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Jiang AJ, Wei HR, Chu S, Wang M, Yan J, Song XL, Xu TL, Zhang Z, Jin Y, Wang W. Upregulation of Acid-Sensing Ion Channel 1a in the Anterior Cingulate Cortex by TNF-α/NF-κB Pathway Contributes to Diabetes-Related Pain. Diabetes 2025; 74:1007-1020. [PMID: 40131336 DOI: 10.2337/db24-0847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
Effective treatment strategies for diabetes-related pain are limited because of its complex pathogenesis, particularly brain mechanisms underlying this disease. The acid-sensing ion channel 1a (ASIC1a) has emerged as a key player in the development and treatment of various types of pain. We investigated the role of ASIC1a in diabetes-related pain and its molecular mechanisms in the anterior cingulate cortex (ACC). Our findings demonstrate that the upregulation of ASIC1a expression drives enhanced activity of excitatory glutamatergic neurons in the ACC (ACCGlu), promoting the development of pain hypersensitivity in streptozotocin (STZ)-induced diabetic male mice. Pharmacologic inhibition and genetic knockout of ASIC1a in ACCGlu neurons significantly reduced neuronal activity and alleviated mechanical and thermal pain sensitizations in STZ-induced diabetes. Furthermore, increased levels of tumor necrosis factor-α (TNF-α) in the ACC upregulated ASIC1a by triggering nuclear factor-κB (NF-κB) pathways, which led to the development of diabetes-related pain. Notably, the clinically used medication, infliximab, exhibited therapeutic effects on diabetes-related pain via its influence on TNF-α/NF-κB/ASIC1a pathway in STZ-treated mice. Collectively, this study identifies ASIC1a as a potential therapeutic target for diabetes-related pain and shows the neutralization of TNF-α leads to pain relief through the TNF-α/NF-κB/ASIC1a pathway in the ACC. These findings hold promise for the development of new clinical therapeutic strategies for diabetes-related pain. ARTICLE HIGHLIGHTS Upregulation of acid-sensing ion channel 1a (ASIC1a) expression in anterior cingulate cortex (ACC) glutamatergic (ACCGlu) neurons drives diabetes-related pain hypersensitivity in mice, and pharmacologic inhibition and genetic knockout of ASIC1a in ACCGlu neurons significantly reduce neuronal hyperactivity and alleviate pain. Tumor necrosis factor-α/nuclear factor-κB signaling in the ACC elevates ASIC1a expression, mechanistically linking neuroinflammation to pain development in diabetic mice. ASIC1a is a potential therapeutic target for diabetes-related pain, offering a pathway-specific strategy for treatment development.
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Affiliation(s)
- Ai-Jun Jiang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of the Institute of Health and Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hong-Rui Wei
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine, Institute of Health and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Sijia Chu
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of the Institute of Health and Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mengyuan Wang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of the Institute of Health and Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jinling Yan
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of the Institute of Health and Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xing-Lei Song
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Anesthesiology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian-Le Xu
- Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Anesthesiology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi Zhang
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine, Institute of Health and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, China
- Center for Advanced Interdisciplinary Science and Biomedicine, Institute of Health and Medicine, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yan Jin
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of the Institute of Health and Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Zheng XZ, Yu HY, Chen YR, Fang JS. Aucubin mitigates the elevation of microglial aerobic glycolysis and inflammation in diabetic neuropathic pain via aldose reductase. World J Diabetes 2025; 16:103915. [DOI: 10.4239/wjd.v16.i5.103915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/26/2025] [Accepted: 02/24/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Treatment of diabetic neuropathy is often limited by side effects. Aucubin, an iridoid glycoside derived from natural plants, exhibits notable anti-inflammatory and antioxidant properties.
AIM To investigate the effects of aucubin on diabetic neuropathic pain (DNP) and glycolysis and inflammation in microglia.
METHODS Streptozotocin (STZ) was used to establish a DNP animal model. Blood glucose levels and body weight of mice were measured following STZ administration. Paw withdrawal threshold was calculated for mechanical allodynia. Paw withdrawal latency was recorded for thermal hyperalgesia. The open field test and elevated plus maze was used to assess locomotor activity and anxiety-like behavior. Western blotting was utilized for analysis of protein expression. Immunofluorescence staining was measured for morphometric analysis of microglia. Glycolysis and ATP synthesis in BV-2 cell lines were detected by metabolic extracellular flux analysis. The SwissTargetPrediction and STRING databases were used for comprehensive screening to identify potential target proteins for aucubin. The molecular docking between the possible target proteins and aucubin was investigated using Auto Dock Tool. The BV-2 cell line was transfected with lentiviral AKR1B1-shRNA to further ascertain the function of AKR1B1 in the impact of aucubin on aerobic glycolysis and inflammation during high glucose stimulation.
RESULTS Aucubin significantly improved pain and anxiety-like behavior in STZ-induced diabetic mice and restored microglial aerobic glycolysis and inflammation. Several public databases and molecular docking studies suggested that AKR1B1, MMP2 and MMP9 are involved in the effect of aucubin on DNP. Aucubin failed to restore aerobic glycolysis and inflammation in the context of AKR1B1 deficiency.
CONCLUSION Aucubin has potential as a therapeutic agent for alleviating DNP by inhibiting expression of AKR1B1.
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Affiliation(s)
- Xue-Zhen Zheng
- Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
| | - Hong-Yan Yu
- Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
| | - Ye-Ru Chen
- Department of Anaesthesiology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou 310058, Zhejiang Province, China
| | - Jian-Sheng Fang
- Department of Anesthesiology, The First People's Hospital of Chun'an County, Hangzhou 311700, Zhejiang Province, China
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Zhang K, Ran R, Zhang CJ, Wang L, Zhang HH. Focus on P2X7R in microglia: its mechanism of action and therapeutic prospects in various neuropathic pain models. Front Pharmacol 2025; 16:1555732. [PMID: 40201695 PMCID: PMC11975881 DOI: 10.3389/fphar.2025.1555732] [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: 01/05/2025] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
Neuropathic pain (NP) is a common symptom of many diseases and is caused by direct or indirect damage to the nervous system. Tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors are typical drugs used in clinical practice to suppress pain. However, these drugs have drawbacks, including a short duration of action, a limited analgesic effect, and possible dependence and side effects. Therefore, developing more effective NP treatment strategies has become a priority in medical research and has attracted much research attention. P2X7 receptor (P2X7R) is a non-selective cation channel activated by adenosine triphosphate and is mainly expressed in microglia in the central nervous system. Microglial P2X7R plays an important role in pain regulation, suggesting that it could be a potential target for drug development. This review comprehensively and objectively discussed the latest research progress of P2X7R, including its structural characteristics, functional properties, relationship with microglial activation and polarization, mechanism of action, and potential therapeutic strategies in multiple NP models. This study aimed to provide in-depth insights into the association between P2X7R and NP and explore the mechanism of action of P2X7R in the pathological process of NP and the translational potential and clinical application prospects of P2X7R antagonists in pain treatment, providing a scientific basis for the precise treatment of NP.
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Affiliation(s)
- Kai Zhang
- Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou, China
- Orthopedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Rui Ran
- Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou, China
- Orthopedics Key Laboratory of Gansu Province, Lanzhou, China
| | | | - Linna Wang
- Lanzhou Biotechnique Development Co., Ltd., Lanzhou, China
| | - Hai-Hong Zhang
- Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou, China
- Orthopedics Key Laboratory of Gansu Province, Lanzhou, China
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Zhang P, Wang C, Li C, Wang J. miR-34a-5p Predicts the Risk of Diabetic Neuropathic Pain and Mediates Neuroinflammation in Microglia via Targeting ENPP3. Immunol Invest 2024; 53:1348-1358. [PMID: 39252196 DOI: 10.1080/08820139.2024.2400550] [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] [Indexed: 09/11/2024]
Abstract
INTRODUCTION The pathogenesis of diabetic neuropathic pain (DNP) is complex involving various processes, which need exploring reliable biomarkers for its early detection and severity prediction. METHODS Study enrolled 181 patients diagnosed with diabetes, among which 74 patients developed DNP. Serum miR-34a-5p levels were compared between DNP patients and non-DNP patients by polymerase chain reaction (PCR), and the potential of miR-34a-5p in predicting the risk and discriminating patients with DNP was evaluated. The regulatory effect of miR-34a-5p on the inflammation, proliferation, and polarization of microglia was evaluated in HMC3 cells treated with high glucose. RESULTS Upregulated miR-34a-5p was identified as a risk factor and discriminated DNP patients miR-34a-5p was positively correlated with the levels of triglyceride (r = 0.797), fasting blood glucose (r = 0.840), and glycated hemoglobin (r = 0.894) of DNP patients. In HMC3 cells, the high-glucose-induced inflammation, promoted cell growth and caused polarization. The knockdown of miR-34a-5p showed the significant protective effect of microglia activation by high glucose, which was reversed by silencing ENPP3. DISCUSSION miR-34a-5p served as a biomarker for the prediction and early detection of DNP and mediated microglia inflammation caused by DNP via modulating ENPP3.
