Cerebral ischemia–reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin–angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood–brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.
{"title":"The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs","authors":"Shuhan Huang, Meng Zhang","doi":"10.1002/nep3.45","DOIUrl":"https://doi.org/10.1002/nep3.45","url":null,"abstract":"Cerebral ischemia–reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin–angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood–brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"205 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141387303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders. The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders. The dysregulation of glutamate signaling, leading to excitotoxicity and neuronal cell death, has been a focal point in understanding the underlying mechanisms of these conditions. This has prompted a paradigm shift in neuroprotection research, with a growing emphasis on targeting ionotropic glutamate receptors (iGluRs) to restore glutamatergic homeostasis. This review provides a comprehensive overview of recent advancements in the field of iGluR‐targeted neuroprotection. We further investigate the implications of glutamate dysregulation in the central nervous system (CNS) disorders, highlighting the complex interplay between excitotoxicity and neuroprotection. We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage, emphasizing the need for innovative therapeutic approaches. This review provides an extensive survey of the burgeoning field of iGluR‐targeted neuroprotection. It showcases the significant potential of a wide array of compounds, encompassing both natural and synthetic agents, to modulate iGluRs and ameliorate excitotoxicity and oxidative stress‐induced neuronal damage. These compounds have demonstrated impressive neuroprotective effects in diverse experimental models, from glutamate‐induced toxicity to traumatic brain injuries. We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation, heralding a promising era in neuroprotection and CNS disorder management.
{"title":"Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection","authors":"Jorge Y. Magdaleno Roman, C. Chapa González","doi":"10.1002/nep3.46","DOIUrl":"https://doi.org/10.1002/nep3.46","url":null,"abstract":"Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders. The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders. The dysregulation of glutamate signaling, leading to excitotoxicity and neuronal cell death, has been a focal point in understanding the underlying mechanisms of these conditions. This has prompted a paradigm shift in neuroprotection research, with a growing emphasis on targeting ionotropic glutamate receptors (iGluRs) to restore glutamatergic homeostasis. This review provides a comprehensive overview of recent advancements in the field of iGluR‐targeted neuroprotection. We further investigate the implications of glutamate dysregulation in the central nervous system (CNS) disorders, highlighting the complex interplay between excitotoxicity and neuroprotection. We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage, emphasizing the need for innovative therapeutic approaches. This review provides an extensive survey of the burgeoning field of iGluR‐targeted neuroprotection. It showcases the significant potential of a wide array of compounds, encompassing both natural and synthetic agents, to modulate iGluRs and ameliorate excitotoxicity and oxidative stress‐induced neuronal damage. These compounds have demonstrated impressive neuroprotective effects in diverse experimental models, from glutamate‐induced toxicity to traumatic brain injuries. We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation, heralding a promising era in neuroprotection and CNS disorder management.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"61 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141387461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel therapeutic strategies and common mechanisms of neurodegenerative diseases","authors":"Š. Lehtonen, Jukka Jolkkonen","doi":"10.1002/nep3.52","DOIUrl":"https://doi.org/10.1002/nep3.52","url":null,"abstract":"","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"100 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141387349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guangtang Chen, Xiaolin Du, Junshuan Cui, Jiaquan Song, Mingsong Xiong, Xi Zeng, Hua Yang, Kaya Xu
The high incidence, mortality, and disability associated with ischemic stroke pose a significant threat to human health. The intestinal microbiota significantly influences the onset, progression, and prognosis of ischemic stroke. Gut flora plays a pivotal role in brain–gut interactions. The reflection of changes in the gut and brain caused by gut microbes facilitates the investigation of early warning biomarkers and potential therapeutic targets for ischemic stroke. In this narrative review of the relationship between gut microbiota and ischemic stroke, we primarily discuss three topics, grounded in real‐world human and animal studies. First, we examined the relationship between ischemic stroke and intestinal microbiota and its metabolites, delineate the overall characteristics of intestinal microbiota dysregulation in ischemic stroke, and assess the potential clinical value, prevailing research controversies, and unique phenomena of intestinal microbiota metabolites such as trimethylamine N‐oxide and short‐chain fatty acids in ischemic stroke. Second, we explored the potential communication pathways between intestinal flora and ischemic stroke based on the brain–gut axis, encompassing metabolic pathways, immune pathways, and neural pathways. Finally, we encapsulated the factors influencing the severity of ischemic stroke via intestinal flora, the pharmacological and nonpharmacological interventions that modulate intestinal flora in treating ischemic stroke, and the current research landscape of intestinal flora in the context of ischemic stroke sequelae.
