Piotr Walczak, Xunming Ji, Shen Li, Johannes Boltze
{"title":"Effects of immunological processes and mild ambient atmosphere alterations on the brain in health and disease.","authors":"Piotr Walczak, Xunming Ji, Shen Li, Johannes Boltze","doi":"10.1002/nep3.57","DOIUrl":"10.1002/nep3.57","url":null,"abstract":"","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":" ","pages":"179-181"},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-09-15DOI: 10.1002/nep3.56
Tobiloba Samuel Olajide, Toheeb O Oyerinde, Omolabake I Omotosho, Oritoke M Okeowo, Olayemi J Olajide, Omamuyouwi M Ijomone
The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.
{"title":"Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.","authors":"Tobiloba Samuel Olajide, Toheeb O Oyerinde, Omolabake I Omotosho, Oritoke M Okeowo, Olayemi J Olajide, Omamuyouwi M Ijomone","doi":"10.1002/nep3.56","DOIUrl":"10.1002/nep3.56","url":null,"abstract":"<p><p>The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"2 3","pages":"182-195"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Svea‐Solveig Mennen, Maren Franta, M. Begemann, Justus B. H. Wilke, Roman Schröder, Umer Javed Butt, Jonathan‐Alexis Cortés‐Silva, Umut Çakır, Marie Güra, Markus de Marées, Vinicius Daguano Gastaldi, J. Burtscher, Julie Schanz, Matthias Bohn, M. Burtscher, Andreas Fischer, Luise Poustka, Peter Hammermann, Markus Stadler, Fred Lühder, Manvendra Singh, K. Nave, K. Miskowiak, H. Ehrenreich
Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O2), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor‐cognitive tasks, provoking a relative decrease in O2 in relation to the acutely augmented requirement. We termed this fundamental, demand‐dependent drop in O2 availability “functional hypoxia.” Major players in the hypoxia response are hypoxia‐inducible factors (HIFs) and associated prolyl‐hydroxylases. HIFs are transcription factors, stabilized by low O2 accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol‐oxidase (2‐aminoethanethiol) dioxygenase. Considering the far‐reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor‐cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well‐being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the “add‐on” value of inspiratory on top of functional hypoxia, induced by motor‐cognitive training, a single‐blind study—with versus without inspiratory hypoxia—is essential and outlined here.
{"title":"Tolerability and first hints for potential efficacy of motor‐cognitive training under inspiratory hypoxia in health and neuropsychiatric disorders: A translational viewpoint","authors":"Svea‐Solveig Mennen, Maren Franta, M. Begemann, Justus B. H. Wilke, Roman Schröder, Umer Javed Butt, Jonathan‐Alexis Cortés‐Silva, Umut Çakır, Marie Güra, Markus de Marées, Vinicius Daguano Gastaldi, J. Burtscher, Julie Schanz, Matthias Bohn, M. Burtscher, Andreas Fischer, Luise Poustka, Peter Hammermann, Markus Stadler, Fred Lühder, Manvendra Singh, K. Nave, K. Miskowiak, H. Ehrenreich","doi":"10.1002/nep3.47","DOIUrl":"https://doi.org/10.1002/nep3.47","url":null,"abstract":"Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O2), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor‐cognitive tasks, provoking a relative decrease in O2 in relation to the acutely augmented requirement. We termed this fundamental, demand‐dependent drop in O2 availability “functional