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Affiliation(s)
- Peiguo Zhang
- Department of Pain, Zibo Central Hospital, Zibo, China
| | - Chenghua Wang
- Department of Neurology, Zibo Central Hospital, Zibo, China
| | - Chengxia Li
- Department of Neurosurgery, Zibo Central Hospital, Zibo, China
| | - Jing Wang
- Department of Radiology, Zibo Central Hospital, Zibo, China
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Asiri YI, Moni SS, Ramar M, Chidambaram K. Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings. Pharmaceuticals (Basel) 2024; 17:1439. [PMID: 39598351 PMCID: PMC11597627 DOI: 10.3390/ph17111439] [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: 07/21/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024] Open
Abstract
Despite major advancements in our understanding of its fundamental causes, pain-both acute and chronic-remains a serious health concern. Various preclinical investigations utilizing diverse animal, cellular, and alternative models are required and frequently demanded by regulatory approval bodies to bridge the gap between the lab and the clinic. Investigating naturally occurring painful disorders can speed up medication development at the preclinical and clinical levels by illuminating molecular pathways. A wide range of animal models related to pain have been developed to elucidate pathophysiological mechanisms and aid in identifying novel targets for treatment. Pain sometimes drugs fail clinically, causing high translational costs due to poor selection and the use of preclinical tools and reporting. To improve the study of pain in a clinical context, researchers have been creating innovative models over the past few decades that better represent pathological pain conditions. In this paper, we provide a summary of traditional animal models, including rodents, cellular models, human volunteers, and alternative models, as well as the specific characteristics of pain diseases they model. However, a more rigorous approach to preclinical research and cutting-edge analgesic technologies may be necessary to successfully create novel analgesics. The research highlights from this review emphasize new opportunities to develop research that includes animals and non-animals using proven methods pertinent to comprehending and treating human suffering. This review highlights the value of using a variety of modern pain models in animals before human trials. These models can help us understand the different mechanisms behind various pain types. This will ultimately lead to the development of more effective pain medications.
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Affiliation(s)
- Yahya I. Asiri
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia;
| | - Sivakumar S. Moni
- Health Research Centre, Jazan University, Jazan 45142, Saudi Arabia;
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Mohankumar Ramar
- Department of Pharmaceutical Sciences, UConn School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA;
| | - Kumarappan Chidambaram
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia;
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Mittal R, McKenna K, Keith G, McKenna E, Sinha R, Lemos JRN, Hirani K. Systematic review of translational insights: Neuromodulation in animal models for Diabetic Peripheral Neuropathy. PLoS One 2024; 19:e0308556. [PMID: 39116099 PMCID: PMC11309513 DOI: 10.1371/journal.pone.0308556] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/23/2024] [Indexed: 08/10/2024] Open
Abstract
Diabetic Peripheral Neuropathy (DPN) is a prevalent and debilitating complication of diabetes, affecting a significant proportion of the diabetic population. Neuromodulation, an emerging therapeutic approach, has shown promise in the management of DPN symptoms. This systematic review aims to synthesize and analyze the current advancements in neuromodulation techniques for the treatment of DPN utilizing studies with preclinical animal models. A comprehensive search was conducted across multiple databases, including PubMed, Scopus, and Web of Science. Inclusion criteria were focused on studies utilizing preclinical animal models for DPN that investigated the efficacy of various neuromodulation techniques, such as spinal cord stimulation, transcranial magnetic stimulation, and peripheral nerve stimulation. The findings suggest that neuromodulation significantly alleviated pain symptoms associated with DPN. Moreover, some studies reported improvements in nerve conduction velocity and reduction in nerve damage. The mechanisms underlying these effects appeared to involve modulation of pain pathways and enhancement of neurotrophic factors. However, the review also highlights the variability in methodology and stimulation parameters across studies, highlighting the need for standardization in future research. Additionally, while the results are promising, the translation of these findings from animal models to human clinical practice requires careful consideration. This review concludes that neuromodulation presents a potentially effective therapeutic strategy for DPN, but further research is necessary to optimize protocols and understand the underlying molecular mechanisms. It also emphasizes the importance of bridging the gap between preclinical findings and clinical applications to improve the management of DPN in diabetic patients.
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Affiliation(s)
- Rahul Mittal
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Keelin McKenna
- Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America
| | - Grant Keith
- School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Evan McKenna
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Rahul Sinha
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Joana R. N. Lemos
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Khemraj Hirani
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
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Jali AM, Banji D, Banji OJF, Hurubi KY, Tawhari FY, Alameer AA, Dohal AS, Zanqoti RA. Navigating Preclinical Models and Medications for Peripheral Neuropathy: A Review. Pharmaceuticals (Basel) 2024; 17:1010. [PMID: 39204115 PMCID: PMC11357099 DOI: 10.3390/ph17081010] [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: 06/13/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/03/2024] Open
Abstract
Peripheral neuropathy (PN) is a multifaceted disorder characterised by peripheral nerve damage, manifesting in symptoms like pain, weakness, and autonomic dysfunction. This review assesses preclinical models in PN research, evaluating their relevance to human disease and their role in therapeutic development. The Streptozotocin (STZ)-induced diabetic rat model is widely used to simulate diabetic neuropathy but has limitations in faithfully replicating disease onset and progression. Cisplatin-induced PN models are suitable for studying chemotherapy-induced peripheral neuropathy (CIPN) and closely resemble human pathology. However, they may not fully replicate the spectrum of sensory and motor deficits. Paclitaxel-induced models also contribute to understanding CIPN mechanisms and testing neuroprotective agents. Surgical or trauma-induced models offer insights into nerve regeneration and repair strategies. Medications such as gabapentin, pregabalin, duloxetine, and fluoxetine have demonstrated promise in these models, enhancing our understanding of their therapeutic efficacy. Despite progress, developing models that accurately mirror human PN remains imperative due to its complex nature. Continuous refinement and innovative approaches are critical for effective drug discovery. This review underscores the strengths and limitations of current models and advocates for an integrated approach to address the complexities of PN better and optimise treatment outcomes.
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Affiliation(s)
- Abdulmajeed M. Jali
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
| | - David Banji
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
| | - Otilia J. F. Banji
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Khalid Y. Hurubi
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
| | - Faisal Y. Tawhari
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
| | - Atheer A. Alameer
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
| | - Atyaf S. Dohal
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
| | - Raha A. Zanqoti
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; (D.B.); (K.Y.H.); (F.Y.T.); (A.A.A.); (A.S.D.); (R.A.Z.)
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Zhang T, Wang L, Chen L. Alleviative effect of microRNA-497 on diabetic neuropathic pain in rats in relation to decreased USP15. Cell Biol Toxicol 2023; 39:1-16. [PMID: 35478295 DOI: 10.1007/s10565-022-09702-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/11/2022] [Indexed: 11/02/2022]
Abstract
The current study tries to discuss the functional role of microRNA-497 (miR-497) in diabetic neuropathic pain (DNP) and the related downstream mechanism. Bioinformatics analysis was implemented for the identification of differentially expressed miRNAs and genes. DNP was simulated in rats through intraperitoneal injection of streptozotocin. The expression patterns of miR-497, USP15, NRF2, and G6PD were then determined. The binding of miR-497 and USP15 was confirmed. Using gain- and loss-of-function assays, we analyzed the critical role of miR-497-mediated USP15 in DNP through the NRF2/G6PD axis. Downregulated miR-497 and elevated USP15 were observed in the dorsal root ganglion neurons isolated from spinal cord tissues of STZ-induced DNP rats. miR-497 could alleviate DNP, which was associated with suppression of USP15, a confirmed target of miR-497. USP15 enhanced the degradation and ubiquitination of NRF2 and induced G6PD expression, leading to the progression of DNP. We highlighted the crucial role of miR-497-mediated USP15 in DNP through the NRF2/G6PD axis. 1. miR-497 is downregulated in DRG neurons from spinal cord tissues of STZ-induced DNP rats. 2. miR-497 inhibits the expression of USP15, thereby alleviating STZ-induced DNP in rats. 3. USP15 promotes ubiquitination and degradation of NRF2, reducing the expression of G6PD. 4. miR-497 alleviates STZ-induced DNP in rats by regulating the USP15/NRF2/G6PD axis.
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Affiliation(s)
- Tonghui Zhang
- Emergency Department, Liaoning Health Industry Group Fukuang General Hospital, Fushun, 113008, People's Republic of China
| | - Ling Wang
- Department of Endocrinology, Liaoning Health Industry Group Fukuang General Hospital, Fushun, 113008, People's Republic of China
| | - Ling Chen
- Department of Endocrinology, The First Affiliated Hospital of Jinzhou Medical University, No.2, Section 5, Renmin Street, Jinzhou, 121000, Liaoning Province, People's Republic of China.