{"title":"Role of gut microbiota in ischemic stroke: A narrative review of human and animal studies","authors":"Guangtang Chen, Xiaolin Du, Junshuan Cui, Jiaquan Song, Mingsong Xiong, Xi Zeng, Hua Yang, Kaya Xu","doi":"10.1002/nep3.44","DOIUrl":"https://doi.org/10.1002/nep3.44","url":null,"abstract":"The high incidence, mortality, and disability associated with ischemic stroke pose a significant threat to human health. The intestinal microbiota significantly influences the onset, progression, and prognosis of ischemic stroke. Gut flora plays a pivotal role in brain–gut interactions. The reflection of changes in the gut and brain caused by gut microbes facilitates the investigation of early warning biomarkers and potential therapeutic targets for ischemic stroke. In this narrative review of the relationship between gut microbiota and ischemic stroke, we primarily discuss three topics, grounded in real‐world human and animal studies. First, we examined the relationship between ischemic stroke and intestinal microbiota and its metabolites, delineate the overall characteristics of intestinal microbiota dysregulation in ischemic stroke, and assess the potential clinical value, prevailing research controversies, and unique phenomena of intestinal microbiota metabolites such as trimethylamine N‐oxide and short‐chain fatty acids in ischemic stroke. Second, we explored the potential communication pathways between intestinal flora and ischemic stroke based on the brain–gut axis, encompassing metabolic pathways, immune pathways, and neural pathways. Finally, we encapsulated the factors influencing the severity of ischemic stroke via intestinal flora, the pharmacological and nonpharmacological interventions that modulate intestinal flora in treating ischemic stroke, and the current research landscape of intestinal flora in the context of ischemic stroke sequelae.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"15 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140967101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurodegenerative diseases, marked by the gradual death of neurons, present a significant and growing public health challenge. Brain‐derived neurotrophic factor (BDNF) is crucial for the survival, development, and synaptic plasticity of neurons. Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with the development and progression of neurodegenerative conditions, underscoring their potential as therapeutic targets. This review aimed to summarize the existing findings regarding BDNF expression, metabolism, and signaling transduction. Furthermore, we reviewed the intricate roles of BDNF signaling pathways in neurodegenerative diseases, elucidating their contributions to disease onset and progression. The latest advancements in targeting BDNF for the treatment of neurodegenerative diseases, including the development of small molecules, nucleic acid‐based therapeutics, and antibody‐based approaches, were also summarized. Despite recent strides, challenges persist, including a lack of comprehensive understanding of BDNF modulation across diverse neurodegenerative contexts and the absence of clinically approved BDNF‐targeted drugs.
{"title":"Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review","authors":"Dong Wang, Zhi‐Chen Lang, Shi-Nan Wei, Wei Wang, Hao Zhang","doi":"10.1002/nep3.43","DOIUrl":"https://doi.org/10.1002/nep3.43","url":null,"abstract":"Neurodegenerative diseases, marked by the gradual death of neurons, present a significant and growing public health challenge. Brain‐derived neurotrophic factor (BDNF) is crucial for the survival, development, and synaptic plasticity of neurons. Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with the development and progression of neurodegenerative conditions, underscoring their potential as therapeutic targets. This review aimed to summarize the existing findings regarding BDNF expression, metabolism, and signaling transduction. Furthermore, we reviewed the intricate roles of BDNF signaling pathways in neurodegenerative diseases, elucidating their contributions to disease onset and progression. The latest advancements in targeting BDNF for the treatment of neurodegenerative diseases, including the development of small molecules, nucleic acid‐based therapeutics, and antibody‐based approaches, were also summarized. Despite recent strides, challenges persist, including a lack of comprehensive understanding of BDNF modulation across diverse neurodegenerative contexts and the absence of clinically approved BDNF‐targeted drugs.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"12 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141021112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally, significantly affecting the quality of life of affected individuals. Systemic drug delivery to the brain is inefficient because of first‐pass metabolism, the blood‐brain barrier (BBB), and the blood‐cerebrospinal fluid barrier. This inefficiency necessitates increased dosage as the disease progresses, leading to severe side effects that compromise the efficacy of the medication. Nose‐to‐brain (N2B) administration bypasses the BBB, allowing delivery of both small molecules and large protein substances to the central nervous system. Compared with systemic administration, this method enhances brain bioavailability, reduces enzymatic degradation, and minimizes systemic adverse reactions. However, the N2B delivery system is associated with several critical challenges, including mucociliary clearance, enzymatic degradation, and drug translocation via efflux mechanisms. This paper provides a comprehensive overview of the current research progress in intranasal treatment of PD, considering both preclinical and clinical studies, and discusses the physiological aspects and limitations of its delivery system.
