Experimental Neurology最新文献

{"title":"Gut microbiota-derived 3-indoleacetic acid confers a protection against sepsis-associated encephalopathy through microglial aryl hydrocarbon receptors.","authors":"Zhi-Bin Huang, Guo-Pan Zhang, Chen-Xin Lu, Cansheng Gong, Xiaotan Gao, Yanqi Lin, Ping Su, Wenyan Xu, Yongbao Lin, Na Lin, Xuyang Wu, Xiaohui Chen, Ting Zheng, Xiaochun Zheng","doi":"10.1016/j.expneurol.2024.115055","DOIUrl":"10.1016/j.expneurol.2024.115055","url":null,"abstract":"<p><strong>Background: </strong>The gut microbiota significantly contributes to the pathogenesis of central nervous system disorders. Among the bioactive molecules produced by the gut microbiota, 3-indoleacetic acid (IAA) has been shown to attenuate oxidative stress and inflammatory responses. This experiment aimed to determine the impacts of IAA on sepsis-associated encephalopathy (SAE) and the underlying mechanisms.</p><p><strong>Methods: </strong>A total of 34 septic patients and 24 healthy controls were included in the analysis of the clinical correlation between fecal IAA and septic encephalopathy. Fecal microbiota transplantation was used to verify the role of the gut microbiota and its metabolites in SAE. Male C57BL/6 mice aged six to eight weeks, pre-treated with IAA via oral gavage, were subjected to the cecal ligation and puncture (CLP) procedures. This treatment was administered either in combination with an aryl hydrocarbon receptor (AhR) antagonist, CH223191, or a CSF1R inhibitor, PLX3397, to eliminate microglia. Both immunofluorescence staining and enzyme-linked immunosorbent assays were used to evaluate microglia activation and inflammatory cytokine secretion. Behavioral assessments were conducted to quantify neurological deficits.</p><p><strong>Results: </strong>A decreased fecal level of IAA was observed in the patients with sepsis-associated delirium (SAD), a manifestation of SAE. A reduced IAA level was significantly associated with worsen clinical outcomes. Fecal microbiota transplantation from the SAD patients induced an SAE-like phenotype in mice, but supplementing exogenous IAA improved the SAE-like phenotype, mediated by microglia. IAA effectively binded with the aryl hydrocarbon receptor (AhR). Furthermore, IAA increased the nuclear activity of AhR in the lipopolysaccharide (LPS)-treated microglial cells, leading to reduced secretion of inflammatory cytokines. The AhR inhibitor CH223191 counteracted the protective effect of IAA against SAE in mice.</p><p><strong>Conclusions: </strong>Gut microbiota-derived IAA confers a protection against SAE by activating AhR in microglia, improving neuronal and cognitive impairments. Thus, IAA holds the promise as a potential therapeutic agent for managing SAE.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115055"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury.","authors":"Mehdi Ahmadian, Erin Erskine, Liisa Wainman, Oliver H Wearing, Jennifer S Duffy, Liam C Stewart, Ryan L Hoiland, Alissa Taki, Raphael R Perim, Gordon S Mitchell, Jonathan P Little, Patrick J Mueller, Glen E Foster, Christopher R West","doi":"10.1016/j.expneurol.2024.115054","DOIUrl":"10.1016/j.expneurol.2024.115054","url":null,"abstract":"<p><p>The loss of medullary control of spinal circuits controlling the heart and blood vessels is a unifying mechanism linking both hemodynamic instability and the risk for cardiovascular diseases (CVD) following spinal cord injury (SCI). As such, new avenues to regulate sympathetic activity are essential to mitigate CVD in this population. Acute intermittent hypoxia (AIH) induces a type of neuroplasticity known as long-term facilitation (LTF), a persistent increase in nerve activity post-AIH in spinal motor circuits. Whether LTF occurs within the sympathetic circuit following SCI is largely unknown. We aimed to test whether AIH elicits sympathetic LTF (i.e., sLTF) and attenuates hypoactivity in sub-lesional splanchnic sympathetic circuits in a male rat model of SCI. In 3 experimental series, we tested whether 1) high-thoracic contusion SCI induces hypoactivity in splanchnic sympathetic nerve activity, 2) AIH elicits sLTF following SCI, and 3) sLTF requires carotid chemoreflex activation or spinal cord tissue hypoxia. Our results indicate that a single-session of AIH therapy (10 × 1 min of F_iO₂ = 0.1, interspersed with 2 min of F_iO₂ = 1.0) delivered at 2 weeks following SCI attenuates SCI-induced sympathetic hypoactivity by eliciting sLTF 90 min post-treatment that is independent of peripheral chemoreflex activation and/or spinal cord hypoxia. These findings advance our mechanistic understanding of AIH in the field and yield new insights into factors underpinning AIH-induced sLTF following SCI in a rat model. Our findings also set the stage for the chronic application of AIH to alleviate secondary complications resulting from sympathetic hypoactivity following SCI.