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Alharthy KM, Balaha MF, Devi S, Altharawi A, Yusufoglu HS, Aldossari RM, Alam A, di Giacomo V. Ameliorative Effects of Isoeugenol and Eugenol against Impaired Nerve Function and Inflammatory and Oxidative Mediators in Diabetic Neuropathic Rats. Biomedicines 2023; 11:1203. [PMID: 37189822 PMCID: PMC10135797 DOI: 10.3390/biomedicines11041203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/08/2023] [Accepted: 04/10/2023] [Indexed: 05/17/2023] Open
Abstract
Diabetic polyneuropathy is characterized by structural abnormalities, oxidative stress, and neuroinflammation. The current study aimed to determine the antinociceptive effects of isoeugenol and eugenol and their combinations in neuropathic pain resulting from streptozotocin (STZ)-induced diabetes and neuroinflammation. Female SD rats were categorized into normal control, diabetic control, and treatment groups. On the 28th day and 45th day, behavioral studies (allodynia and hyperalgesia) were performed to analyze the development and protection of diabetic polyneuropathy. The levels of inflammatory and oxidative mediators, such as superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), catalase, reduced glutathione, and thiobarbituric acid reactive substances (TBARS), were estimated. In addition, the level of nerve growth factor (NGF) was estimated at the end of the study in different groups. The anti-NGF treatment decreased its upregulation in the dorsal root ganglion significantly. The results showed that isoeugenol, eugenol, and their combination have therapeutic potential against neuronal and oxidative damage induced by diabetes. In particular, both compounds significantly affected behavioral function in treated rats and showed neuroprotection against diabetic neuropathy, and their combination had synergistic effects.
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Affiliation(s)
- Khalid M. Alharthy
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (K.M.A.); (R.M.A.)
| | - Mohamed F. Balaha
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
- Pharmacology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
| | - Sushma Devi
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India;
| | - Ali Altharawi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Hasan S. Yusufoglu
- Department of Pharmacognosy & Pharmaceutical Chemistry, College of Dentistry & Pharmacy, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia;
| | - Rana M. Aldossari
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (K.M.A.); (R.M.A.)
| | - Aftab Alam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Viviana di Giacomo
- Department of Pharmacy, “Gabriele d’Annunzio” University, Via dei Vestini 31, 66100 Chieti, Italy;
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Jadhav VB, Vaghela JS. Sphaeranthus indicus Linn ameliorates streptozotocin-induced experimental diabetic neuropathy by targeting oxidative stress-mediated alterations. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-022-00444-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Abstract
Background
Diabetes-induced neuropathic pain is manifested as a lowering of nerve transmission rate, increased discomfort, sensual loss, and axonal degradation, and is the most prevalent secondary consequence of diabetes. Diabetes is a devitalizing disease affecting people from diverse groups in both developing and industrialized countries. The inflammation pathway and oxidative stress both contribute considerably to diabetic peripheral neuropathy via the activation of inflammatory cytokines. Hyperglycemia-mediated neural oxidative stress and damage activates a number of metabolic pathways, causing diabetic neuropathy. The current study investigated the neuroprotective potential of methanolic extract of Sphaeranthus indicus Linn (MESI) in ameliorating diabetic neuropathic pain induced by administration of streptozotocin in rats.
Results
Four weeks after intraperitoneal treatment of streptozotocin (STZ), there was a significant decrease in mechano-tactile allodynia and mechanical and thermal hyperalgesia. Furthermore, STZ-induced oxidative stress increases the extent of neural lipid peroxidation (LPO), as evidenced by increased MDA levels, decreases the activities of endogenous antioxidants such as superoxide dismutase (SOD) and glutathione (GSH), and alters sciatic neural histoarchitecture. Chronic administration of methanolic extract of Sphaeranthus indicus Linn (MESI) for 4 weeks significantly and dose-dependently attenuated the decrease in levels of nociceptive thresholds, endogenous antioxidants (SOD and GSH), and increase in LPO. Furthermore, MESI significantly restored sciatic neural histoarchitecture.
Conclusion
The amelioration of streptozotocin-induced diabetic neuropathy by methanolic extract of Sphaeranthus indicus Linn (MESI) could be attributed to its antinociceptive, antioxidant, and neuroprotective properties.
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11
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Kan HW, Ho YC, Chang YS, Hsieh YL. SEPT9 Upregulation in Satellite Glial Cells Associated with Diabetic Polyneuropathy in a Type 2 Diabetes-like Rat Model. Int J Mol Sci 2022; 23:ijms23169372. [PMID: 36012625 PMCID: PMC9409324 DOI: 10.3390/ijms23169372] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Despite the worldwide prevalence and severe complications of type 2 diabetes mellitus (T2DM), the pathophysiological mechanisms underlying the development of diabetic polyneuropathy (DPN) are poorly understood. Beyond strict control of glucose levels, clinical trials for reversing DPN have largely failed. Therefore, understanding the pathophysiological and molecular mechanisms underlying DPN is crucial. Accordingly, this study explored biochemical and neuropathological deficits in a rat model of T2DM induced through high-fat diet (HFD) feeding along with two low-dose streptozotocin (STZ) injections; the deficits were explored through serum lipid, neurobehavioral, neurophysiology, neuropathology, and immunohistochemistry examinations. Our HFD/STZ protocol induced (1) mechanical hyperalgesia and depression-like behaviors, (2) loss of intraepidermal nerve fibers (IENFs) and reduced axonal diameters in sural nerves, and (3) decreased compound muscle action potential. In addition to hyperglycemia, which was correlated with the degree of mechanical hyperalgesia and loss of IENFs, we observed that hypertriglyceridemia was the most dominant deficit in the lipid profiles of the diabetic rats. In particular, SEPT9, the fourth component of the cytoskeleton, increased in the satellite glial cells (SGCs) of the dorsal root ganglia (DRG) in the T2DM-like rats. The number of SEPT9(+) SGCs/DRG was correlated with serum glucose levels and mechanical thresholds. Our findings indicate the putative molecular mechanism underlying DPN, which presumably involves the interaction of SGCs and DRG neurons; nevertheless, further functional research is warranted to clarify the role of SEPT9 in DPN.
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Affiliation(s)
- Hung-Wei Kan
- School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
- Correspondence: (H.-W.K.); (Y.-L.H.); Tel.: +886-7-6151100 (H.-W.K.); +886-7-3121101 (Y.-L.H.)
| | - Yu-Cheng Ho
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
| | - Ying-Shuang Chang
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yu-Lin Hsieh
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Correspondence: (H.-W.K.); (Y.-L.H.); Tel.: +886-7-6151100 (H.-W.K.); +886-7-3121101 (Y.-L.H.)
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12
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Sasajima S, Kondo M, Ohno N, Ujisawa T, Motegi M, Hayami T, Asano S, Asano-Hayami E, Nakai-Shimoda H, Inoue R, Yamada Y, Miura-Yura E, Morishita Y, Himeno T, Tsunekawa S, Kato Y, Nakamura J, Kamiya H, Tominaga M. Thermal gradient ring reveals thermosensory changes in diabetic peripheral neuropathy in mice. Sci Rep 2022; 12:9724. [PMID: 35697861 PMCID: PMC9192750 DOI: 10.1038/s41598-022-14186-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 05/18/2022] [Indexed: 12/03/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) includes symptoms of thermosensory impairment, which are reported to involve changes in the expression or function, or both, of nociceptive TRPV1 and TRPA1 channels in rodents. In the present study, we did not find changes in the expression or function of TRPV1 or TRPA1 in DPN mice caused by STZ, although thermal hypoalgesia was observed in a murine model of DPN or TRPV1−/− mice with a Plantar test, which specifically detects temperature avoidance. With a Thermal Gradient Ring in which mice can move freely in a temperature gradient, temperature preference can be analyzed, and we clearly discriminated the temperature-dependent phenotype between DPN and TRPV1−/− mice. Accordingly, we propose approaches with multiple behavioral methods to analyze the progression of DPN by response to thermal stimuli. Attention to both thermal avoidance and preference may provide insight into the symptoms of DPN.
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Affiliation(s)
- Sachiko Sasajima
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.,Division of Cell Signaling, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan
| | - Masaki Kondo
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
| | - Nobuhiko Ohno
- Department of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.,Division of Ultrastructural Research, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan
| | - Tomoyo Ujisawa
- Division of Cell Signaling, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.,Thermal Biology Group, Exploratory Research Center on Life and Living Systems (ExCELLS), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan
| | - Mikio Motegi
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Tomohide Hayami
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Saeko Asano
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Emi Asano-Hayami
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Hiromi Nakai-Shimoda
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Rieko Inoue
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yuichiro Yamada
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Emiri Miura-Yura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yoshiaki Morishita
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Tatsuhito Himeno
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Shin Tsunekawa
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yoshiro Kato
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Jiro Nakamura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.,Department of Innovative Diabetes Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan. .,Thermal Biology Group, Exploratory Research Center on Life and Living Systems (ExCELLS), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan. .,Department of Physiological Sciences, Sokendai, Okazaki, Japan.