{"title":"Research progress on intranasal treatment for Parkinson's disease","authors":"Puyuan Wen, Chao Ren","doi":"10.1002/nep3.42","DOIUrl":"https://doi.org/10.1002/nep3.42","url":null,"abstract":"Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally, significantly affecting the quality of life of affected individuals. Systemic drug delivery to the brain is inefficient because of first‐pass metabolism, the blood‐brain barrier (BBB), and the blood‐cerebrospinal fluid barrier. This inefficiency necessitates increased dosage as the disease progresses, leading to severe side effects that compromise the efficacy of the medication. Nose‐to‐brain (N2B) administration bypasses the BBB, allowing delivery of both small molecules and large protein substances to the central nervous system. Compared with systemic administration, this method enhances brain bioavailability, reduces enzymatic degradation, and minimizes systemic adverse reactions. However, the N2B delivery system is associated with several critical challenges, including mucociliary clearance, enzymatic degradation, and drug translocation via efflux mechanisms. This paper provides a comprehensive overview of the current research progress in intranasal treatment of PD, considering both preclinical and clinical studies, and discusses the physiological aspects and limitations of its delivery system.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"109 26","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140678821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steroids and ecdysteroids have been shown to exhibit a range of biological effects, including anti‐inflammatory, anticancer, and neuroprotective. This systematic review aims to highlight the evidence‐based neuroprotective and antioxidant effects of steroids and ecdysteroids in SH‐SY5Y neuroblastoma cells. A comprehensive literature search was conducted on May 11, 2023, without publication source restrictions, using various electronic databases, including PubMed, Web of Science (WoS), Scopus, and Cumulative Index to Nursing and Allied Health Literature. Of 103 articles, only 20 studies were included for investigating the neuroprotective effects of steroids and ecdysteroids in SH‐SY5Y cells exposed to oxidative stress or neurotoxic agents. The risk of bias and quality assessment of the included studies were evaluated in accordance with the Nature Publication Quality Improvement Project specific criteria. The selected studies reported the antioxidant effects of the tested compounds on SH‐SY5Y cells and demonstrated their ability to scavenge free radicals and prevent lipid peroxidation. These findings suggest that neurosteroids have potential therapeutic applications for the prevention and treatment of neurodegenerative diseases characterized by oxidative stress and neuronal damage. Some studies have investigated the molecular mechanisms underlying the neuroprotective and antioxidant effects of steroids and ecdysteroids in SH‐SY5Y cells. These mechanisms include the activation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, and the modulation of various signaling pathways, including the phosphoinositide 3‐kinase/protein kinase B and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathways. This review provides evidence that the tested compounds have remarkable neuroprotective and antioxidant effects in human neuroblastoma SH‐SY5Y cells.
