expression level of some MAPK-pathway components in hippocampal excitotoxic cell death in the neonatal rats using an experimental model of subcutaneous monosodium glutamate (MSG) administration on postnatal days (PD) 1, 3, 5 and 7. Data were collected at different ages through PD 14. Cell viability was evaluated using fluorescein diacetate mixed with propidium iodide (FDA-PI), and the Nissl-staining technique was used to evaluate histological damage. Transcriptional changes were also investigated in 98 components of the MAPK pathway that are associated with cell damage. These results are an evidence of that repetitive use of MSG, in neonatal rats, induces cell damage-associated transcriptional changes of MAPK components, that might reflect a differential stage of both biochemical and molecular brain maturation. This work also suggests that some of the proteins evaluated such as phosphorylated retinoblastoma (pRb) protein, which was up-regulated, could regulate the response to excitotoxic through modulation of the process of re-entry into the cell cycle in the hippocampus of rats treated with MSG.
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Affiliation(s)
- Martha Catalina Rivera-Carvantes
- Cellular Neurobiology Laboratory, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Zapopan, Jal., Mexico.
| | - José Jaime Jarero-Basulto
- Cellular Neurobiology Laboratory, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Zapopan, Jal., Mexico
| | - Alfredo Ignacio Feria-Velasco
- Cellular Neurobiology Laboratory, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Zapopan, Jal., Mexico
| | - Carlos Beas-Zárate
- Regeneration and Neural Development Laboratory, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Zapopan, Jal., Mexico
| | - Mónica Navarro-Meza
- Department of Health and Wellness, CUSur, University of Guadalajara, Ciudad Guzman, Jal., Mexico
| | - Mariana Berenice González-López
- Cellular Neurobiology Laboratory, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Zapopan, Jal., Mexico
| | - Graciela Gudiño-Cabrera
- Regeneration and Neural Development Laboratory, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Zapopan, Jal., Mexico
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Drugs to Alter Extracellular Concentration of Glutamate: Modulators of Glutamate Uptake Systems. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-1-4939-7228-9_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Gribkoff VK, Kaczmarek LK. The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology 2017; 120:11-19. [PMID: 26979921 PMCID: PMC5820030 DOI: 10.1016/j.neuropharm.2016.03.021] [Citation(s) in RCA: 236] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 02/14/2016] [Accepted: 03/11/2016] [Indexed: 12/31/2022]
Abstract
An important goal of biomedical research is to translate basic research findings into useful medical advances. In the field of neuropharmacology this requires understanding disease mechanisms as well as the effects of drugs and other compounds on neuronal function. Our hope is that this information will result in new or improved treatment for CNS disease. Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. As a result, CNS drug discovery and development programs have been subjected to significant cutbacks and eliminations over the last decade. While there has been recent resurgence of interest in CNS targets, these past changes in priority of the pharmaceutical and biotech industries reflect several well-documented realities. CNS drugs in general have higher failure rates than non-CNS drugs, both preclinically and clinically, and in some areas, such as the major neurodegenerative diseases, the clinical failure rate for disease-modifying treatments has been 100%. The development times for CNS drugs are significantly longer for those drugs that are approved, and post-development regulatory review is longer. In this introduction we review some of the reasons for failure, delineating both scientific and technical realities, some unique to the CNS, that have contributed to this. We will focus on major neurodegenerative disorders, which affect millions, attract most of the headlines, and yet have witnessed the fewest successes. We will suggest some changes that, when coupled with the approaches discussed in the rest of this special volume, may improve outcomes in future CNS-targeted drug discovery and development efforts. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders".
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Affiliation(s)
- Valentin K Gribkoff
- Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
| | - Leonard K Kaczmarek
- Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Muengtaweepongsa S, Srivilaithon W. Targeted temperature management in neurological intensive care unit. World J Methodol 2017; 7:55-67. [PMID: 28706860 PMCID: PMC5489424 DOI: 10.5662/wjm.v7.i2.55] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/12/2017] [Accepted: 05/18/2017] [Indexed: 02/06/2023] Open
Abstract
Targeted temperature management (TTM) shows the most promising neuroprotective therapy against hypoxic/ischemic encephalopathy (HIE). In addition, TTM is also useful for treatment of elevated intracranial pressure (ICP). HIE and elevated ICP are common catastrophic conditions in patients admitted in Neurologic intensive care unit (ICU). The most common cause of HIE is cardiac arrest. Randomized control trials demonstrate clinical benefits of TTM in patients with post-cardiac arrest. Although clinical benefit of ICP control by TTM in some specific critical condition, for an example in traumatic brain injury, is still controversial, efficacy of ICP control by TTM is confirmed by both in vivo and in vitro studies. Several methods of TTM have been reported in the literature. TTM can apply to various clinical conditions associated with hypoxic/ischemic brain injury and elevated ICP in Neurologic ICU.