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13
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Antinociceptive and Antiallodynic Activity of Some 3-(3-Methylthiophen-2-yl)pyrrolidine-2,5-dione Derivatives in Mouse Models of Tonic and Neuropathic Pain. Int J Mol Sci 2022; 23:ijms23074057. [PMID: 35409413 PMCID: PMC8999233 DOI: 10.3390/ijms23074057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 11/16/2022] Open
Abstract
Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds 3, 4, 6, and 9), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely 3, 6, and 9, demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound 3 attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound 3 did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal (i.p.) injection.
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14
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Hossain MJ, Kendig MD, Letton ME, Morris MJ, Arnold R. Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions. Diabetes Metab J 2022; 46:198-221. [PMID: 35385634 PMCID: PMC8987683 DOI: 10.4093/dmj.2021.0347] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/25/2022] [Indexed: 11/08/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the 'Neurodiab' criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.
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Affiliation(s)
- Md Jakir Hossain
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Michael D. Kendig
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Meg E. Letton
- Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Margaret J. Morris
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Ria Arnold
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
- Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
- Department of Exercise and Rehabilitation, School of Medical, Indigenous and Health Science, University of Wollongong, Wollongong, Australia
- Corresponding author: Ria Arnold https://orcid.org/0000-0002-7469-6587 Department of Exercise Physiology, School of Health Sciences, UNSW Sydney, Sydney, NSW 2052, Australia E-mail:
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15
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Chanda D, Ray S, Chakraborti D, Sen S, Mitra A. Interleukin-6 Levels in Patients With Diabetic Polyneuropathy. Cureus 2022; 14:e21952. [PMID: 35155045 PMCID: PMC8820488 DOI: 10.7759/cureus.21952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2022] [Indexed: 11/30/2022] Open
Abstract
Introduction Diabetic polyneuropathy (DPN) is a common chronic complication of type 2 diabetes. The pathogenesis of DPN is still debated, but proinflammatory cytokine mediators like interleukin-6 (IL-6) are possibly involved. We conducted this cross-sectional observational study to assess whether IL-6 levels increase in patients with DPN. Materials and methods This study was conducted at the Institute of Post Graduate Medical Education and Research Hospital in Kolkata, India, from 2016 to 2017. The study included 57 patients aged 30 to 60 years diagnosed with type 2 diabetes with neuropathy on clinical examination and nerve conduction study. Patients with neuropathy due to other causes were excluded. The study participants were assigned into one of four groups. Group 1 (n=15) served as healthy control patients, Group 2 (n=12) contained patients with type 2 diabetes without neuropathy, Group 3 (n=20) contained patients with type 2 diabetes with painful neuropathy, and Group 4 (n=10) contained patients with type 2 diabetes with painless neuropathy. We compared IL-6 levels between each group. Results There was no significant difference in serum IL-6 levels between healthy controls (Group 1) and patients with type 2 diabetes without neuropathy (Group 2). However, we noted a significant increase in serum IL-6 levels among patients with painful DPN (Group 3) compared to control groups. Interestingly, serum IL-6 levels were higher in patients with painful DPN (Group 3) than patients with painless DPN (Group 4). Conclusions IL-6 increases significantly in painful diabetic neuropathy patients compared to patients with diabetes with painless neuropathy and thus may have a role in the pathogenesis of pain in DPN. Serum IL6 level can be a potential noninvasive marker of painful DPN, and it can help distinguish painful DPN from other causes of pain in patients with diabetes.
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Affiliation(s)
- Debarati Chanda
- Physiology, Jagannath Gupta Institute of Medical Science and Hospital, Kolkata, IND
| | - Saswati Ray
- Physiology, Jagannath Gupta Institute of Medical Science and Hospital, Kolkata, IND
| | - Debjani Chakraborti
- Physiology, Jagannath Gupta Institute of Medical Science and Hospital, Kolkata, IND
| | - Sangita Sen
- Physiology, Institute of Post Graduate Medical Education & Research, Kolkata, IND
| | - Asis Mitra
- Internal Medicine, Ruby General Hospital, Kolkata, IND
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16
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Riff R, Naamani O, Mazar J, Haviv YS, Chaimovitz C, Douvdevani A. A 1 and A 2A adenosine receptors play a protective role to reduce prevalence of autoimmunity following tissue damage. Clin Exp Immunol 2021; 205:278-287. [PMID: 33894002 PMCID: PMC8374218 DOI: 10.1111/cei.13607] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/17/2022] Open
Abstract
Adenosine is a potent modulator that has a tremendous effect on the immune system. Adenosine affects T cell activity, and is necessary in maintaining the T helper/regulatory T cell (Treg ) ratio. Adenosine signalling is also involved in activating neutrophils and the formation of neutrophil extracellular traps (NETs), which has been linked to autoimmune disorders. Therefore, adenosine, through its receptors, is extremely important in maintaining homeostasis and involved in the development of autoimmune diseases. In this study, we aim to evaluate the role of adenosine A1 and A2A receptors in involvement of autoimmune diseases. We studied adenosine regulation by NETosis in vitro, and used two murine models of autoimmune diseases: type I diabetes mellitus (T1DM) induced by low-dose streptozotocin and pristane-induced systemic lupus erythematosus (SLE). We have found that A1 R enhances and A2A R suppresses NETosis. In addition, in both models, A1 R-knock-out (KO) mice were predisposed to the development of autoimmunity. In the SLE model in wild-type (WT) mice we observed a decline of A1 R mRNA levels 6 h after pristane injection that was parallel to lymphocyte reduction. Following pristane, 43% of A1 R-KO mice suffered from lupus-like disease while WT mice remained without any sign of disease at 36 weeks. In WT mice, at 10 days A2A R mRNA levels were significantly higher compared to A1R-KO mice. Similar to SLE, in the T1DM model the presence of A1 R and A2A R was protective. Our data suggest that, in autoimmune diseases, the acute elimination of lymphocytes and reduction of DNA release due to NETosis depends upon A1 R desensitization and long-term suppression of A2A R.
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MESH Headings
- Adenosine/metabolism
- Animals
- Autoimmunity/immunology
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Disease Models, Animal
- Extracellular Traps/immunology
- Lupus Erythematosus, Systemic/immunology
- Lupus Erythematosus, Systemic/pathology
- Lymphopenia/immunology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Neutrophil Activation/immunology
- Neutrophils/immunology
- RNA, Messenger/genetics
- Receptor, Adenosine A1/genetics
- Receptor, Adenosine A1/metabolism
- Receptor, Adenosine A2A/genetics
- Receptor, Adenosine A2A/metabolism
- Signal Transduction/immunology
- Streptozocin
- Terpenes
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Affiliation(s)
- Reut Riff
- Departments of Clinical Biochemistry and PharmacologyFaculty of Health SciencesBen‐Gurion University of the Negev and Soroka University Medical CenterBeer‐ShevaIsrael
- Present address:
Weizmann Institute of ScienceWolfson Building 158, 234 Herzl StreetFehovot7610001Israel
| | - Oshri Naamani
- Departments of Clinical Biochemistry and PharmacologyFaculty of Health SciencesBen‐Gurion University of the Negev and Soroka University Medical CenterBeer‐ShevaIsrael
- Department of ScienceHemdat HadaromCollege of EducationNetivotIsrael
| | - Julia Mazar
- Laboratory of Nephrology HematologyFaculty of Health SciencesBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Yosef S. Haviv
- Department of Nephrology HematologyFaculty of Health SciencesBen‐Gurion University of the Negev and Soroka University Medical CenterBeer‐ShevaIsrael
| | - Cidio Chaimovitz
- Department of Nephrology HematologyFaculty of Health SciencesBen‐Gurion University of the Negev and Soroka University Medical CenterBeer‐ShevaIsrael
| | - Amos Douvdevani
- Departments of Clinical Biochemistry and PharmacologyFaculty of Health SciencesBen‐Gurion University of the Negev and Soroka University Medical CenterBeer‐ShevaIsrael
- Department of Nephrology HematologyFaculty of Health SciencesBen‐Gurion University of the Negev and Soroka University Medical CenterBeer‐ShevaIsrael
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17
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Viisanen H, Nuotio U, Kambur O, Mahato AK, Jokinen V, Lilius T, Li W, Santos HA, Karelson M, Rauhala P, Kalso E, Sidorova YA. Novel RET agonist for the treatment of experimental neuropathies. Mol Pain 2021; 16:1744806920950866. [PMID: 32811276 PMCID: PMC7440726 DOI: 10.1177/1744806920950866] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain. We then introduced a series of chemical changes to improve the biological activity of these compounds and tested an optimized compound named BT44 in a panel of biological assays. BT44 efficiently and selectively stimulated the GFL receptor RET and activated the intracellular mitogene-activated protein kinase/extracellular signal-regulated kinase pathway in immortalized cells. In cultured sensory neurons, BT44 stimulated neurite outgrowth with an efficacy comparable to that of GFLs. BT44 alleviated mechanical hypersensitivity in surgery- and diabetes-induced rat models of neuropathic pain. In addition, BT44 normalized, to a certain degree, the expression of nociception-related neuronal markers which were altered by spinal nerve ligation, the neuropathy model used in this study. Our results suggest that the GFL mimetic BT44 is a promising new lead for the development of novel disease-modifying agents for the treatment of neuropathy and neuropathic pain.
