Experimental Neurology最新文献

{"title":"Repetitive cortical spreading depolarizations are prolonged early after experimental traumatic brain injury","authors":"Faith V. Best ,&nbsp;Jed A. Hartings ,&nbsp;Laura B. Ngwenya","doi":"10.1016/j.expneurol.2024.115120","DOIUrl":"10.1016/j.expneurol.2024.115120","url":null,"abstract":"<div><div>Cortical spreading depolarizations (CSDs) are the most common electrophysiological dysfunction following a traumatic brain injury (TBI), and clustered CSDs (≥3 CSDs in 2 h) are associated with poor outcomes 6 months after TBI. While many experimental studies have investigated a single CSD after injury, no known studies have investigated how time after injury affects the characteristics and impact of a CSD cluster. This study sought to determine the characteristics of a cluster of repetitive CSDs when induced at three different time points after moderate experimental TBI. Adult male Sprague Dawley rats underwent a lateral fluid percussion or sham injury, and repetitive CSDs were induced 0-, 3-, or 7-days post injury (dpi). Properties were analyzed from 2-h-long electrocorticographic (ECoG) and laser Doppler flowmetry (LDF) recordings. We did not observe deterioration of CSDs (2-Way ANOVA, <em>p</em> = 0.3572), depressions of background electrical activity (<em>p</em> = 0.0991), or hemodynamic responses (<em>p</em> = 0.1298) over the course of the recording. Repetitive CSD direct current shift durations were the longest when induced at 0dpi (<em>p</em> = 0.0161), while the durations of CSDs induced at 3dpi and 7dpi were similar to CSD durations in uninjured tissue (<em>p</em> = 0.9857). No differences were seen in the depression of background activity duration (<em>p</em> = 0.1901), and normal hemodynamic responses were observed at each time point. These findings confirm that CSDs are prolonged in impaired tissue and suggest that the impaired tissue may be more at risk of further damage when repetitive CSDs occur early after injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115120"},"PeriodicalIF":4.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876563","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":"Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh syndrome","authors":"Alyssa Huff ,&nbsp;Luiz Marcelo Oliveira ,&nbsp;Marlusa Karlen-Amarante ,&nbsp;Favour Ebiala ,&nbsp;Jan Marino Ramirez ,&nbsp;Franck Kalume","doi":"10.1016/j.expneurol.2024.115123","DOIUrl":"10.1016/j.expneurol.2024.115123","url":null,"abstract":"<div><div>Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, there was no difference in swallow motor pattern, breathing regeneration, weight, and life expectancy in the Vglut2-Ndufs4-KO CH mice compared to control CH, indicating a phenotypic rescue or prevention. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing discoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115123"},"PeriodicalIF":4.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876473","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":"Sodium ferulate attenuates ischaemic stroke by mediating the upregulation of thrombospondin-4 expression and combined treatment with bone marrow mesenchymal stem cells","authors":"Qian Zhang ,&nbsp;Zhiqiang Zhang ,&nbsp;Yihong Xiu ,&nbsp;Tianyu Zou ,&nbsp;Yaping Quan","doi":"10.1016/j.expneurol.2024.115124","DOIUrl":"10.1016/j.expneurol.2024.115124","url":null,"abstract":"<div><div>Ischaemic stroke is one of the major diseases affecting human health, involving complex and diverse pathological mechanisms, including inflammatory response, oxidative stress and angiogenesis. Sodium ferulate (SF) exerts a protective effect on cerebral ischaemia/reperfusion and when combined with bone marrow mesenchymal stem cells (BMSCs), has a considerable therapeutic effect on brain injury in rats. Here, we speculate that SF also exerts cerebroprotective effects. In this study, we found that after SF intervention, thrombospondin 4 (TSP4) protein expression increased in oxygen glucose deprivation/restoration (OGD/R)–treated human brain microvascular endothelial cells (HBMECs). In addition, the transfection of sh-TPS4 reversed the inhibitory effects of SF on inflammatory infiltration, oxidative stress and apoptosis and promoted effects on cell migration and angiogenesis. BMSCs have strong proliferation ability and multi-directional differentiation potential and alleviate brain injury. We found that compared with wild-type BMSCs, the TSP4-modified BMSCs had a more considerable effect that alleviated OGD/R-induced cell injury. Furthermore, SF combined with TSP4-modified BMSCs promoted the repair of damaged OGD/R-treated HBMECs by activating the PI3K/AKT/mTOR pathway. In the rat middle cerebral artery occlusion (MCAO) model, the therapeutic effect of SF combined with BMSCs on brain injury in rats was better than that of SF alone, and the therapeutic effect of the TSP4-modified BMSCs was better than that of the wild-type BMSCs. In conclusion, our results showed that SF upregulated TSP4 expression and combined with BMSCs to promote repair of damaged OGD/R-treated HBMECs and improve ischaemic stroke in rats.