类固醇和蜕皮甾醇已被证明具有一系列生物效应，包括抗炎、抗癌和神经保护作用。本系统综述旨在强调类固醇和蜕皮激素对 SH-SY5Y 神经母细胞瘤细胞的神经保护和抗氧化作用的证据基础。2023 年 5 月 11 日，我们利用各种电子数据库（包括 PubMed、Web of Science (WoS)、Scopus 和 Cumulative Index to Nursing and Allied Health Literature）进行了全面的文献检索，没有出版物来源限制。在103篇文章中，只有20篇研究纳入了类固醇和蜕皮激素对暴露于氧化应激或神经毒剂的SH-SY5Y细胞的神经保护作用的调查。根据自然出版质量改进项目的特定标准，对所纳入研究的偏倚风险和质量评估进行了评估。所选研究报告了受测化合物对 SH-SY5Y 细胞的抗氧化作用，并证明了它们清除自由基和防止脂质过氧化的能力。这些研究结果表明，神经类固醇在预防和治疗以氧化应激和神经元损伤为特征的神经退行性疾病方面具有潜在的治疗用途。一些研究调查了类固醇和蜕皮激素对 SH-SY5Y 细胞神经保护和抗氧化作用的分子机制。这些机制包括激活超氧化物歧化酶和谷胱甘肽过氧化物酶等抗氧化酶，以及调节各种信号通路，包括磷脂肌醇3-激酶/蛋白激酶B和丝裂原活化蛋白激酶/细胞外信号调节激酶通路。本综述提供的证据表明，所测试的化合物对人类神经母细胞瘤 SH-SY5Y 细胞具有显著的神经保护和抗氧化作用。
{"title":"Beyond boundaries: Neuroprotective effects of steroids and ecdysteroids in SH‐SY5Y cells ‐ A systematic review","authors":"B. A. Tayeb, I. K. Njangiru, Renáta Minorics","doi":"10.1002/nep3.37","DOIUrl":"https://doi.org/10.1002/nep3.37","url":null,"abstract":"Steroids and ecdysteroids have been shown to exhibit a range of biological effects, including anti‐inflammatory, anticancer, and neuroprotective. This systematic review aims to highlight the evidence‐based neuroprotective and antioxidant effects of steroids and ecdysteroids in SH‐SY5Y neuroblastoma cells. A comprehensive literature search was conducted on May 11, 2023, without publication source restrictions, using various electronic databases, including PubMed, Web of Science (WoS), Scopus, and Cumulative Index to Nursing and Allied Health Literature. Of 103 articles, only 20 studies were included for investigating the neuroprotective effects of steroids and ecdysteroids in SH‐SY5Y cells exposed to oxidative stress or neurotoxic agents. The risk of bias and quality assessment of the included studies were evaluated in accordance with the Nature Publication Quality Improvement Project specific criteria. The selected studies reported the antioxidant effects of the tested compounds on SH‐SY5Y cells and demonstrated their ability to scavenge free radicals and prevent lipid peroxidation. These findings suggest that neurosteroids have potential therapeutic applications for the prevention and treatment of neurodegenerative diseases characterized by oxidative stress and neuronal damage. Some studies have investigated the molecular mechanisms underlying the neuroprotective and antioxidant effects of steroids and ecdysteroids in SH‐SY5Y cells. These mechanisms include the activation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, and the modulation of various signaling pathways, including the phosphoinositide 3‐kinase/protein kinase B and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathways. This review provides evidence that the tested compounds have remarkable neuroprotective and antioxidant effects in human neuroblastoma SH‐SY5Y cells.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"67 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140366284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mitigating the impact of mechanisms causing neuronal degeneration","authors":"Xunming Ji, Piotr Walczak, Johannes Boltze","doi":"10.1002/nep3.41","DOIUrl":"https://doi.org/10.1002/nep3.41","url":null,"abstract":"","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"36 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140229052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yong Peng, Xiuli Zhang, Yandan Tang, Shunqing He, Guilan Rao, Quan Chen, Yahui Xue, Hong Jin, Shu Liu, Ziyang Zhou, Yun Xiang
The pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE—an animal model of MS) is primarily mediated by T cells. However, recent studies have only focused on interleukin (IL)‐17‐secreting CD4+ T‐helper cells, also known as Th17 cells. This study aimed to compare Th17 cells and IL‐17‐secreting CD8+ T‐cytotoxic cells (Tc17) in the context of MS/EAE.Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein peptides 35–55 (MOG35–55), pertussis toxin, and complete Freund's adjuvant to establish the EAE animal model. T cells were isolated from the spleen (12–14 days postimmunization). CD4+ and CD8+ T cells were purified using isolation kit and then differentiated into Th17 and Tc17, respectively, using MOG35–55 and IL‐23. The secretion levels of interferon‐γ (IFN‐γ) and IL‐17 were measured via enzyme‐linked immunosorbent assay using cultured CD4+ and CD8+ T cell supernatants. The pathogenicity of Tc17 and Th17 cells was assessed through adoptive transfer (tEAE), with the clinical course assessed using an EAE score (0–5). Hematoxylin and eosin as well as Luxol fast blue staining were used to examine the spinal cord. Purified CD8+ CD3+ and CD4+ CD3+ cells differentiated into Tc17 and Th17 cells, respectively, were stimulated with MOG35–55 peptide for proliferation assays.The results showed that Tc17 cells (15,951 ± 1985 vs. 55,709 ± 4196 cpm; p < 0.050) exhibited a weaker response to highest dose (20 μg/mL) MOG35–55 than Th17 cells. However, this response was not dependent on Th17 cells. After the 48 h stimulation, at the highest dose (20 μg/mL) of MOG35–55. Tc17 cells secreted lower levels of IFN‐γ (280.00 ± 15.00 vs. 556.67 ± 15.28 pg/mL, p < 0.050) and IL‐17 (102.67 ± 5.86 pg/mL vs. 288.33 ± 12.58 pg/mL; p < 0.050) than Th17 cells. Similar patterns were observed for IFN‐γ secretion at 96 and 144 h. Furthermore, Tc17 cell‐induced tEAE mice exhibited similar EAE scores to Th17 cell‐induced tEAE mice and also showed similar inflammation and demyelination.The degree of pathogenicity of Tc17 cells in EAE is lower than that of Th17 cells. Future investigation on different immune cells and EAE models is warranted to determine the mechanisms underlying MS.