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Affiliation(s)
- Hanna Viisanen
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Ulpukka Nuotio
- Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Oleg Kambur
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Arun Kumar Mahato
- Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Viljami Jokinen
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tuomas Lilius
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Wei Li
- Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.,Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki, Finland
| | - Hélder A Santos
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki, Finland.,Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Mati Karelson
- Institute of Chemistry, Tartu University, Tartu, Estonia
| | - Pekka Rauhala
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Eija Kalso
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Yulia A Sidorova
- Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.,Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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18
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Hernández-Munive AK, Rebolledo-Solleiro D, Fernández-Guasti A. Reduced sexual motivation of diabetic female rats: Restoration with insulin. Horm Behav 2021; 132:104992. [PMID: 33991798 DOI: 10.1016/j.yhbeh.2021.104992] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/30/2021] [Accepted: 04/27/2021] [Indexed: 01/27/2023]
Abstract
The aim of this study was to evaluate female rat sexual motivation in a model of diabetes mellitus type 1. Severe hyperglycemia was induced in ovariectomized Wistar rats by injecting streptozotocin [STZ, 100 mg/kg, i.p.]. Ten days later, females received estradiol benzoate (10 μg/rat, s.c.) plus progesterone (3 mg/rat, s.c.). A group of STZ-treated animals was administered with insulin (2-4 U) every 12 h for 10 days, which normalized glucose levels. In the partner preference (PP) and sexual incentive motivation (SIM) tests, control females spent more time close to a sexually experienced male (SE) than with a castrated male (CM). STZ-treated females stayed the same amount of time with both stimuli, that is, they lost their sexual preference. We also evaluated the sense of smell using two behavioral tests, one related to sexual odors (SO) and another one to food odors (FO). In the SO test, control females spent more time sniffing the sawdust coming from cages that contained SE males; hyperglycemic females remained the same amount of time sniffing the sawdust of both stimuli: SE and CM. In the FO test, no differences were found between control and STZ-treated groups. Insulin treatment reverted the changes observed in hyperglycemic females in the PP, SIM and SO tests. These data suggest that severe hyperglycemia decreases sexual motivation and that insulin recovers such diminution.
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Affiliation(s)
- A K Hernández-Munive
- Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, México City, Mexico
| | - D Rebolledo-Solleiro
- Laboratorio de Neurobiología Conductual, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, México City, Mexico; Escuela Internacional de Medicina, Universidad Anáhuac, Cancún, Mexico
| | - A Fernández-Guasti
- Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, México City, Mexico.
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19
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Ammonium Glycyrrhizinate Prevents Apoptosis and Mitochondrial Dysfunction Induced by High Glucose in SH-SY5Y Cell Line and Counteracts Neuropathic Pain in Streptozotocin-Induced Diabetic Mice. Biomedicines 2021; 9:biomedicines9060608. [PMID: 34073550 PMCID: PMC8227813 DOI: 10.3390/biomedicines9060608] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/17/2021] [Accepted: 05/23/2021] [Indexed: 01/25/2023] Open
Abstract
Glycyrrhiza glabra, commonly known as liquorice, contains several bioactive compounds such as flavonoids, sterols, triterpene, and saponins; among which, glycyrrhizic acid, an oleanane-type saponin, is the most abundant component in liquorice root. Diabetic peripheral neuropathy is one of the major complications of diabetes mellitus, leading to painful condition as neuropathic pain. The pathogenetic mechanism of diabetic peripheral neuropathy is very complex, and its understanding could lead to a more suitable therapeutic strategy. In this work, we analyzed the effects of ammonium glycyrrhizinate, a derivate salt of glycyrrhizic acid, on an in vitro system, neuroblastoma cells line SH-SY5Y, and we observed that ammonium glycyrrhizinate was able to prevent cytotoxic effect and mitochondrial fragmentation after high-glucose administration. In an in vivo experiment, we found that a short-repeated treatment with ammonium glycyrrhizinate was able to attenuate neuropathic hyperalgesia in streptozotocin-induced diabetic mice. In conclusion, our results showed that ammonium glycyrrhizinate could ameliorate diabetic peripheral neuropathy, counteracting both in vitro and in vivo effects induced by high glucose, and might represent a complementary medicine for the clinical management of diabetic peripheral neuropathy.
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Notartomaso S, Scarselli P, Mascio G, Liberatore F, Mazzon E, Mammana S, Gugliandolo A, Cruccu G, Bruno V, Nicoletti F, Battaglia G. N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy. Mol Pain 2021; 16:1744806920904292. [PMID: 32009537 PMCID: PMC6997966 DOI: 10.1177/1744806920904292] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
N-Acetylcysteine, one of the most prescribed antioxidant drugs, enhances pain
threshold in rodents and humans by activating mGlu2 metabotropic glutamate
receptors. Here, we assessed the analgesic activity of N-acetylcysteine in the
streptozotocin model of painful diabetic neuropathy and examined the effect of
N-acetylcysteine on proteins that are involved in mechanisms of nociceptive
sensitization. Mice with blood glucose levels ≥250 mg/dl in response to a single
intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg) were used for the
assessment of mechanical pain thresholds. Systemic treatment with
N-acetylcysteine (100 mg/kg, i.p., either single injection or daily injections
for seven days) caused analgesia in diabetic mice. N-acetylcysteine-induced
analgesia was abrogated by the Sxc− inhibitors, sulfasalazine (8 mg/kg, i.p.), erastin (30 mg/kg,
i.p.), and sorafenib (10 mg/kg, i.p.), or by the mGlu2/3 receptor antagonist,
LY341495 (1 mg/kg, i.p.). Repeated administrations of N-acetylcysteine in
diabetic mice reduced ERK1/2 phosphorylation in the dorsal region of the lumbar
spinal cord. The analgesic activity of N-acetylcysteine was occluded by the MEK
inhibitor, PD0325901 (25 mg/kg, i.p.), the TRPV1 channel blocker, capsazepine
(40 mg/kg, i.p.), or by a cocktail of NMDA and mGlu5 metabotropic glutamate
receptor antagonists (memantine, 25 mg/kg, plus MTEP, 5 mg/kg,
both i.p.). These findings offer the first demonstration that N-acetylcysteine
relieves pain associated with diabetic neuropathy and holds promise for the use
of N-acetylcysteine as an add-on drug in diabetic patients.
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Affiliation(s)
| | - Pamela Scarselli
- IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
| | - Giada Mascio
- IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
| | | | | | - Santa Mammana
- IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy
| | | | - Giorgio Cruccu
- Department of Human Neuroscience, Sapienza University, Rome, Italy
| | - Valeria Bruno
- IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.,Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Ferdinando Nicoletti
- IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.,Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Giuseppe Battaglia
- IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.,Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
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Djuichou Nguemnang SF, Tsafack EG, Mbiantcha M, Ateufack G, Yousseu Nana W, Atsamo AD, Adjouzem CF, Matah Marthe Mba V, Ben Besong E. Antihypernociceptive, Anxiolytic, and Antidepressant Properties of Aqueous and Ethanol Extracts of Dissotis thollonii Cogn. (Melastomataceae) in Mice. Adv Pharmacol Pharm Sci 2020; 2020:8886894. [PMID: 33015629 PMCID: PMC7525301 DOI: 10.1155/2020/8886894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/01/2020] [Accepted: 09/14/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetic neuropathy, which affects 7 to 9% of the world's population and that is usually accompanied by anxiety and depression, is chronic pain that results from impaired function of the central or peripheral nervous system. This study aimed at evaluating the antihypernociceptive, antiallodynic, anxiolytic, and antidepressant effects of Dissotis thollonii extracts. Diabetic neuropathy was induced by intraperitoneal injection of streptozotocin (200 mg/kg) in mice. The aqueous and ethanol extracts (250 and 500 mg/kg) were administered orally. Hyperalgesia (thermal and chemical), allodynia (mechanical and thermal), anxiety (high plus labyrinth, light-dark box, and social interaction), and depression (open field test, suspension test tail, and forced swimming test) were evaluated, and then the levels of some cytokines and growth factors were determined. The aqueous and ethanol extracts of Dissotis thollonii demonstrated significant antihypernociceptive (inhibition of hyperalgesia and allodynia), anxiolytic, and antidepressant activities in mice made diabetic by STZ. The extracts also significantly inhibited (p < 0.001) the levels of TNF-α, IL-1β, and IL-6 in the blood as well as the levels of TNF-α, IL-1β, IL-6, IGF, and NGF in the sciatic nerve. This study shows that the extracts of Dissotis thollonii have antihypernociceptive and neuroprotective effects which could be linked to the inhibition of proinflammatory cytokines and growth factors in the blood and the sciatic nerve.