hypoxia.” Major players in the hypoxia response are hypoxia‐inducible factors (HIFs) and associated prolyl‐hydroxylases. HIFs are transcription factors, stabilized by low O2 accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol‐oxidase (2‐aminoethanethiol) dioxygenase. Considering the far‐reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor‐cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well‐being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the “add‐on” value of inspiratory on top of functional hypoxia, induced by motor‐cognitive training, a single‐blind study—with versus without inspiratory hypoxia—is essential and outlined here.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"2 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141266792","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}
Aravind Parthasarathy, Ramesha Hanumanthappa, Sarojini R. Bulbule, Kiran P.C., Hemalatha Nanjaiah, Gopinath G., Siddaiah B.M., David Muniswamy, Devaraju Kuramkote Shivanna
Oxidative stress impairs the function of calcium‐binding proteins and deregulates calcium signaling in living organisms. We have previously explored the overexpression of calcium‐binding protein genes in a reactive oxygen and nitrogen species‐induced in vitro cell model of stress that leads to apoptosis. However, in in vivo models, low levels of stress leads to depressive‐like behavior. Here, we aimed to analyze gene expression of major calcium‐binding proteins (calcineurin, calmodulin, calsyntenin, synaptotagmin, and calreticulin) and N‐methyl‐d‐aspartic acid (NMDA) receptor subunits (glutamate receptor ionotropic [GluN] GluN1, GluN2A, and GluN2B) in the hippocampus of stress‐induced rats.Six‐week‐old male Wistar rats were assigned to two stress induction groups and a control group without stress (n = 6). Stress was induced by using H2O2 (3% in water) or by immobilization (using a sticky mat) over a period of 30 days. Expression of calcium‐binding protein genes in the hippocampus, antioxidant assays, structural alterations in hippocampal neurons, and depressive‐like behavior were determined.Expression of genes encoding calcium‐binding proteins calcineurin, calsyntenin, synaptotagmin and NMDA receptor subunit GluN1 was enhanced in both chemical and physical stress‐induced rats compared with control rats (4.25 ± 0.05 vs. 1.03 ± 0.02, p < 0.05, 2.05 ± 0.08 vs. 1.03 ± 0.02, p < 0.005; 2.2 ± 0.4 vs. 1.02 ± 0.03, p < 0.05, 1.98 ± 0.07 vs. 1.02 ± 0.03, p < 0.005; 1.4 ± 0.6 vs. 1.15 ± 0.09, p < 0.05, 1.39 ± 0.05 vs. 1.15 ± 0.09, p < 0.005), respectively. In stress‐induced rats, neurons in the CA2 region of the hippocampus were fewer and appeared disorganized compared with control rats. Furthermore, stress‐induced rats showed decreased mobility and lower sucrose preference in behavioral studies compared with control rats.Lower levels of reactive oxygen and nitrogen species (RONS) can also lead to stress in rats by affecting their calcium signaling, buffering capacity in the neurons leading to depressive symptoms.
氧化应激会损害钙结合蛋白的功能，并使生物体内的钙信号转导失调。我们以前曾在活性氧和氮物种诱导的体外应激细胞模型中探讨过表达钙结合蛋白基因导致细胞凋亡的问题。然而，在体内模型中，低水平的应激会导致类似抑郁的行为。在这里，我们旨在分析应激诱导的大鼠海马中主要钙结合蛋白（钙神经蛋白、钙调蛋白、钙鞘氨醇、突触表蛋白和钙调蛋白）和 N-甲基-d-天冬氨酸（NMDA）受体亚基（谷氨酸受体离子型 [GluN] GluN1、GluN2A 和 GluN2B）的基因表达。将六周大的雄性 Wistar 大鼠分为两个应激诱导组和一个无应激对照组（n = 6）。应激诱导采用 H2O2（3% 水溶液）或固定（使用粘性垫），为期 30 天。与对照组相比，化学和物理应激诱导组大鼠的钙结合蛋白钙调蛋白、钙拮抗蛋白、突触肽和 NMDA 受体亚基 GluN1 的基因表达均有所增强（4.25 ± 0.05 vs. 1.03 ± 0.02, p < 0.05, 2.05 ± 0.08 vs. 1.03 ± 0.02, p < 0.005; 2.2 ± 0.4 vs. 1.02 ± 0.03, p < 0.05, 1.98 ± 0.07 vs. 1.02 ± 0.03，p < 0.005；1.4 ± 0.6 vs. 1.15 ± 0.09，p < 0.05，1.39 ± 0.05 vs. 1.15 ± 0.09，p < 0.005）。与对照组大鼠相比，应激诱导组大鼠海马 CA2 区的神经元数量更少，而且显得杂乱无章。此外，与对照组大鼠相比，应激诱导组大鼠在行为研究中表现出活动能力下降和蔗糖偏好降低。
