Experimental Neurology最新文献

{"title":"Molecular and functional changes in GABAergic transmission during epileptogenesis in a rat model of post-traumatic epilepsy","authors":"Noora Puhakka ,&nbsp;Pierangelo Cifelli ,&nbsp;Gabriele Ruffolo ,&nbsp;Alessandro Gaeta ,&nbsp;Cristina Roseti ,&nbsp;Angela Di Iacovo ,&nbsp;Johanna Tiilikainen ,&nbsp;Xavier Ekolle Ndode-Ekane ,&nbsp;Anssi Lipponen ,&nbsp;Meinrad Drexel ,&nbsp;Günther Sperk ,&nbsp;Asla Pitkänen ,&nbsp;Eleonora Palma","doi":"10.1016/j.expneurol.2025.115183","DOIUrl":"10.1016/j.expneurol.2025.115183","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is one of the leading causes of structural epilepsy. Our objective was to investigate the molecular and functional dysregulation of GABAergic neurotransmission during a wide time window from acute to chronic phases of epileptogenesis after TBI. Perilesional and thalamic tissues sampled from a clinically relevant animal model of post-traumatic epilepsy induced by lateral fluid-percussion injury were investigated using <em>in situ</em> hybridization, immunohistochemistry and RNA sequencing. For functional analysis, we utilized a membrane microtransplantation technique in <em>Xenopus</em> oocytes in order to overcome the technical difficulties that would stem from recording directly from highly damaged lesional and perilesional brain tissues. Already at 6 to 24 h post-TBI we found a dysregulation in the expression of GABA_AR β3- and δ-subunits, which persisted for up to 4 months. Further, gene set enrichment analysis revealed a negative enrichment of GABA receptor signaling in the perilesional cortex and ipsilateral thalamus. These changes occurred in parallel to the dysregulation of the two main cation-chloride cotransporter genes (<em>Slc12a2</em> and <em>Slc12a5</em>) both in the perilesional cortex and the ipsilateral thalamus. Our functional analysis revealed that the GABA current reversal potential (E_GABA) was shifted towards more depolarized values in the perilesional cortex and ipsilateral thalamus. Our data demonstrate a rapid onset and long-lasting duration of GABAergic dysfunction after TBI and support the hypothesis that an early treatment with agents modulating the GABAergic transmission in the thalamo-cortical-thalamic circuitry may suppress early seizures as well as prevent or slow down epileptogenesis after TBI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"387 ","pages":"Article 115183"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406477","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":"Traumatic brain injury-induced anxiety: Injury and plasticity of the central noradrenergic system","authors":"Shigeharu Tsuda ,&nbsp;Jiamei Hou ,&nbsp;Floyd J. Thompson ,&nbsp;Prodip K. Bose","doi":"10.1016/j.expneurol.2025.115182","DOIUrl":"10.1016/j.expneurol.2025.115182","url":null,"abstract":"<div><div>Long-term anxiety is a hallmark symptom following traumatic brain injury (TBI). Although the central noradrenergic system (CNAS) is known to play a critical role in anxiety by regulating the excitability of several intricately interconnected brain structures via its projections to them, critical questions remain regarding the nature and extent of TBI-induced neuroplastic alterations in the CNAS and how these alterations relate to anxiety disorders. Knowledge relative to these questions is pivotal to development and refinement of therapies for TBI-associated anxiety disorders, including post-traumatic stress disorder. To this end, this study was designed to determine the impacts of chronic TBI on neuroplasticity of the CNAS and their significance in anxiety disorders in a clinically relevant rodent model. A standardized weight-drop model was used to produce controlled impacts of mild-to-moderate TBI in rats. Following the elevated plus maze tests to longitudinally assess anxiety-like behavior at 2 and 18 weeks post-injury of TBI animals, brain tissues of naïve and TBI rats were coronally sectioned and immunostained for a noradrenergic (NA) marker (dopamine β-hydroxylase) and neuronal nuclei in the central NA production sites and critical anxiety-regulating brain