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115054"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease","authors":"Sara El-desouky ,&nbsp;Mohammad Abdel-Halim ,&nbsp;Reem K. Fathalla ,&nbsp;Ashraf H. Abadi ,&nbsp;Gary A. Piazza ,&nbsp;Mohamed Salama ,&nbsp;Sabry Ahmed El-khodery ,&nbsp;Mohamed A. Youssef ,&nbsp;Sara Elfarrash","doi":"10.1016/j.expneurol.2024.115058","DOIUrl":"10.1016/j.expneurol.2024.115058","url":null,"abstract":"<div><div>Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, <em>RF26,</em> using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. <em>RF26</em> successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, <em>RF26</em> -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of <em>RF26</em> as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"384 ","pages":"Article 115058"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of PAR1 contributes to ferroptosis of Schwann cells and inhibits regeneration of myelin sheath after sciatic nerve crush injury in rats via Hippo-YAP/ACSL4 pathway.","authors":"Wu Zhimin, Sun Jun, Liao Zhi, Sun Tao, Huang Lixin, Jia Qiao, Cong Ling, Chuan Chen, Zhang Baoyu, Wang Hui","doi":"10.1016/j.expneurol.2024.115053","DOIUrl":"10.1016/j.expneurol.2024.115053","url":null,"abstract":"<p><strong>Objective: </strong>Peripheral nerve injury (PNI) is characterized by high incidence and sequela rate. Recently, there was increasing evidence that has shown ferroptosis may impede functional recovery. Our objective is to explore the novel mechanism that regulates ferroptosis after PNI.</p><p><strong>Methods: </strong>LC-MS/MS proteomics was used to explore the possible differential signals, while PCR array was performed to investigate the differential factors. Besides, we also tried to activate or inhibit the key factors and then observe the level of ferroptosis. Regeneration of myelin sheath was finally examined in vivo via transmission electron microscopy.</p><p><strong>Results: </strong>Proteomics analysis suggested coagulation signal was activated after sciatic nerve crush injury, in which high expression of F2 (encoding thrombin) and F2r (encoding PAR1) were observed. Both thrombin and PAR1-targeted activator TRAP6 can induce ferroptosis in RSC96 cells, which can be rescued by Vorapaxar (PAR1 targeted inhibitor) in vitro. Further PCR array revealed that activation of PAR1 induced ferroptosis in RSC96 cells by increasing expression of YAP and ACSL4. Immunofluorescence of sciatic nerve confirmed that the expression of YAP and ACSL4 were simultaneously reduced after PAR1 inhibition, which may contribute to myelin regeneration after injury in SD rats.</p><p><strong>Conclusion: </strong>Inhibition of PAR1 can relieve ferroptosis after sciatic nerve crush injury in SD rats through Hippo-YAP/ACSL4 pathway, thereby regulating myelin regeneration after injury. In summary, PAR1/Hippo-YAP/ACSL4 pathway may be a promising therapeutic target for promoting functional recovery post-sciatic crush injury.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115053"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conceptualization and standardization of a non-invasive closed head injury model using directed shockwave to mice","authors":"Mohd Aleem,&nbsp;Princy Verma,&nbsp;Kailash Manda","doi":"10.1016/j.expneurol.2024.115051","DOIUrl":"10.1016/j.expneurol.2024.115051","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with closed head injury (CHI) being one of the most common forms of TBI. Preclinical modeling of TBI is challenging due to confounding factors like craniectomy and poorly controlled injury severity. This study proposes a non-invasive CHI model using directed shockwaves. The mice heads were exposed to the shockwave and accommodated together following the implantation of RFID tags for automated neurocognitive assessment. Following a 13-days paradigm, mice underwent a digital gait analysis and subsequent classical behavioral test paradigms for affective, cognitive, and locomotor functions. Qualitative and quantitative histopathological assessment was carried out for shockwave pulses-dependent changes in terms of lesion volume, neuronal death, dendritic complexity, and spine density. Studies showed shockwave pulses-dependent differences in survivability, righting reflex, neural damage, and death. Shockwave-exposed mice showed significantly impaired learning and cognitive flexibility. Interestingly, exposed mice showed locomotor hyperactivity and risk-taking behavior (lack of anxiety) along with depression-like phenotypes. Our result suggests that the shockwave-based CHI models result in the clinically relevant phenotype and are precisely controlled for reproducibility.