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Affiliation(s)
- Stephanie Flore Djuichou Nguemnang
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - Eric Gonzal Tsafack
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - Marius Mbiantcha
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - Gilbert Ateufack
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - William Yousseu Nana
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - Albert Donatien Atsamo
- Laboratory of Animal Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaoundé, Cameroon
| | - Carine Flore Adjouzem
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - Vanessa Matah Marthe Mba
- Laboratory of Animal Physiology and Phytopharmacology, Department of Animal Biology, Faculty of Science, University of Dschang, P.O. Box 67 Dschang, Cameroon
| | - Egbe Ben Besong
- Department of Zoology and Animal Physiology, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon
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22
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Jiang BC, Liu T, Gao YJ. Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential. Pharmacol Ther 2020; 212:107581. [DOI: 10.1016/j.pharmthera.2020.107581] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 05/15/2020] [Indexed: 02/08/2023]
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23
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Langeslag M, Kress M. The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain. Expert Opin Ther Targets 2020; 24:869-884. [PMID: 32589067 DOI: 10.1080/14728222.2020.1787989] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: Neuropathic pain disorders are diverse, and the currently available therapies are ineffective in the majority of cases. Therefore, there is a major need for gaining novel mechanistic insights and developing new treatment strategies for neuropathic pain. Areas covered: We performed an in-depth literature search on the molecular mechanisms and systemic importance of the ceramide-to-S1P rheostat regulating neuron function and neuroimmune interactions in the development of neuropathic pain. Expert opinion: The S1P receptor modulator FTY720 (fingolimod, Gilenya®), LPA receptor antagonists and several mechanistically related compounds in clinical development raise great expectations for treating neuropathic pain disorders. Research on S1P receptors, S1P receptor modulators or SPHK inhibitors with distinct selectivity, pharmacokinetics and safety must provide more mechanistic insight into whether they may qualify as useful treatment options for neuropathic pain disorders. The functional relevance of genetic variations within the ceramide-to-S1P rheostat should be explored for an enhanced understanding of neuropathic pain pathogenesis. The ceramide-to-S1P rheostat is emerging as a critically important regulator hub of neuroimmune interactions along the pain pathway, and improved mechanistic insight is required to develop more precise and effective drug treatment options for patients suffering from neuropathic pain disorders.
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Affiliation(s)
- Michiel Langeslag
- Institute of Physiology, DPMP, Medical University Innsbruck , Austria
| | - Michaela Kress
- Institute of Physiology, DPMP, Medical University Innsbruck , Austria
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Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (Vienna) 2020; 127:589-624. [PMID: 32036431 PMCID: PMC7148276 DOI: 10.1007/s00702-020-02145-7] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/19/2020] [Indexed: 02/07/2023]
Abstract
Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.
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Affiliation(s)
- Daniela C Rosenberger
- Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Vivian Blechschmidt
- Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Hans Timmerman
- Department of Anesthesiology, Pain Center, University Medical Center of Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - André Wolff
- Department of Anesthesiology, Pain Center, University Medical Center of Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - Rolf-Detlef Treede
- Department of Neurophysiology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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25
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Suleiman JB, Mohamed M, Bakar ABA. A systematic review on different models of inducing obesity in animals: Advantages and limitations. J Adv Vet Anim Res 2020; 7:103-114. [PMID: 32219116 PMCID: PMC7096124 DOI: 10.5455/javar.2020.g399] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 12/20/2022] Open
Abstract
Several animals have been in the limelight of basic research associated with metabolic diseases like obesity. Obesity can be considered as a significant public health concern in the world. It raises the chances for a variety of disease conditions that includes diabetes, hypertension, liver disease, and cancers, which, in turn, decreases the overall lifespan of adult men and women. The World Health Organization has considered obesity as a global epidemic. Researchers have made several attempts to classify human obesity, but none have been successful. Animal obesity can be classified based on their etiology; however, till now, no animal model of obesity can replicate models of the human condition, they have only provided clues into the causes, aftermaths, and preventive remedy to human adiposity. Over the years, there are varieties of animal models used to induce obesity. Some of them include monogenic, polygenic, surgical, seasonal, and other models of obesity. Apart from the advantages of these models, most of them are accompanied by limitations. The primary purpose of this review is, therefore, to highlight the several models with their advantages and limitations. By knowing the benefits and limitations of animal models of obesity, researchers may be at liberty to select the appropriate one for the study of obesity.
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Affiliation(s)
- Joseph Bagi Suleiman
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Malaysia
| | - Mahaneem Mohamed
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Malaysia
| | - Ainul Bahiyah Abu Bakar
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Malaysia
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26
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Cheng RX, Feng Y, Liu D, Wang ZH, Zhang JT, Chen LH, Su CJ, Wang B, Huang Y, Ji RR, Hu J, Liu T. The role of Na v1.7 and methylglyoxal-mediated activation of TRPA1 in itch and hypoalgesia in a murine model of type 1 diabetes. Theranostics 2019; 9:4287-4307. [PMID: 31285762 PMCID: PMC6599654 DOI: 10.7150/thno.36077] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 04/26/2019] [Indexed: 12/23/2022] Open
Abstract
Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. Methods: Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naïve mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. Results: I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of Trpa1 (Trpa1-/-), pharmacological blockade of TRPA1 and Nav1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1-/-mice. Conclusion: This study revealed that Nav1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.
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27
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Pham VM, Matsumura S, Katano T, Funatsu N, Ito S. Diabetic neuropathy research: from mouse models to targets for treatment. Neural Regen Res 2019; 14:1870-1879. [PMID: 31290436 PMCID: PMC6676867 DOI: 10.4103/1673-5374.259603] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Diabetic neuropathy is one of the most serious complications of diabetes, and its increase shows no sign of stopping. Furthermore, current clinical treatments do not yet approach the best effectiveness. Thus, the development of better strategies for treating diabetic neuropathy is an urgent matter. In this review, we first discuss the advantages and disadvantages of some major mouse models of diabetic neuropathy and then address the targets for mechanism-based treatment that have been studied. We also introduce our studies on each part. Using stem cells as a source of neurotrophic factors to target extrinsic factors of diabetic neuropathy, we found that they present a promising treatment.
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Affiliation(s)
- Vuong M Pham
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan; Singapore Institute for Neurotechnology (SINAPSE), National University of Singapore, Singapore
| | - Shinji Matsumura
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan
| | - Tayo Katano
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan
| | - Nobuo Funatsu
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan
| | - Seiji Ito
- Department of Medical Chemistry, Kansai Medical University, Hirakata; Department of Anesthesiology, Osaka Medical College, Takatsuki, Osaka, Japan
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Agarwal N, Helmstädter J, Rojas DR, Bali KK, Gangadharan V, Kuner R. Evoked hypoalgesia is accompanied by tonic pain and immune cell infiltration in the dorsal root ganglia at late stages of diabetic neuropathy in mice. Mol Pain 2018; 14:1744806918817975. [PMID: 30453826 PMCID: PMC6311571 DOI: 10.1177/1744806918817975] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Diabetic peripheral neuropathy is a major debilitating late complication of diabetes, which significantly reduces the quality of life in patients. Diabetic peripheral neuropathy is associated with a wide spectrum of sensory abnormalities, where in loss of sensation or hypoalgesia to applied external stimuli is paradoxically accompanied by debilitating tonic spontaneous pain. In numerous studies on animal models of diabetic peripheral neuropathy, behavioural measurements have been largely confined to analysis of evoked withdrawal to mechanical and thermal stimuli applied to dermatomes, whereas spontaneous, on-going pain has not been widely studied. In the Streptozotocin model of type 1 diabetes, we employed the Conditioned Place Preference test to assess tonic pain. Our results indicate that both phases, that is, early evoked hypersensitivity (i.e. 5–7 weeks post-Streptozotocin) as well as late stage hypoalgesia (i.e. 17–20 weeks post-Streptozotocin) are accompanied by significant tonic pain in mice with diabetic peripheral neuropathy. We also report on the temporal relation between on-going pain and neuropathological changes in the dorsal root ganglia of mice with diabetic peripheral neuropathy up to 6 months post-Streptozotocin. Neither early hypersensitivity nor late hypoalgesia were associated with markers of cellular stress in the dorsal root ganglia. Whereas significant neutrophil infiltration was observed in the dorsal root ganglia over both early and late stages post-Streptozotocin, T-cell infiltration in the dorsal root ganglia was prominent at late stages post-Streptozotocin. Thus, longitudinal analyses reveal that similar to patients with chronic diabetic peripheral neuropathy, mice show tonic pain despite sensory loss after several months in the Streptozotocin model, which is accompanied by neuroimmune interactions in the dorsal root ganglia.