{"title":"Stress enhances expression of calcium‐binding proteins and NMDAR subunit genes in the rat hippocampus","authors":"Aravind Parthasarathy, Ramesha Hanumanthappa, Sarojini R. Bulbule, Kiran P.C., Hemalatha Nanjaiah, Gopinath G., Siddaiah B.M., David Muniswamy, Devaraju Kuramkote Shivanna","doi":"10.1002/nep3.35","DOIUrl":"https://doi.org/10.1002/nep3.35","url":null,"abstract":"Oxidative stress impairs the function of calcium‐binding proteins and deregulates calcium signaling in living organisms. We have previously explored the overexpression of calcium‐binding protein genes in a reactive oxygen and nitrogen species‐induced in vitro cell model of stress that leads to apoptosis. However, in in vivo models, low levels of stress leads to depressive‐like behavior. Here, we aimed to analyze gene expression of major calcium‐binding proteins (calcineurin, calmodulin, calsyntenin, synaptotagmin, and calreticulin) and N‐methyl‐d‐aspartic acid (NMDA) receptor subunits (glutamate receptor ionotropic [GluN] GluN1, GluN2A, and GluN2B) in the hippocampus of stress‐induced rats.Six‐week‐old male Wistar rats were assigned to two stress induction groups and a control group without stress (n = 6). Stress was induced by using H2O2 (3% in water) or by immobilization (using a sticky mat) over a period of 30 days. Expression of calcium‐binding protein genes in the hippocampus, antioxidant assays, structural alterations in hippocampal neurons, and depressive‐like behavior were determined.Expression of genes encoding calcium‐binding proteins calcineurin, calsyntenin, synaptotagmin and NMDA receptor subunit GluN1 was enhanced in both chemical and physical stress‐induced rats compared with control rats (4.25 ± 0.05 vs. 1.03 ± 0.02, p < 0.05, 2.05 ± 0.08 vs. 1.03 ± 0.02, p < 0.005; 2.2 ± 0.4 vs. 1.02 ± 0.03, p < 0.05, 1.98 ± 0.07 vs. 1.02 ± 0.03, p < 0.005; 1.4 ± 0.6 vs. 1.15 ± 0.09, p < 0.05, 1.39 ± 0.05 vs. 1.15 ± 0.09, p < 0.005), respectively. In stress‐induced rats, neurons in the CA2 region of the hippocampus were fewer and appeared disorganized compared with control rats. Furthermore, stress‐induced rats showed decreased mobility and lower sucrose preference in behavioral studies compared with control rats.Lower levels of reactive oxygen and nitrogen species (RONS) can also lead to stress in rats by affecting their calcium signaling, buffering capacity in the neurons leading to depressive symptoms.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"46 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141274035","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}
Yang Zhu, L.M. Liao, Shihao Gao, Yong Tao, Hao Huang, Xiangqin Fang, Changyan Yuan, C. Gao