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Geng LY, Qian FY, Qian JF, Zhang ZJ. The combination of plasma glutamate and physical impairment after acute stroke as a potential indicator for the early-onset post-stroke depression. J Psychosom Res 2017; 96:35-41. [PMID: 28545791 DOI: 10.1016/j.jpsychores.2017.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 12/21/2016] [Accepted: 01/07/2017] [Indexed: 12/11/2022]
Abstract
OBJECTS The present study aimed to investigate the relationship of plasma glutamate levels with the early-onset of post-stroke depression (PSD) and to further explore the prognostic value of plasma glutamate combined with clinical characteristics for the early-onset PSD in the acute ischemic stroke patients. METHODS Seventy-four patients who admitted to the hospital within 24h of acute ischemic stroke were consecutively recruited and followed up for 2weeks. The Beck Depression Inventory (BDI) and 17-item Hamilton Depression Rating Scale (HAMD-17) were used to screen for depressive symptoms 14days after stroke. Diagnoses of depression were made in accordance with DSM-IV. Plasma glutamate levels were determined by High Performance Liquid Chromatography (HPLC) on days 1 and 14 after stroke for all patients. RESULTS Plasma glutamate levels were significantly lower in PSD patients than those of non-PSD patients on day 1 after stroke. ROC curve analyses revealed an AUC (area under the ROC curve) of 0.724 (95% CI: 0.584-0.863, p=0.004) and of 0.669 (95% CI: 0.523-0.814, p=0.030) for National Institute of Health Stroke Scale (NIHSS) scores and plasma glutamate levels on day 1 respectively. Combined ROC analyses using the two factors revealed the highest AUC of 0.804 (95% CI: 0.685-0.922, P<0.0001). CONCLUSIONS These results indicated an association between the early-onset PSD and a low plasma glutamate level following acute ischemic stroke. The combination of reduced plasma glutamate levels and physical impairment (determined by NIHSS) 1day after acute ischemic stroke was a potential diagnostic indicator for early-onset PSD.
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Affiliation(s)
- Lei-Yu Geng
- Neurologic Department of Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
| | - Fang-Yuan Qian
- Neurologic Department of Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
| | - Jun-Feng Qian
- Neurologic Department of Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
| | - Zhi-Jun Zhang
- Neurologic Department of Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
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Abstract
The human brain requires uninterrupted delivery of blood-borne oxygen and nutrients to sustain its function. Focal ischemia, particularly, ischemic stroke, and global ischemia imposed by cardiac arrest disrupt the brain's fuel supply. The resultant ATP depletion initiates a complex injury cascade encompassing intracellular Ca2+ overload, glutamate excitotoxicity, oxido-nitrosative stress, extracellular matrix degradation, and inflammation, culminating in neuronal and astroglial necrosis and apoptosis, neurocognitive deficits, and even death. Unfortunately, brain ischemia has proven refractory to pharmacological intervention. Many promising treatments afforded brain protection in animal models of focal and global ischemia, but failed to improve survival and neurocognitive recovery of stroke and cardiac arrest patients in randomized clinical trials. The culprits are the blood-brain barrier (BBB) that limits transferral of medications to the brain parenchyma, and the sheer complexity of the injury cascade, which presents a daunting array of targets unlikely to respond to monotherapies. Erythropoietin is a powerful neuroprotectant capable of interrupting multiple aspects of the brain injury cascade. Preclinical research demonstrates erythropoietin's ability to suppress glutamate excitotoxicity and intracellular Ca2+ overload, dampen oxidative stress and inflammation, interrupt the apoptotic cascade, and preserve BBB integrity. However, the erythropoietin dosages required to traverse the BBB and achieve therapeutically effective concentrations in the brain parenchyma impose untoward side effects. Recent discoveries that hypoxia induces erythropoietin production within the brain and that neurons, astroglia, and cerebrovascular endothelium harbor membrane erythropoietin receptors, raise the exciting prospect of harnessing endogenous erythropoietin to protect the brain from the ravages of ischemia-reperfusion.
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Affiliation(s)
- Robert T Mallet
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, United States.
| | - Myoung-Gwi Ryou
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, United States; Tarleton State University, Fort Worth, TX, United States
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