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"384 ","pages":"Article 115051"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models","authors":"Valeria Casiraghi ,&nbsp;Marta Nice Sorce ,&nbsp;Serena Santangelo ,&nbsp;Sabrina Invernizzi ,&nbsp;Patrizia Bossolasco ,&nbsp;Chiara Lattuada ,&nbsp;Cristina Battaglia ,&nbsp;Marco Venturin ,&nbsp;Vincenzo Silani ,&nbsp;Claudia Colombrita ,&nbsp;Antonia Ratti","doi":"10.1016/j.expneurol.2024.115057","DOIUrl":"10.1016/j.expneurol.2024.115057","url":null,"abstract":"<div><div>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined.</div><div>In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes <em>UNC13A</em> and <em>POLDIP3</em> as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D <em>in vitro</em> model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin.</div><div>Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable <em>in vitro</em> platforms for future drug screening approaches in ALS.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115057"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sevoflurane aggravates cognitive impairment in OSAS mice through tau phosphorylation and mitochondrial dysfunction.","authors":"Feixiang Li, Dujuan Li, Bingqing Gong, Zichen Song, Yang Yu, Yonghao Yu, Yongyan Yang","doi":"10.1016/j.expneurol.2024.115056","DOIUrl":"10.1016/j.expneurol.2024.115056","url":null,"abstract":"<p><p>With an aging population, the incidence of obstructive sleep apnea syndrome (OSAS) is rising, resulting in a growing number of patients undergoing surgery who are also affected by OSAS. The combined impact of anesthetic drugs and OSAS-related neurological damage has drawn significant attention. Here, wild-type (WT) and Tau-knockout (Tau-KO) mice were subjected to intermittent hypoxia and sevoflurane exposure to induce OSAS and sevoflurane-induced neurotoxicity. Protein expression of tau phosphorylation (Tau-Ser202/Thr205 and Tau-Ser422) was measured by Western blotting. Immunofluorescence was used to visualize tau phosphorylation (Tau-Ser202/Thr205) in the hippocampal CA1 region. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. Cognitive functions were assessed using the Morris water maze and Y-maze tests. We found that compared to the WT OSAS group, sevoflurane significantly increased tau phosphorylation and mitochondrial dysfunction in WT OSAS mice, leading to cognitive impairment. Interestingly, idebenone treatment mitigated sevoflurane-induced mitochondrial dysfunction and cognitive impairment in WT OSAS mice, but it did not affect tau phosphorylation. Compared to the Tau-KO control group, Tau-KO OSAS mice exhibited mitochondrial dysfunction and cognitive impairment, but sevoflurane did not exacerbate mitochondrial dysfunction or cognitive impairment in these mice. These findings suggest that sevoflurane exacerbates cognitive impairments in OSAS mice through tau phosphorylation-induced mitochondrial dysfunction, but also uncovered differing mechanisms between cognitive impairments induced by OSAS and those exacerbated by sevoflurane.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115056"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking new Frontiers: The cellular and molecular impact of extracorporeal shock wave therapy (ESWT) on central nervous system (CNS) disorders and peripheral nerve injuries (PNI)","authors":"Baodan Cao ,&nbsp;Xiaobin Tang ,&nbsp;Chuangjian Liu ,&nbsp;Guangyu Xu ,&nbsp;Mingcheng Lei ,&nbsp;Fan Wu ,&nbsp;Wei Chen ,&nbsp;Hongbin Ni ,&nbsp;Feng Zhang","doi":"10.1016/j.expneurol.2024.115052","DOIUrl":"10.1016/j.expneurol.2024.115052","url":null,"abstract":"<div><div>Neurological disorders encompassing both central nervous system (CNS) diseases and peripheral nerve injuries (PNI), represent significant challenges in modern clinical practice. Conditions such as stroke, spinal cord injuries, and carpal tunnel syndrome can cause debilitating impairments, leading to reduced quality of life and placing a heavy burden on healthcare systems. Current treatment strategies, including pharmacological interventions and surgical procedures, often yield limited results, and many patients experience suboptimal outcomes or treatment-associated risks. In light of these limitations, there is a growing interest in exploring non-invasive therapeutic alternatives. Among these, extracorporeal shock wave therapy (ESWT) has eme rged as a promising modality, demonstrating efficacy in musculoskeletal conditions and gaining attention for its potential role in neurological disorders. This manuscript aims to provide a comprehensive overview of the cellular and molecular mechanisms underlying ESWT, focusing on its therapeutic applications in CNS diseases and