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well‐established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy‐related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high‐frequency rTMS (HF‐rTMS) regimen has value in AD therapy, and that promising single‐site protocols, such as HF‐rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征是认知功能逐渐退化，目前尚无有效的治疗方法。重复经颅磁刺激（rTMS）是一种成熟的非侵入性脑部刺激方法，临床上用于治疗各种神经精神疾病，如抑郁症、神经性疼痛和中风后功能障碍。越来越多的证据表明，经颅磁刺激可提高注意力缺失症患者的认知能力。然而，其最佳治疗方案和精确机制目前尚不清楚，阻碍了其临床应用。在本综述中，我们旨在总结和讨论经颅磁刺激治疗中与疗效相关的参数，包括刺激频率、刺激模式、刺激强度和刺激线圈的配置。此外，我们还回顾了临床研究中对这些因素进行不同组合的经颅磁刺激治疗方案。根据我们的分析，我们认为多部位高频经颅磁刺激（HF-rTMS）疗法在治疗注意力缺失症方面具有价值，而应用于左侧背外侧前额叶皮层、楔前区或小脑的高频经颅磁刺激等有前景的单部位疗法则需要在更大规模的临床研究中进行验证。最后，我们从大脑网络调节以及细胞和分子反应的角度，全面回顾了经颅磁刺激对认知障碍症神经保护作用的潜在机制。总之，经颅磁刺激对 AD 的总体治疗效果可能是多种机制相互作用的结果。本综述为经颅磁刺激治疗 AD 的未来临床应用和科学研究提供了理论和实践依据。
{"title":"Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms","authors":"Yang Zhu, L.M. Liao, Shihao Gao, Yong Tao, Hao Huang, Xiangqin Fang, Changyan Yuan, C. Gao","doi":"10.1002/nep3.40","DOIUrl":"https://doi.org/10.1002/nep3.40","url":null,"abstract":"Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well‐established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy‐related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high‐frequency rTMS (HF‐rTMS) regimen has value in AD therapy, and that promising single‐site protocols, such as HF‐rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"101 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140079934","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":"Exploring novel experimental treatments for major neurodegenerative disorders","authors":"Xunming Ji, Piotr Walczak, Johannes Boltze","doi":"10.1002/nep3.31","DOIUrl":"https://doi.org/10.1002/nep3.31","url":null,"abstract":"","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138966425","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}
D. Talhada, Robert Nilsson, Severin Walser, Georgios Michalettos, K. Ruscher
Treatment with levodopa enhances recovery of lost neurological functions in preclinical stroke models and patients. Here, we studied whether dopamine signaling modulates GABAergic neurotransmission in parvalbumin‐positive interneurons after experimental stroke.Following block randomization, mice were subjected to experimental stroke induced by photothrombosis (PT). Two days after the insult, mice were treated either with the D1 receptor antagonist by R(+)‐SCH‐23390 (0.1 mg/kg), the selective D1 receptor agonist (R)‐(+)‐SKF‐38393 hydrochloride (1 mg/kg), the D2 receptor agonist R(−)‐2,10,11‐trihydroxy‐N‐propyl‐noraporphine hydrobromide hydrate (TNPA) (1 mg/kg), the D2 receptor antagonist S‐(−)‐eticlopride hydrochloride (0.3 mg/kg), or vehicle (saline) by daily intraperitoneal injection for five consecutive days, respectively. Recovery of function was assessed by paw placement and foot fault test before and on Days 2 and 7 after surgery.Mice treated with TNPA showed a statistically significant improvement of recovery compared to all other treatment conditions. Synthesis of gamma‐aminobutyric acid (GABA) was quantified by levels of full‐length and cleaved glutamate acid decarboxylase 67 and 65 (GAD65 and GAD67) in the peri‐infarct area and homotypic regions of the contralateral cortex. Compared to the other treatments, TNPA significantly reduced the level of the GAD67 isoform both in the ischemic and contralateral hemispheres. Levels of GAD65 were found significantly higher in the contralateral hemisphere in TNPA‐treated mice after PT accompanied by an increase in the 58 kDa‐truncated form.Our results point toward reduced GABA synthesis in a D2 receptor‐mediated mechanism possibly contributing to counteract functional inhibition after stroke.