structures. We discovered that TBI caused robust losses of NA cells in the locus coeruleus and NA innervation of the central nucleus of the amygdala, an emotional processing center. Conversely, TBI caused intense gains of NA cells in the A2/A1 cell groups and NA innervation of other major anxiety-regulating regions. These changes coincided with progressively elevated anxiety-like behavior. Possibly, NA properties of A2/A1 cells were upregulated to compensate for the TBI-induced severe cell losses in the locus coeruleus. We conclude that these bi-directional vast alterations in the CNAS following chronic TBI contribute to dysregulated anxiety and, in part, the pathophysiology of human post-traumatic stress disorder.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"388 ","pages":"Article 115182"},"PeriodicalIF":4.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390538","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":"Advances in brain ischemia mechanisms and treatment approaches: Recent insights and inflammation-driven risks","authors":"Doyoon Kim ,&nbsp;Satoru Morikawa ,&nbsp;Taneaki Nakagawa ,&nbsp;Hideyuki Okano ,&nbsp;Yoshitaka Kase","doi":"10.1016/j.expneurol.2025.115177","DOIUrl":"10.1016/j.expneurol.2025.115177","url":null,"abstract":"<div><div>The application of existing radical treatments for stroke is limited to a small number of cases, with current practices predominantly focusing on conservative therapy. This review examines the pathophysiology of excitotoxicity, oxidative stress, and inflammation during brain ischemia caused by stroke, highlighting insights into each pathology and reporting the latest therapeutic developments that are expected to serve as new treatment options. Finally, we outline the recent attention given to the relationship between periodontal disease and stroke. We propose addressing the limitations of existing treatments for stroke and suggest novel therapeutic approaches while also presenting the potential contribution of periodontal disease treatment to the prevention of stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115177"},"PeriodicalIF":4.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374041","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":"Proportional recovery in mice with cortical stroke","authors":"Aref Kalantari ,&nbsp;Carolin Hambrock ,&nbsp;Christian Grefkes ,&nbsp;Gereon R. Fink ,&nbsp;Markus Aswendt","doi":"10.1016/j.expneurol.2025.115180","DOIUrl":"10.1016/j.expneurol.2025.115180","url":null,"abstract":"<div><div>The proportional Recovery Rule (PRR) has been frequently used to predict recovery of lost motor function in acute stroke patients. However, it still needs to be explored whether the same concept applies to preclinical, i.e. animal models of stroke recovery. To address this question, we investigated behavioral data from 125 adult male C57Bl/6 J mice with photothrombotic strokes in the sensorimotor cortex. Lesion size and location were determined in the first week using in vivo T2-weighted MRI. Motor recovery was evaluated repeatedly over four weeks using the cylinder, grid walk, and rotating beam test. Recovery trajectories were analyzed using a newly formulated Mouse Recovery Rule (MRR), comparing it against the traditional PRR. Initial findings indicated variable recovery patterns, which were separated using a stepwise linear regression approach resulting in two clusters: 47 % PRR and 53 % MRR. No significant correlation was found between recovery patterns and lesion size or location, suggesting that other biological factors drive individual differences in recovery. Of note, in the MRR cluster, animals recovered to 90 % of their initial behavioral state within the first four weeks post-stroke, which is higher than the 70 % recovery usually reported in human PRR studies. This study demonstrates the complexity of translating the PRR to stroke recovery models in mice and underscores the need for species-specific recovery models. Our findings have implications for designing and interpreting therapeutic strategies for stroke recovery in preclinical settings, with the potential to improve the predictive accuracy of stroke recovery assessments.