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Affiliation(s)
- Nitin Agarwal
- Institute of Pharmacology, Heidelberg University, Germany
| | | | - Daniel R Rojas
- Institute of Pharmacology, Heidelberg University, Germany
| | - Kiran K Bali
- Institute of Pharmacology, Heidelberg University, Germany
| | | | - Rohini Kuner
- Institute of Pharmacology, Heidelberg University, Germany
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29
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Wang L, Luo T, Bao Z, Li Y, Bu W. Intrathecal circHIPK3 shRNA alleviates neuropathic pain in diabetic rats. Biochem Biophys Res Commun 2018; 505:644-650. [PMID: 30286957 DOI: 10.1016/j.bbrc.2018.09.158] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 09/25/2018] [Indexed: 12/13/2022]
Abstract
Neuropathic pain is one of the most common diabetic complications and significantly decrease the quality of life. The aetiology of the painful diabetic neuropathic pain is not fully clear. Circular RNAs (circRNAs) have been identified as miRNA sponges and involved in various biological processes, including pain. CircHIPK3 is a circRNA that have been shown to be an oncogene or tumor suppressor to regulate cancer cells growth by sponging multiple miRNAs. However, the role of circHIPK3 in diabetic neuropathic pain remains unknown. The aim of the present study was to elucidate the possible role of circHIPK3 in the control of diabetic neuropathic pain. We found that circHIPK3 are highly abundant in serum from diabetes patients who suffered from neuropathic pain and in dorsal root ganglion from STZ-induced diabetes rats. Upregulation of circHIPK3 was positively associated with grade neuropathic pain in patients with type 2 diabetes. Silencing circHIPK3 alleviated neuropathic pain in diabetic rats, which was involved in neuroinflammation. Further mechanistic investigation demonstrated that circHIPK3 interacted with miR-124 and negatively regulated its expression. MiR-124 inhibitor can reverse circHIPK3 knockdown-mediated alleviation of neuropathic pain and inhibition of neuroinflammation in diabetic rats. We present the first evidence that intrathecal circHIPK3 shRNA treatment can be used to treat neuropathic pain of diabetic rats.
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MESH Headings
- Animals
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/complications
- Ganglia, Spinal/metabolism
- Gene Expression Regulation
- Humans
- Injections, Spinal
- Intracellular Signaling Peptides and Proteins/genetics
- Male
- MicroRNAs/genetics
- Neuralgia/complications
- Neuralgia/genetics
- Neuralgia/therapy
- Nuclear Proteins/genetics
- PC12 Cells
- Protein Serine-Threonine Kinases/genetics
- RNA/genetics
- RNA, Circular
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- Rats
- Rats, Sprague-Dawley
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Affiliation(s)
- Liang Wang
- Chongqing Medical University, Chongqing, 400016, China; Department of Medical Imaging, Inner Mongolia People's Hospital, Hohhot, 010017, China
| | - Tianyou Luo
- Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Zhihua Bao
- Department of Endocrinology, Inner Mongolia International Mongolian Hospital, 010020, China
| | - Yuan Li
- Department of Medical Imaging, Inner Mongolia People's Hospital, Hohhot, 010017, China
| | - WenJin Bu
- Department of Medical Imaging, Inner Mongolia People's Hospital, Hohhot, 010017, China
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30
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Feng FB, Qiu HY. Neuroprotective effect of tanshinone IIA against neuropathic pain in diabetic rats through the Nrf2/ARE and NF-κB signaling pathways. Kaohsiung J Med Sci 2018; 34:428-437. [DOI: 10.1016/j.kjms.2018.03.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 02/11/2018] [Accepted: 03/07/2018] [Indexed: 12/19/2022] Open
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31
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Hiyama H, Yano Y, So K, Imai S, Nagayasu K, Shirakawa H, Nakagawa T, Kaneko S. TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy. Mol Pain 2018; 14:1744806918789812. [PMID: 29968518 PMCID: PMC6055098 DOI: 10.1177/1744806918789812] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Background Diabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice. Results Streptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration. Conclusion These results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.
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Affiliation(s)
- Haruka Hiyama
- 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Yuichi Yano
- 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Kanako So
- 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.,2 Department of Applied Pharmaceutics and Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Satoshi Imai
- 3 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan
| | - Kazuki Nagayasu
- 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Hisashi Shirakawa
- 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
| | - Takayuki Nakagawa
- 3 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan
| | - Shuji Kaneko
- 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan
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Liu C, Li C, Deng Z, Du E, Xu C. Long Non-coding RNA BC168687 is Involved in TRPV1-mediated Diabetic Neuropathic Pain in Rats. Neuroscience 2018; 374:214-222. [PMID: 29421435 DOI: 10.1016/j.neuroscience.2018.01.049] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/22/2018] [Accepted: 01/24/2018] [Indexed: 02/08/2023]
Abstract
Long noncoding RNAs (lncRNAs) participate in a diverse range of molecular and biological processes, and dysregulation of lncRNAs has been observed in the pathogenesis of various human diseases. We observed alterations in mechanical withdrawal thresholds (MWT) and thermal withdrawal latencies (TWL) in streptozotocin (STZ)-induced diabetic rats treated with small interfering RNA (siRNA) of lncRNA BC168687. We detected expression of transient receptor potential vanilloid type 1 (TRPV1) in rat dorsal root ganglia (DRG) by a series of molecular experiments. We determined relative levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in rat serum by enzyme-linked immunosorbent assay (ELISA). In addition, we examined extracellular regulated protein kinases (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways by Western blot (WB). We showed that the MWT and TWL of diabetic rats increased significantly compared with control. Expression of TRPV1 receptors in DRG substantially decreased. Relative levels of TNF-α and IL-1β in the serum of lncRNA BC168687 siRNA-treated rats were reduced. Phosphorylation (p)-ERK and p-p38 signaling pathways in DRG were also decreased. Taken together, we concluded lncRNA BC168687 siRNA may alleviate TRPV1-mediated diabetic neuropathic pain.
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Affiliation(s)
- Chenglong Liu
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang 330006, PR China
| | - Congcong Li
- The Second Clinical Medical College of Nanchang University, Nanchang 330006, PR China
| | - Zeyu Deng
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang 330006, PR China
| | - Errong Du
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang 330006, PR China
| | - Changshui Xu
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang 330006, PR China.
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St John Smith E. Advances in understanding nociception and neuropathic pain. J Neurol 2018; 265:231-238. [PMID: 29032407 PMCID: PMC5808094 DOI: 10.1007/s00415-017-8641-6] [Citation(s) in RCA: 181] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/02/2017] [Accepted: 10/03/2017] [Indexed: 12/11/2022]
Abstract
Pain results from the activation of a subset of sensory neurones termed nociceptors and has evolved as a "detect and protect" mechanism. However, lesion or disease in the sensory system can result in neuropathic pain, which serves no protective function. Understanding how the sensory nervous system works and what changes occur in neuropathic pain are vital in identifying new therapeutic targets and developing novel analgesics. In recent years, technologies such as optogenetics and RNA-sequencing have been developed, which alongside the more traditional use of animal neuropathic pain models and insights from genetic variations in humans have enabled significant advances to be made in the mechanistic understanding of neuropathic pain.
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Affiliation(s)
- Ewan St John Smith
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
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Barrière DA, Noll C, Roussy G, Lizotte F, Kessai A, Kirby K, Belleville K, Beaudet N, Longpré JM, Carpentier AC, Geraldes P, Sarret P. Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications. Sci Rep 2018; 8:424. [PMID: 29323186 PMCID: PMC5765114 DOI: 10.1038/s41598-017-18896-5] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 12/19/2017] [Indexed: 12/15/2022] Open
Abstract
The epidemic of type 2 diabetes mellitus (T2DM) is fueled by added fructose consumption. Here, we thus combined high-fat/high-fructose diet, with multiple low-dose injections of streptozotocin (HF/HF/Stz) to emulate the long-term complications of T2DM. HF/HF/Stz rats, monitored over 56 weeks, exhibited metabolic dysfunctions associated with the different stages of the T2DM disease progression in humans: an early prediabetic phase characterized by an hyperinsulinemic period with modest dysglycemia, followed by a late stage of T2DM with frank hyperglycemia, normalization of insulinemia, marked dyslipidemia, hepatic fibrosis and pancreatic β-cell failure. Histopathological analyses combined to [18F]-FDG PET imaging further demonstrated the presence of several end-organ long-term complications, including reduction in myocardial glucose utilization, renal dysfunction as well as microvascular neuropathy and retinopathy. We also provide for the first time a comprehensive µ-PET whole brain imaging of the changes in glucose metabolic activity within discrete cerebral regions in HF/HF/Stz diabetic rats. Altogether, we developed and characterized a unique non-genetic preclinical model of T2DM adapted to the current diet and lifestyle that recapitulates the major metabolic features of the disease progression, from insulin resistance to pancreatic β-cell dysfunction, and closely mimicking the target-organ damage occurring in type 2 diabetic patients at advanced stages.
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Affiliation(s)
- David André Barrière
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada.
| | - Christophe Noll
- Département de Médecine, Service d'Endocrinologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada
| | - Geneviève Roussy
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada
| | - Farah Lizotte
- Département de Médecine, Service d'Endocrinologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada
| | - Anissa Kessai
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada
| | - Karyn Kirby
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada
| | - Karine Belleville
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada
| | - Nicolas Beaudet
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada
| | - Jean-Michel Longpré
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada
| | - André C Carpentier
- Département de Médecine, Service d'Endocrinologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada
| | - Pedro Geraldes
- Département de Médecine, Service d'Endocrinologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada
| | - Philippe Sarret
- Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada.