{"title":"Activation of dopamine 2 receptors modulates glutamate decarboxylases 65 and 67 during stroke recovery in mice","authors":"D. Talhada, Robert Nilsson, Severin Walser, Georgios Michalettos, K. Ruscher","doi":"10.1002/nep3.28","DOIUrl":"https://doi.org/10.1002/nep3.28","url":null,"abstract":"Treatment with levodopa enhances recovery of lost neurological functions in preclinical stroke models and patients. Here, we studied whether dopamine signaling modulates GABAergic neurotransmission in parvalbumin‐positive interneurons after experimental stroke.Following block randomization, mice were subjected to experimental stroke induced by photothrombosis (PT). Two days after the insult, mice were treated either with the D1 receptor antagonist by R(+)‐SCH‐23390 (0.1 mg/kg), the selective D1 receptor agonist (R)‐(+)‐SKF‐38393 hydrochloride (1 mg/kg), the D2 receptor agonist R(−)‐2,10,11‐trihydroxy‐N‐propyl‐noraporphine hydrobromide hydrate (TNPA) (1 mg/kg), the D2 receptor antagonist S‐(−)‐eticlopride hydrochloride (0.3 mg/kg), or vehicle (saline) by daily intraperitoneal injection for five consecutive days, respectively. Recovery of function was assessed by paw placement and foot fault test before and on Days 2 and 7 after surgery.Mice treated with TNPA showed a statistically significant improvement of recovery compared to all other treatment conditions. Synthesis of gamma‐aminobutyric acid (GABA) was quantified by levels of full‐length and cleaved glutamate acid decarboxylase 67 and 65 (GAD65 and GAD67) in the peri‐infarct area and homotypic regions of the contralateral cortex. Compared to the other treatments, TNPA significantly reduced the level of the GAD67 isoform both in the ischemic and contralateral hemispheres. Levels of GAD65 were found significantly higher in the contralateral hemisphere in TNPA‐treated mice after PT accompanied by an increase in the 58 kDa‐truncated form.Our results point toward reduced GABA synthesis in a D2 receptor‐mediated mechanism possibly contributing to counteract functional inhibition after stroke.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139001845","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}
Activation of neuroprotective and particularly later neurorestorative mechanisms after stroke attempts to restore or compensate for lost functions. This potentially opens a wide window for restorative therapies to promote brain repair and improve long‐term functional recovery. Although extensively demonstrated in the preclinical setting, the efficacy of cell‐based therapies in stroke patients has been modest at best, if any at all. Translational failure may be due to the ineffective survival and integration of transplanted cells in pro‐death stroke microenvironments that are not conducive for the structural reconstruction of damaged brain tissue and repair‐related network reorganization. Optimal systemic delivery, timing, cell product, and dose remain open as well. Fortunately, a better understanding of the brain plasticity mechanisms underlying stroke recovery has ushered in a combination approach of cell‐based therapy and rehabilitation that is aimed at achieving additive, synergistic, or even maximal beneficial effects. This novel combination therapy is not only targeted at promoting exogenous and endogenous cell survival and augmenting stand‐alone restorative mechanisms but also at utilizing rehabilitation to facilitate a graft–host structural and functional integration and plasticity that would effectively remodel stroke tissue and restitute lost functions. This review presents an overview of the combination of cell‐based therapy and experimental rehabilitation in stroke models. It also discusses associated shortcomings as well as proposes strategies to address them and help facilitate the advancement of this combination approach.