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115124"},"PeriodicalIF":4.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876583","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":"Oxygen–glucose-deprived peripheral blood mononuclear cells act on hypoxic lesions after ischemia-reperfusion injury","authors":"Takeshi Kanayama ,&nbsp;Masahiro Hatakeyama ,&nbsp;Natsuki Akiyama ,&nbsp;Yutaka Otsu ,&nbsp;Osamu Onodera ,&nbsp;Takayoshi Shimohata ,&nbsp;Masato Kanazawa","doi":"10.1016/j.expneurol.2024.115121","DOIUrl":"10.1016/j.expneurol.2024.115121","url":null,"abstract":"<div><h3>Background</h3><div>Despite advances in reperfusion therapies, ischemic stroke remains a major cause of long-term disability due to residual hypoxic lesions persisting after macrovascular reperfusion. These residual hypoxic lesions, caused by microvascular dysfunction, represent an important therapeutic target. We previously demonstrated that oxygen–glucose-deprived peripheral blood mononuclear cells (OGD-PBMCs) migrate to ischemic brain regions and promote functional recovery after stroke. This recovery occurs through mechanisms involving hypoxia-inducible factor-1α, exosomal miR-155-5p, and vascular endothelial growth factor (VEGF). However, it remains unclear whether OGD-PBMCs target hypoxic regions.</div></div><div><h3>Methods</h3><div>We evaluated cerebral blood flow using a laser speckle flow imaging system. Next, we utilized pimonidazole to investigate the presence of hypoxic lesions after ischemia–reperfusion injury in a rat suture occlusion model in immunohistochemical analyses. We also compared levels of a cell surface receptor in human PBMCs by flow cytometric analysis under normoxic and OGD conditions.</div></div><div><h3>Results</h3><div>We found persistent pimonidazole-positive hypoxic lesions at 10- and 28-days post-reperfusion despite restored gross cerebral perfusion. Treatment with the C-X-C motif chemokine receptor 4 (CXCR4) inhibitor AMD3100 before and after OGD-PBMCs administration reduced the number of OGD-PBMCs in the brain parenchyma compared to the control group (<em>P</em> = 0.018). Administered OGD-PBMCs localized within these hypoxic regions via the stromal cell-derived factor-1/CXCR4 chemotactic axis. OGD-PBMCs enhanced VEGF expression, specifically within hypoxic lesions, compared to the phosphate-buffered saline group (<em>P</em> &lt; 0.01). Furthermore, OGD-PBMCs reduced the number of pimonidazole-positive hypoxic cells in the ischemic core on 28 days. These findings demonstrate that OGD-PBMCs selectively migrate to and modulate the microenvironment of hypoxic lesions following cerebral ischemia-reperfusion injury.</div></div><div><h3>Conclusion</h3><div>Targeting these residual hypoxic regions may underline the therapeutic effects of OGD-PBMC treatment and represent a promising strategy for improving stroke recovery despite successful recanalization.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115121"},"PeriodicalIF":4.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age differences in organophosphorus nerve agent-induced seizure, blood brain barrier integrity, and neurodegeneration in midazolam-treated rats","authors":"Donna A. Nguyen ,&nbsp;Jerome Niquet ,&nbsp;Brenda Marrero-Rosado ,&nbsp;Caroline R. Schultz ,&nbsp;Michael F. Stone ,&nbsp;Marcio de Araujo Furtado ,&nbsp;Abiel K. Biney ,&nbsp;Lucille A. Lumley","doi":"10.1016/j.expneurol.2024.115122","DOIUrl":"10.1016/j.expneurol.2024.115122","url":null,"abstract":"<div><div>Exposure to organophosphorus nerve agents irreversibly inhibits acetylcholinesterase and may lead to cholinergic crisis and seizures. Although benzodiazepines are the standard of care after nerve agent-induced status epilepticus, when treatment is delayed for up to 30 min or more, refractory status epilepticus can develop. Adult male rodents are often utilized for evaluation of therapeutic efficacy against nerve agent exposure. However, there may be age and sex differences in toxicity and in therapeutic response. We previously reported that juvenile rats are less susceptible to the lethal effects of soman compared to adults, while pups are the most susceptible. Here, we report on age and sex differences in delayed midazolam treatment efficacy on survival, seizures and brain pathology. Male and female pups, juvenile and adult rats were exposed to an equitoxic dose of soman and treated with atropine sulfate and the oxime asoxime chloride (HI-6 dimethanesulphonate) 1 min after exposure and with midazolam 40 min after seizure onset, determined by EEG in juvenile and adult rats, and by behavior in pups. Survival, seizure data, and spontaneous recurrent seizures were evaluated. Brains were processed to assess neurodegeneration, neuroinflammation, and blood brain barrier (BBB) integrity. Juvenile and adult rats exposed to soman and treated with midazolam had BBB disruption, epileptogenesis, neurodegeneration, microglial activation, and astrogliosis; adult rats had poorer outcomes. Pups and juvenile rats exposed to soman had poor survival prior to midazolam treatment but most survived once treated; overall, neurodegeneration or disrupted BBB integrity was not detected in midazolam-treated pups. We found that age is a determinant factor in soman-induced toxicity and response to standard medical countermeasures. In addition, we observed sex differences in response to soman in juveniles and males with respect to body weight growth curves and in neuronal loss in juveniles and adults. Adjunct therapies to midazolam are warranted and it is important to evaluate both age and sex as factors in therapeutic response.