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115180"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363892","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":"Prolyl hydroxylase inhibitor desidustat improves stroke outcomes via enhancing efferocytosis in mice with chronic kidney disease","authors":"Harpreet Kaur ,&nbsp;Nilesh Pandey ,&nbsp;Lakshmi Chandaluri ,&nbsp;Nirvana Shaaban ,&nbsp;Alexa Martinez ,&nbsp;Evan Kidder ,&nbsp;Vishal J. Patel ,&nbsp;Samadhan G. Kshirsagar ,&nbsp;Dhananjay Kumar ,&nbsp;Louise Frausto ,&nbsp;Rajan Pandit ,&nbsp;Koral S.E. Richard ,&nbsp;Sumit Kumar Anand ,&nbsp;Sandeep Das ,&nbsp;Ajit Vikram ,&nbsp;Tarek Magdy ,&nbsp;Xiao-Hong Lu ,&nbsp;A. Wayne Orr ,&nbsp;Harilal Patel ,&nbsp;Ravi Kumar Trivedi ,&nbsp;Nirav Dhanesha","doi":"10.1016/j.expneurol.2025.115181","DOIUrl":"10.1016/j.expneurol.2025.115181","url":null,"abstract":"<div><div>Patients with chronic kidney disease (CKD) are at a significantly increased risk of stroke and experience worse stroke outcomes and higher mortality. CKD exacerbates stroke risk and severity through a complex interplay of systemic inflammation, oxidative stress, and impaired clearance of uremic toxins, leading to neuroinflammation and microglial activation. Current acute ischemic stroke treatments, while effective in the general population, do not adequately address CKD-specific mechanisms, limiting their efficacy in this high-risk population. Prolyl hydroxylase domain (PHD) inhibitors have shown promise in treating anemia associated with CKD and may offer cerebroprotective benefits. However, the effects of PHD2 inhibition on long-term sensorimotor outcomes and the underlying mechanisms in mice with CKD remain largely unknown. Here, we investigated the impact of CKD on stroke severity and assessed the therapeutic potential of desidustat, a PHD inhibitor, in improving stroke outcomes. Using an adenine-induced CKD mouse model, we demonstrated that CKD exacerbated stroke-induced long-term sensorimotor deficits, increased neuroinflammation, and impaired microglial efferocytosis via dysregulation of the ADAM17-MerTK axis. Desidustat treatment in mice with CKD significantly improved long-term sensorimotor functional outcomes and reduced post-stroke neuroinflammation while enhancing microglial efferocytosis by reducing ADAM17 and enhancing microglial MerTK expression. In vitro studies using human-induced microglia-like cells further confirmed the ability of desidustat to enhance efferocytosis of apoptotic neurons by reducing the cleavage of MerTK. These findings suggest that desidustat may serve as a novel therapeutic strategy for improving stroke outcomes in patients with CKD, a population at high risk for stroke and poor functional recovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115181"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363834","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":"Mineral coated microparticles delivering Interleukin-4, Interleukin-10, and Interleukin-13 reduce inflammation and improve function after spinal cord injury in a rat","authors":"Daniel J. Hellenbrand ,&nbsp;Jae Sung Lee ,&nbsp;Ethan J. Mickelson ,&nbsp;Matthew C. Baer ,&nbsp;Emily L. Ott ,&nbsp;Natalie R. Martinson ,&nbsp;Matthew R. Celeen ,&nbsp;Keegan H. Hilger ,&nbsp;Brooke E. Nielsen ,&nbsp;Alison N. Jacobs ,&nbsp;Raveena R. Mishra ,&nbsp;Samuel A. Hurley ,&nbsp;William L. Murphy ,&nbsp;Amgad S. Hanna","doi":"10.1016/j.expneurol.2025.115179","DOIUrl":"10.1016/j.expneurol.2025.115179","url":null,"abstract":"<div><div>After spinal cord injury (SCI) there is excessive inflammation and extensive infiltration of immune cells that leads to additional neural damage. Interleukin (IL)-4, IL-10, and IL-13 are anti-inflammatories that have been shown to reduce several pro-inflammatory species, alter macrophage state, and provide neuroprotection. However, these anti-inflammatories have a short half-life, do not cross the blood-spinal cord barrier, and large systemic doses of ant-inflammatory cytokines can cause increased susceptibility to infections.