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Brini AT, Amodeo G, Ferreira LM, Milani A, Niada S, Moschetti G, Franchi S, Borsani E, Rodella LF, Panerai AE, Sacerdote P. Therapeutic effect of human adipose-derived stem cells and their secretome in experimental diabetic pain. Sci Rep 2017; 7:9904. [PMID: 28851944 PMCID: PMC5575274 DOI: 10.1038/s41598-017-09487-5] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 07/25/2017] [Indexed: 02/08/2023] Open
Abstract
Painful neuropathy is one of the complications of diabetes mellitus that adversely affects patients'quality of life. Pharmacological treatments are not fully satisfactory, and novel approaches needed. In a preclinical mouse model of diabetes the effect of both human mesenchymal stromal cells from adipose tissue (hASC) and their conditioned medium (hASC-CM) was evaluated. Diabetes was induced by streptozotocin. After neuropathic hypersensitivity was established, mice were intravenously injected with either 1 × 106 hASC or with CM derived from 2 × 106 hASC. Both hASC and CM (secretome) reversed mechanical, thermal allodynia and thermal hyperalgesia, with a rapid and long lasting effect, maintained up to 12 weeks after treatments. In nerves, dorsal root ganglia and spinal cord of neuropathic mice we determined high IL-1β, IL-6 and TNF-α and low IL-10 levels. Both treatments restored a correct pro/antinflammatory cytokine balance and prevented skin innervation loss. In spleens of streptozotocin-mice, both hASC and hASC-CM re-established Th1/Th2 balance that was shifted to Th1 during diabetes. Blood glucose levels were unaffected although diabetic animals regained weight, and kidney morphology was recovered by treatments. Our data show that hASC and hASC-CM treatments may be promising approaches for diabetic neuropathic pain, and suggest that cell effect is likely mediated by their secretome.
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Affiliation(s)
- Anna T Brini
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Vanvitelli 32, 20129, Milan, Italy.,IRCCS Galeazzi Orthopaedic Institute, via Galeazzi 4, 20161, Milan, Italy
| | - Giada Amodeo
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita' degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy
| | - Lorena M Ferreira
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Vanvitelli 32, 20129, Milan, Italy.,IRCCS Galeazzi Orthopaedic Institute, via Galeazzi 4, 20161, Milan, Italy
| | - Anna Milani
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Vanvitelli 32, 20129, Milan, Italy.,IRCCS Galeazzi Orthopaedic Institute, via Galeazzi 4, 20161, Milan, Italy
| | - Stefania Niada
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Vanvitelli 32, 20129, Milan, Italy.,IRCCS Galeazzi Orthopaedic Institute, via Galeazzi 4, 20161, Milan, Italy
| | - Giorgia Moschetti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita' degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy
| | - Silvia Franchi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita' degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy
| | - Elisa Borsani
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, viale Europa 11, 25123, Brescia, Italy
| | - Luigi F Rodella
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, viale Europa 11, 25123, Brescia, Italy
| | - Alberto E Panerai
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita' degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy
| | - Paola Sacerdote
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita' degli Studi di Milano, via Vanvitelli 32, 20129, Milan, Italy.
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Wang J, Sun Z, Wang Y, Wang H, Guo Y. The role and mechanism of glutamic NMDA receptor in the mechanical hyperalgesia in diabetic rats. Neurol Res 2017; 39:1006-1013. [PMID: 28814157 DOI: 10.1080/01616412.2017.1364515] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Some studies have shown that painful neuropathy is a common and costly complication of both type 1 and type 2 diabetes mellitus, and glutamate is involved in the process although the mechanisms are not clear. The purpose of the present study was to investigate the effect of N-methyl-D-aspartate (NMDA) receptor on mechanical hyperalgesia in diabetic rats and the possible mechanism. METHODS Diabetic rat model was established by intraperitoneal injection of streptozotocin (STZ, 1%, 70 mg/kg) once, and evaluated by the change in the fasting blood glucose. The mechanical hyperalgesia was estimated by mechanical withdrawal threshold (MWT) using a set of calibrated Von Frey's filaments. In addition, the expressions of phosphorylated NMDA NR1 and phosphorylated cAMP response element binding protein (pCREB) in L4/L5 dorsal horns of spinal cord were observed. RESULTS Behavioral results showed that MK-801, an antagonist of NMDA receptor, could reduce the proportion of mechanical hyperalgesia in diabetic rats from 76.67 to 20.00%. Meanwhile, the mean MWTs in STZ group or saline-treated STZ group decreased significantly at 3-8 week, while, the MWTs in MK-801 treated STZ group were significant higher than those in STZ or saline-treated STZ group. In addition, the expressions of NMDA NR1 and pCREB in L4/5 dorsal horns of spinal cord were significant higher in diabetic rats, and MK-801 down-regulated their expressions partly. CONCLUSION All these results suggested that NMDA receptor and pCREB in the spinal cord were involved in the regulation of mechanical hyperalgesia in diabetic rats.
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Affiliation(s)
- Jin Wang
- a Department of Clinical Medicine , Xi'an Jiaotong University Health Science Center , Xi'an , China
| | - Zhaohui Sun
- a Department of Clinical Medicine , Xi'an Jiaotong University Health Science Center , Xi'an , China
| | - Yuzhao Wang
- a Department of Clinical Medicine , Xi'an Jiaotong University Health Science Center , Xi'an , China
| | - Huisheng Wang
- b Department of Physiology and Pathophysiology , Xi'an Jiaotong University Health Science Center , Xi'an , China
| | - Yuan Guo
- b Department of Physiology and Pathophysiology , Xi'an Jiaotong University Health Science Center , Xi'an , China
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Antinociceptive interaction of gabapentin with minocycline in murine diabetic neuropathy. Inflammopharmacology 2017; 25:91-97. [DOI: 10.1007/s10787-017-0308-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/31/2017] [Indexed: 02/07/2023]
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Kiasalari Z, Rahmani T, Mahmoudi N, Baluchnejadmojarad T, Roghani M. Diosgenin ameliorates development of neuropathic pain in diabetic rats: Involvement of oxidative stress and inflammation. Biomed Pharmacother 2017; 86:654-661. [DOI: 10.1016/j.biopha.2016.12.068] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 11/29/2016] [Accepted: 12/16/2016] [Indexed: 12/31/2022] Open
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Gris G, Portillo-Salido E, Aubel B, Darbaky Y, Deseure K, Vela JM, Merlos M, Zamanillo D. The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats. Sci Rep 2016; 6:24591. [PMID: 27087602 PMCID: PMC4834548 DOI: 10.1038/srep24591] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 03/23/2016] [Indexed: 12/31/2022] Open
Abstract
E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.
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Affiliation(s)
- Georgia Gris
- Department of Pharmacology, Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain
| | - Enrique Portillo-Salido
- Department of Pharmacology, Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain
| | - Bertrand Aubel
- Department of Pharmacology, Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain
| | | | - Kristof Deseure
- Laboratory of Anesthesiology, University of Antwerp, Antwerp, Belgium
| | - José Miguel Vela
- Department of Pharmacology, Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain
| | - Manuel Merlos
- Department of Pharmacology, Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain
| | - Daniel Zamanillo
- Department of Pharmacology, Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain
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Abstract
The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat and mouse models of type 1 diabetes. This chapter will review the creation and use of other rodent models that have been developed in order to investigate the contribution of factors besides insulin deficiency to the development and progression of diabetic neuropathy as it occurs in obesity, type 1 or type 2 diabetes. Diabetic peripheral neuropathy is a complex disorder with multiple mechanisms contributing to its development and progression. Even though many animal models have been developed and investigated, no single model can mimic diabetic peripheral neuropathy as it occurs in humans. Nonetheless, animal models can play an important role in improving our understanding of the etiology of diabetic peripheral neuropathy and in performing preclinical screening of potential new treatments. To date treatments found to be effective for diabetic peripheral neuropathy in rodent models have failed in clinical trials. However, with the identification of new endpoints for the early detection of diabetic peripheral neuropathy and the understanding that a successful treatment may require a combination therapeutic approach there is hope that an effective treatment will be found.
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Affiliation(s)
- M A Yorek
- Iowa City Health Care System, Iowa City, IA, United States; University of Iowa, Iowa City, IA, United States; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, United States.
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Sałat K, Gdula-Argasińska J, Malikowska N, Podkowa A, Lipkowska A, Librowski T. Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:613-23. [PMID: 26984821 PMCID: PMC4866991 DOI: 10.1007/s00210-016-1230-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 03/07/2016] [Indexed: 01/02/2023]
Abstract
Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer’s disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals’ locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti-inflammatory properties in mice. These results confirm the validity of its use in diabetic patients.
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