多发性硬化症（MS）和实验性自身免疫性脑脊髓炎（EAE，一种 MS 的动物模型）的发病机制主要由 T 细胞介导。然而，最近的研究仅关注分泌白细胞介素（IL）-17 的 CD4+ T 辅助细胞，也称为 Th17 细胞。用髓鞘少突胶质糖蛋白肽35-55（MOG35-55）、百日咳毒素和完全弗氏佐剂免疫雌性C57BL/6小鼠，建立EAE动物模型。从脾脏分离 T 细胞（免疫后 12-14 天）。用分离试剂盒纯化CD4+和CD8+ T细胞，然后用MOG35-55和IL-23将其分别分化成Th17和Tc17。培养的 CD4+ 和 CD8+ T 细胞上清液通过酶联免疫吸附试验测定了干扰素-γ（IFN-γ）和 IL-17 的分泌水平。Tc17和Th17细胞的致病性通过收养性转移（tEAE）进行评估，临床病程通过EAE评分（0-5分）进行评估。检查脊髓时使用了苏木精、伊红和卢克索快蓝染色法。结果显示，Tc17细胞（15951 ± 1985 vs. 55709 ± 4196 cpm; p < 0.050）对最高剂量（20 μg/mL）MOG35-55的反应弱于Th17细胞。然而，这种反应并不依赖于 Th17 细胞。经过 48 小时的刺激后，在最高剂量（20 μg/mL）MOG35-55 的作用下，Tc17 细胞的分泌水平低于 Th17 细胞。Tc17细胞分泌的IFN-γ（280.00 ± 15.00 vs. 556.67 ± 15.28 pg/mL，p < 0.050）和IL-17（102.67 ± 5.86 pg/mL vs. 288.33 ± 12.58 pg/mL，p < 0.050）水平低于Th17细胞。此外，Tc17细胞诱导的tEAE小鼠表现出与Th17细胞诱导的tEAE小鼠相似的EAE评分，也表现出相似的炎症和脱髓鞘。未来有必要对不同的免疫细胞和EAE模型进行研究，以确定多发性硬化症的发病机制。
{"title":"Role of autoreactive Tc17 cells in the pathogenesis of experimental autoimmune encephalomyelitis","authors":"Yong Peng, Xiuli Zhang, Yandan Tang, Shunqing He, Guilan Rao, Quan Chen, Yahui Xue, Hong Jin, Shu Liu, Ziyang Zhou, Yun Xiang","doi":"10.1002/nep3.38","DOIUrl":"https://doi.org/10.1002/nep3.38","url":null,"abstract":"The pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE—an animal model of MS) is primarily mediated by T cells. However, recent studies have only focused on interleukin (IL)‐17‐secreting CD4+ T‐helper cells, also known as Th17 cells. This study aimed to compare Th17 cells and IL‐17‐secreting CD8+ T‐cytotoxic cells (Tc17) in the context of MS/EAE.Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein peptides 35–55 (MOG35–55), pertussis toxin, and complete Freund's adjuvant to establish the EAE animal model. T cells were isolated from the spleen (12–14 days postimmunization). CD4+ and CD8+ T cells were purified using isolation kit and then differentiated into Th17 and Tc17, respectively, using MOG35–55 and IL‐23. The secretion levels of interferon‐γ (IFN‐γ) and IL‐17 were measured via enzyme‐linked immunosorbent assay using cultured CD4+ and CD8+ T cell supernatants. The pathogenicity of Tc17 and Th17 cells was assessed through adoptive transfer (tEAE), with the clinical course assessed using an EAE score (0–5). Hematoxylin and eosin as well as Luxol fast blue staining were used to examine the spinal cord. Purified CD8+ CD3+ and CD4+ CD3+ cells differentiated into Tc17 and Th17 cells, respectively, were stimulated with MOG35–55 peptide for proliferation assays.The results showed that Tc17 cells (15,951 ± 1985 vs. 55,709 ± 4196 cpm; p < 0.050) exhibited a weaker response to highest dose (20 μg/mL) MOG35–55 than Th17 cells. However, this response was not dependent on Th17 cells. After the 48 h stimulation, at the highest dose (20 μg/mL) of MOG35–55. Tc17 cells secreted lower levels of IFN‐γ (280.00 ± 15.00 vs. 556.67 ± 15.28 pg/mL, p < 0.050) and IL‐17 (102.67 ± 5.86 pg/mL vs. 288.33 ± 12.58 pg/mL; p < 0.050) than Th17 cells. Similar patterns were observed for IFN‐γ secretion at 96 and 144 h. Furthermore, Tc17 cell‐induced tEAE mice exhibited similar EAE scores to Th17 cell‐induced tEAE mice and also showed similar inflammation and demyelination.The degree of pathogenicity of Tc17 cells in EAE is lower than that of Th17 cells. Future investigation on different immune cells and EAE models is warranted to determine the mechanisms underlying MS.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"3 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140234891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matteo Haupt, Stefan T Gerner, Thorsten R Doeppner