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115122"},"PeriodicalIF":4.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876456","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":"Disruption of RNA-binding proteins in neurological disorders","authors":"Luyang Huang,&nbsp;Bo Zhao,&nbsp;Youzhong Wan","doi":"10.1016/j.expneurol.2024.115119","DOIUrl":"10.1016/j.expneurol.2024.115119","url":null,"abstract":"<div><div>RNA-binding proteins (RBPs) are multifunctional proteins essential for the regulation of RNA processing and metabolism, contributing to the maintenance of cell homeostasis by modulating the expression of target genes. Many RBPs have been associated with neuron-specific processes vital for neuronal development and survival. RBP dysfunction may result in aberrations in RNA processing, which subsequently initiate a cascade of effects. Notably, RBPs are involved in the onset and progression of neurological disorders <em>via</em> diverse mechanisms. Disruption of RBPs not only affects RNA processing, but also promotes the abnormal aggregation of proteins into toxic inclusion bodies, and contributes to immune responses that drive the progression of neurological diseases. In this review, we summarize recent discoveries relating to the roles of RBPs in neurological diseases, discuss their contributions to such conditions, and highlight the unique functions of these RBPs within the nervous system.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115119"},"PeriodicalIF":4.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871955","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":"Suppression of cGAS/STING pathway-triggered necroptosis in the hippocampus relates H2S to attenuate cognitive dysfunction of Parkinson's disease","authors":"Xin-Le Huang ,&nbsp;Yu Hu ,&nbsp;Wu Jiang ,&nbsp;Jia-Mei Jiang ,&nbsp;Wei Zou ,&nbsp;Ping Zhang ,&nbsp;Xiao-Qing Tang","doi":"10.1016/j.expneurol.2024.115093","DOIUrl":"10.1016/j.expneurol.2024.115093","url":null,"abstract":"<div><h3>Background</h3><div>Cognitive dysfunction is the most severe non-motor symptom of Parkinson's disease (PD). Our previous study revealed that hydrogen sulfide (H₂S) ameliorates cognitive dysfunction in PD, but the underlying mechanisms remain unclear. Hippocampal necroptosis plays a vital role in cognitive dysfunction, while the cGAS/STING pathway triggers necroptosis. To understand the mechanism underlying the inhibitory role of H₂S in cognitive dysfunction of PD, we explored whether H₂S reduces the enhancement of necroptosis and the activation of the cGAS/STING pathway in the hippocampus of the rotenone (ROT)-induced PD rat model.</div></div><div><h3>Method</h3><div>Adult Sprague-Dawley (SD) rats were pre-treated with NaHS (30 or 100 μmol/kg/d, <em>i.p.</em>) for 7 days and then co-treated with ROT (2 mg/kg/d, <em>s.i.</em>) for 35 days. The Y-maze and Morris water maze (MWM) tests were used to assess the cognitive function. Hematoxylin-eosin (H&amp;E) staining was used to detect the hippocampal pathological morphology. Western blotting analysis was used to measure the expressions of proteins. Enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factors.</div></div><div><h3>Result</h3><div>NaHS (a donor of H₂S) mitigated cognitive dysfunction in ROT-exposed rats, according to the Y-maze and MWM tests. NaHS treatment also markedly down-regulated the expressions of necroptosis-related proteins (RIPK1, RIPK3, and MLKL) and decreased the levels of necroptosis-related inflammatory factors (IL-6 and IL-1β) in the hippocampus of ROT-exposed rats. Furthermore, NaHS treatment reduced the expressions of cGAS/STING pathway-related proteins (cGAS, STING, p-TBK1^Ser172, p-IRF3^Ser396, and p-P65^Ser536) and decreased the contents of pro-inflammation factors (INF-β and TNF-α) in the hippocampus of ROT-exposed rats.</div></div><div><h3>Conclusion</h3><div>H₂S attenuates the cGAS/STING pathway-triggered necroptosis in the hippocampus, which is related to H₂S to attenuate cognitive dysfunction in PD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115093"},"PeriodicalIF":4.