{"title":"The potential of a combined cell‐based therapy and rehabilitation approach for stroke recovery","authors":"Abdulhameed Bakreen, Jukka Jolkkonen","doi":"10.1002/nep3.27","DOIUrl":"https://doi.org/10.1002/nep3.27","url":null,"abstract":"Activation of neuroprotective and particularly later neurorestorative mechanisms after stroke attempts to restore or compensate for lost functions. This potentially opens a wide window for restorative therapies to promote brain repair and improve long‐term functional recovery. Although extensively demonstrated in the preclinical setting, the efficacy of cell‐based therapies in stroke patients has been modest at best, if any at all. Translational failure may be due to the ineffective survival and integration of transplanted cells in pro‐death stroke microenvironments that are not conducive for the structural reconstruction of damaged brain tissue and repair‐related network reorganization. Optimal systemic delivery, timing, cell product, and dose remain open as well. Fortunately, a better understanding of the brain plasticity mechanisms underlying stroke recovery has ushered in a combination approach of cell‐based therapy and rehabilitation that is aimed at achieving additive, synergistic, or even maximal beneficial effects. This novel combination therapy is not only targeted at promoting exogenous and endogenous cell survival and augmenting stand‐alone restorative mechanisms but also at utilizing rehabilitation to facilitate a graft–host structural and functional integration and plasticity that would effectively remodel stroke tissue and restitute lost functions. This review presents an overview of the combination of cell‐based therapy and experimental rehabilitation in stroke models. It also discusses associated shortcomings as well as proposes strategies to address them and help facilitate the advancement of this combination approach.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"503 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138982927","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}
Elizabeth Mendoza‐Portillo, Estefania Aleman‐Navarro, G. Aleph Prieto, Yvonne Rosenstein, Jose J. Lozano‐Nuevo, Araceli Perez‐Lopez
Abstract More than 670 million cases of coronavirus disease 2019 (COVID‐19) have been recorded worldwide in the 3 years since the start of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic. About 45% of survivors of COVID‐19 develop a syndrome known as long‐term COVID, in which symptoms persist even months after the acute infection. About 76% of patients with long COVID experience neurological manifestations. Moreover, patients who have survived COVID‐19 have an increased risk of cerebral venous thrombosis. This case report describes a 41‐year‐old woman who developed neurological manifestations associated with jugular vein thrombosis 24 h after administration of the Oxford–AstraZeneca (ChAdOx1 nCoV‐19) vaccine (AstraZeneca‐Serum Institute of India). She had been infected with SARS‐CoV‐2 three months before vaccination. Although initially suspected to be a case of vaccine‐induced immune thrombotic thrombocytopenia (VITT) in view of her recent vaccination, the patient did not have any hallmarks of VITT, such as thrombocytopenia, an increased d ‐dimer level, or antibodies against platelet factor‐4. Moreover, the neurological manifestations were associated with a high concentration of inflammatory cytokines, including interleukin (IL)‐6, IL‐17A, and IL‐21, and elevated neutrophil levels in cerebrospinal fluid, suggesting that inflammatory immune components had a role in the development of thrombotic events and pointing to an alternative diagnosis. In this case, the laboratory results indicated that the neurological manifestations associated with jugular vein thrombosis were not associated with VITT. Therefore, we propose that the thrombosis of the left jugular vein was a sequela of SARS‐CoV‐2 infection.