Stem cell‐based therapies and extracellular vesicle (EV) treatment have demonstrated significant potential for neuroprotection against ischemic stroke. Although the neuroprotective mechanisms are not yet fully understood, targeting microglia is central to promoting neuroprotection. Microglia are the resident immune cells of the central nervous system. These cells are crucial in the pathogenesis of ischemic stroke. They respond rapidly to the site of injury by releasing pro‐inflammatory cytokines, phagocytizing dead cells and debris, and recruiting peripheral immune cells to the ischemic area. Although these responses are essential for clearing damage and initiating tissue repair, excessive or prolonged microglial activation can exacerbate brain injury, leading to secondary neuroinflammation and neurodegeneration. Moreover, microglia exhibit a dynamic range of activation states with the so‐called M1 pro‐inflammatory and M2 anti‐inflammatory phenotypes, representing the two ends of the spectrum. The delivery of both EVs and stem cells modulates microglial activation, suppressing pro‐inflammatory genes, influencing the expression of transcription factors, and altering receptor expression, ultimately contributing to neuroprotection. These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke. In this review, we examine the current state of knowledge regarding the role of microglia in ischemic stroke, including their molecular and cellular mechanisms, activation states, and interactions with other cells. We also discuss the multifaceted contributions of microglia to stem cell‐ and EV‐based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.
{"title":"The dual role of microglia in ischemic stroke and its modulation via extracellular vesicles and stem cells","authors":"Matteo Haupt, Stefan T Gerner, Thorsten R Doeppner","doi":"10.1002/nep3.39","DOIUrl":"https://doi.org/10.1002/nep3.39","url":null,"abstract":"Stem cell‐based therapies and extracellular vesicle (EV) treatment have demonstrated significant potential for neuroprotection against ischemic stroke. Although the neuroprotective mechanisms are not yet fully understood, targeting microglia is central to promoting neuroprotection. Microglia are the resident immune cells of the central nervous system. These cells are crucial in the pathogenesis of ischemic stroke. They respond rapidly to the site of injury by releasing pro‐inflammatory cytokines, phagocytizing dead cells and debris, and recruiting peripheral immune cells to the ischemic area. Although these responses are essential for clearing damage and initiating tissue repair, excessive or prolonged microglial activation can exacerbate brain injury, leading to secondary neuroinflammation and neurodegeneration. Moreover, microglia exhibit a dynamic range of activation states with the so‐called M1 pro‐inflammatory and M2 anti‐inflammatory phenotypes, representing the two ends of the spectrum. The delivery of both EVs and stem cells modulates microglial activation, suppressing pro‐inflammatory genes, influencing the expression of transcription factors, and altering receptor expression, ultimately contributing to neuroprotection. These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke. In this review, we examine the current state of knowledge regarding the role of microglia in ischemic stroke, including their molecular and cellular mechanisms, activation states, and interactions with other cells. We also discuss the multifaceted contributions of microglia to stem cell‐ and EV‐based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.","PeriodicalId":505813,"journal":{"name":"Neuroprotection","volume":"78 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140282288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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