PNI, thereby shedding light on its potential to revolutionize the treatment landscape for neurological conditions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"384 ","pages":"Article 115052"},"PeriodicalIF":4.6,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing data standards to advance translation in spinal cord injury.","authors":"Vanessa K Noonan, Suzanne Humphreys, Fin Biering-Sorensen, Susan Charlifue, Yuying Chen, James D Guest, Linda A T Jones, Jennifer French, Eva Widerstrom-Noga, Vance P Lemmon, Allen W Heinemann, Jan M Schwab, Aaron A Phillips, Marzieh Mussavi Rizi, John L K Kramer, Catherine R Jutzeler, Abel Torres-Espin","doi":"10.1016/j.expneurol.2024.115048","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.115048","url":null,"abstract":"<p><p>Data standards are available for spinal cord injury (SCI). The International SCI Data Sets were created in 2002 and there are currently 27 freely available. In 2015 the National Institute of Neurological Disorders and Stroke developed clinical common data elements to promote clinical data sharing in SCI. The objective of this paper is to provide an overview of SCI data standards, describe learnings from the traumatic brain injury (TBI) field using data to enhance research and care, and discuss future opportunities in SCI. Given the complexity of SCI, frameworks such as a systems medicine approach and Big Data perspective have been advanced. Implementation of these frameworks require multi-modal data and a shift towards open science and principles such as requiring data to be FAIR (Findable, Accessible, Interoperable and Reusable). Advanced analytics such as artificial intelligence require data to be interoperable so data can be exchanged among different technology systems and software applications. The TBI field has multiple ongoing initiatives to promote sharing and data reuse for both pre-clinical and clinical studies, which is an opportunity for the SCI field given these injuries can often occur concomitantly. The adoption of interoperable standards, data sharing, open science, and the use of advanced analytics in SCI is needed to facilitate translation in research and care. It is critical that people with lived experience are engaged to ensure data are relevant and enhances quality of life.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115048"},"PeriodicalIF":4.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of GABAergic system as a therapeutic option in stroke.","authors":"Milka Perovic, Damjan Pavlovic, Zoe Palmer, Mariana S B Udo, Cristiane T Citadin, Krista M Rodgers, Celeste Yin-Chien Wu, Quanguang Zhang, Hung Wen Lin, Vesna Tesic","doi":"10.1016/j.expneurol.2024.115050","DOIUrl":"10.1016/j.expneurol.2024.115050","url":null,"abstract":"<p><p>Stroke is one of the leading causes of death and permanent adult disability worldwide. Despite the improvements in reducing the rate and mortality, the societal burden and costs of treatment associated with stroke management are increasing. Most of the therapeutic approaches directly targeting ischemic injury have failed to reduce short- and long-term morbidity and mortality and more effective therapeutic strategies are still needed to promote post-stroke functional recovery. Decades of stroke research have been focused on hyperexcitability and glutamate-induced excitotoxicity in the acute phase of ischemia and their relation to motor deficits. Recent advances in understanding the pathophysiology of stroke have been made with several lines of evidence suggesting that changes in the neurotransmission of the major inhibitory system via γ-Aminobutyric acid (GABA) play a particularly important role in functional recovery and deserve further attention. The present review provides an overview of how GABAergic neurotransmission changes correlate with stroke recovery and outlines GABAergic system modulators with special emphasis on neurosteroids that have been shown to affect stroke pathogenesis or plasticity or to protect against cognitive decline. Supporting evidence from both animal and human clinical studies is presented and the potential for GABA signaling-targeted therapies for stroke is discussed to translate this concept to human neural repair therapies. Age and sex are considered crucial parameters related to the pathophysiology of stroke and important factors in the development of therapeutic pharmacological strategies. Future work is needed to deepen our knowledge of the neurochemical changes after stroke, extend the conceptual framework, and allow for the development of more effective interventions that include the modulation of the inhibitory system.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115050"},"PeriodicalIF":4.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}