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785022","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":"Optical coherence tomography enables longitudinal evaluation of cell graft-directed remodeling in stroke lesions","authors":"Honour O. Adewumi ,&nbsp;Matthew G. Simkulet ,&nbsp;Gülce Küreli ,&nbsp;John T. Giblin ,&nbsp;Arnaldo Bisbal Lopez ,&nbsp;Şefik Evren Erdener ,&nbsp;John Jiang ,&nbsp;David A. Boas ,&nbsp;Timothy M. O’Shea","doi":"10.1016/j.expneurol.2024.115117","DOIUrl":"10.1016/j.expneurol.2024.115117","url":null,"abstract":"<div><div>Stem cell grafting can promote glial repair of adult stroke injuries during the subacute wound healing phase, but graft survival and glial repair outcomes are perturbed by lesion severity and mode of injury. To better understand how stroke lesion environments alter the functions of cell grafts, we employed optical coherence tomography (OCT) to longitudinally image mouse cortical photothrombotic ischemic strokes treated with allogeneic neural progenitor cell (NPC) grafts. OCT angiography, signal intensity, and signal decay resulting from optical scattering were assessed at multiple timepoints across two weeks in mice receiving an NPC graft or an injection of saline at two days after stroke. OCT scattering information revealed pronounced axial lesion contraction that naturally occurred throughout the subacute wound healing phase that was not modified by either NPC or saline treatment. By analyzing OCT signal intensity along the coronal plane, we observed dramatic contraction of the cortex away from the imaging window in the first week after stroke which impaired conventional OCT angiography but which enabled the detection of NPC graft-induced glial repair. There was moderate, but variable, NPC graft survival at photothrombotic strokes at two weeks which was inversely correlated with acute stroke lesion sizes as measured by OCT prior to treatment, suggesting a prognostic role for OCT imaging and reinforcing the dominant effect of lesion size and severity on graft outcome. Overall, our findings demonstrate the utility of OCT imaging for both tracking and predicting natural and treatment-directed changes in ischemic stroke lesion cores.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115117"},"PeriodicalIF":4.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853620","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":"Insight into cerebral microvessel endothelial regulation of cognitive impairment: A systematic review of the causes and consequences","authors":"Chang Liu ,&nbsp;Xiaoyu Chen ,&nbsp;Shaojie Yang ,&nbsp;Xuncui Wang ,&nbsp;Peiyang Sun ,&nbsp;Jingji Wang ,&nbsp;Guoqi Zhu","doi":"10.1016/j.expneurol.2024.115116","DOIUrl":"10.1016/j.expneurol.2024.115116","url":null,"abstract":"<div><div>Research on cognitive impairment (CI) has increasingly focused on the central nervous system, identifying numerous neuronal targets and circuits of relevance for CI pathogenesis and treatment. Brain microvascular endothelial cells (BMECs) form a barrier between the peripheral and central nervous systems, constituting the primary component of the blood-brain barrier (BBB) and playing a vital role in maintaining neural homeostasis. Stemming from the recognition of the close link between vascular dysfunction and CI, in recent years intense research has been devoted to characterize the pathological changes and molecular mechanisms underlying BMEC dysfunction both during normal aging and in disorders of cognition such as Alzheimer's disease and vascular dementia. In this review, keywords such as “dementia”, “cognitive impairment”, and “endothelium” were used to search PubMed and Web of Science. Based on the literature thus retrieved, we first review some common triggers of CI, <em>i.e.</em>, amyloid beta and tau deposition, chronic cerebral hypoperfusion, hyperglycemia, viral infections, and neuroinflammation, and describe the specific mechanisms responsible for endothelial damage. Second, we review molecular aspects of endothelial damage leading to BBB disruption, neuronal injury, and myelin degeneration, which are crucial events underlying CI. Finally, we summarize the potential targets of endothelial damage in the development of cognitive dysfunction associated with Alzheimer's disease, vascular dementia, type 2 diabetes mellitus, and physiological aging. A thorough understanding of the induction mechanism and potential outcomes of microvascular endothelial damage is of great significance for the study of CI, to guide both diagnostic and therapeutic approaches for its prevention and treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115116"},"PeriodicalIF":4.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827947","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":"Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis","authors":"Alessandra Pistolesi ,&nbsp;Giuseppe Ranieri ,&nbsp;Maura Calvani ,&nbsp;Daniele Guasti ,&nbsp;Alberto Chiarugi ,&nbsp;Daniela Buonvicino","doi":"10.1016/j.expneurol.2024.115095","DOIUrl":"10.1016/j.expneurol.2024.115095","url":null,"abstract":"<div><div>Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115095"},"PeriodicalIF":4.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824077","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}