{"title":"Neurological manifestations with jugular vein thrombosis linked to an inflammatory profile may be a sequela of long COVID","authors":"Elizabeth Mendoza‐Portillo, Estefania Aleman‐Navarro, G. Aleph Prieto, Yvonne Rosenstein, Jose J. Lozano‐Nuevo, Araceli Perez‐Lopez","doi":"10.1002/nep3.24","DOIUrl":"https://doi.org/10.1002/nep3.24","url":null,"abstract":"Abstract More than 670 million cases of coronavirus disease 2019 (COVID‐19) have been recorded worldwide in the 3 years since the start of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic. About 45% of survivors of COVID‐19 develop a syndrome known as long‐term COVID, in which symptoms persist even months after the acute infection. About 76% of patients with long COVID experience neurological manifestations. Moreover, patients who have survived COVID‐19 have an increased risk of cerebral venous thrombosis. This case report describes a 41‐year‐old woman who developed neurological manifestations associated with jugular vein thrombosis 24 h after administration of the Oxford–AstraZeneca (ChAdOx1 nCoV‐19) vaccine (AstraZeneca‐Serum Institute of India). She had been infected with SARS‐CoV‐2 three months before vaccination. Although initially suspected to be a case of vaccine‐induced immune thrombotic thrombocytopenia (VITT) in view of her recent vaccination, the patient did not have any hallmarks of VITT, such as thrombocytopenia, an increased d ‐dimer level, or antibodies against platelet factor‐4. Moreover, the neurological manifestations were associated with a high concentration of inflammatory cytokines, including interleukin (IL)‐6, IL‐17A, and IL‐21, and elevated neutrophil levels in cerebrospinal fluid, suggesting that inflammatory immune components had a role in the development of thrombotic events and pointing to an alternative diagnosis. In this case, the laboratory results indicated that the neurological manifestations associated with jugular vein thrombosis were not associated with VITT. Therefore, we propose that the thrombosis of the left jugular vein was a sequela of SARS‐CoV‐2 infection.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":" 39","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135243081","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}
Jie Liu, Heleen van Beusekom, Xian‐Le Bu, Gong Chen, Paulo Henrique Rosado de Castro, Xiaochun Chen, Xiaowei Chen, Andrew N. Clarkson, Tracy D. Farr, Yuhong Fu, Jianping Jia, Jukka Jolkkonen, Woojin Scott Kim, Paula Korhonen, Shen Li, Yajie Liang, Guang‐Hui Liu, Guiyou Liu, Yu‐Hui Liu, Tarja Malm, Xiaobo Mao, Joaquim Miguel Oliveira, Mike M. Modo, Pedro Ramos‐Cabrer, Karsten Ruscher, Weihong Song, Jun Wang, Xuanyue Wang, Yun Wang, Haitao Wu, Lize Xiong, Yi Yang, Keqiang Ye, Jin‐Tai Yu, Xin‐Fu Zhou, Marietta Zille, Colin L. Masters, Piotr Walczak, Boltze Johannes, Xunming Ji, Yan‐Jiang Wang
Abstract The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid‐β (Aβ) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti‐Aβ antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aβ and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aβ from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.
人口老龄化的全球趋势导致阿尔茨海默病(AD)发病率的增加和相关的社会经济负担。淀粉样蛋白β (a β)代谢异常被认为是AD的一个重要病理机制，最近使用抗a β抗体的临床试验结果也支持了这一观点。尽管如此，目前的治疗方法对认知的好处是有限的。AD的病因是多因素的，包括Aβ和tau积聚、神经炎症、脱髓鞘、血管功能障碍和合并症，这些因素共同导致广泛的大脑神经变性和认知障碍。因此，仅仅从大脑中去除Aβ可能不足以对抗神经变性和保持认知。为了获得对AD的有效治疗，有必要(1)对导致神经退行性变的各种机制进行广泛的研究，包括神经成像技术的早期检测和更精确地表征从细胞到全系统水平的分子事件;(2)确定针对不同神经退行性变机制的神经保护干预靶点;(3)发现新的和最佳的神经保护干预策略组合，以维持AD患者的认知功能。阿尔茨海默病神经保护研究倡议的目标是促进协调，多学科的努力，以制定系统的神经保护策略，以对抗AD。目的是减轻阿尔茨海默病的所有病理过程，目标是停止甚至逆转认知能力下降。
{"title":"Preserving cognitive function in patients with Alzheimer's disease: The Alzheimer's disease neuroprotection research initiative (ADNRI)","authors":"Jie Liu, Heleen van Beusekom, Xian‐Le Bu, Gong Chen, Paulo Henrique Rosado de Castro, Xiaochun Chen, Xiaowei Chen, Andrew N. Clarkson, Tracy D. Farr, Yuhong Fu, Jianping Jia, Jukka Jolkkonen, Woojin Scott Kim, Paula Korhonen, Shen Li, Yajie Liang, Guang‐Hui Liu, Guiyou Liu, Yu‐Hui Liu, Tarja Malm, Xiaobo Mao, Joaquim Miguel Oliveira, Mike M. Modo, Pedro Ramos‐Cabrer, Karsten Ruscher, Weihong Song, Jun Wang, Xuanyue Wang, Yun Wang, Haitao Wu, Lize Xiong, Yi Yang, Keqiang Ye, Jin‐Tai Yu, Xin‐Fu Zhou, Marietta Zille, Colin L. Masters, Piotr Walczak, Boltze Johannes, Xunming Ji, Yan‐Jiang Wang","doi":"10.1002/nep3.23","DOIUrl":"https://doi.org/10.1002/nep3.23","url":null,"abstract":"Abstract The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid‐β (Aβ) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti‐Aβ antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aβ and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aβ from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136237396","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号