</div><div>In this study, we used mineral coated microparticles (MCMs) to bind, stabilize and deliver biologically active IL-4, IL-10, and IL-13 in a sustained manner directly to the injury site. Rats with a T10 SCI were given an intraspinal injection of cytokine-loaded MCMs 6 h post-injury. Testing of 27 cytokine/chemokine levels 24 h post-injury demonstrated that MCMs delivering IL-4, IL-10, and IL-13 significantly reduced inflammation (<em>P</em> &lt; 0.0001). Rats treated with MCMs+(IL-4, IL-10, IL-13) had significantly higher Basso-Beattie-Bresnahan locomotor rating scores (<em>P</em> = 0.0021), Ladder Rung Test scores (P = 0.0021), and significantly longer latency threshold with the Hargreaves Test (<em>P</em> = 0.0123), compared to Injured Controls. Analyses of post-fixed spinal cords revealed significantly less spinal cord atrophy (<em>P</em> = 0.0344) in rats treated with MCMs+(IL-4, IL-10, IL-13), and diffusion tensor imaging tractography revealed significantly more tracts spanning the injury site (<em>P</em> = 0.0025) in rats treated with MCMs+(IL-4, IL-10, IL-13) compared to Injured Controls.</div><div>In conclusion, MCMs delivering IL-4, IL-10, and IL-13 significantly reduced inflammation post-SCI, resulting in significantly less spinal cord damage and a significant improvement in hind limb function.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115179"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143234391","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":"Heliox alleviates ischemia-reperfusion-induced damage to neuronal cells by repressing the USP46-SNX5 Axis-triggered ferroptosis","authors":"Hualing Yang ,&nbsp;Zhanxiang Wang ,&nbsp;Wei Xiong ,&nbsp;Liying Zhou ,&nbsp;Shuai Yu","doi":"10.1016/j.expneurol.2025.115175","DOIUrl":"10.1016/j.expneurol.2025.115175","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral ischemia-reperfusion (I/R) causes brain cell dysfunction and death. Heliox treatment shows therapeutic benefits in treating certain respiratory conditions. Here, we explore the mechanism by which heliox alleviates ferroptosis of neuronal cells injured by I/R treatment.</div></div><div><h3>Method</h3><div>OGD/R-treated SH-SY5Y cells were used and screened for USPs whose expression is induced by OGD/R but suppressed by heliox treatment. Mass spectrometry was conducted to identify proteins that interact with USP46. The impact of SNX5 deficiency on the ferroptosis of USP46-overexpressing neuronal cells following sequential OGD/R and heliox treatment was also explored. Finally, the effect of USP46 overexpression on brain cell ferroptosis in a cerebral I/R rat model was explored.</div></div><div><h3>Results</h3><div>Deubiquitinase USP46 is targeted by heliox treatment in neuronal cells. USP46 expression is stimulated by I/R, and its overexpression enhances ferroptosis in I/R-treated neuronal cells. USP46 interacts with and deubiquitinates SNX5, a ferroptosis promoter, thereby increasing its stability. The knockdown of SNX5 abolishes the ferroptosis-promoting effect of USP46 in I/R-treated neuronal cells. Excessive USP46 attenuates the protective effect of heliox treatment on I/R-triggered cerebral damage in a rat model.</div></div><div><h3>Conclusion</h3><div>These observations highlight the ferroptosis-promoting function of the USP46-SNX5 axis in I/R-treated neuronal cells.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115175"},"PeriodicalIF":4.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255122","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":"Combined treatment targeting Ca2+ store mediated Ca2+ release and store-operated calcium entry reduces secondary axonal degeneration and improves functional outcome after SCI","authors":"Emma Jones ,&nbsp;Spencer O. Ames ,&nbsp;Jesse Brooks ,&nbsp;Johnny Morehouse ,&nbsp;Norah Hill ,&nbsp;Katsuhiko Mikoshiba ,&nbsp;Akinobu Suzuki ,&nbsp;David P. Stirling","doi":"10.1016/j.expneurol.2025.115178","DOIUrl":"10.1016/j.expneurol.2025.115178","url":null,"abstract":"<div><div>Store-operated calcium entry (SOCE) is crucial for cellular processes, including cellular calcium homeostasis and signaling. However, uncontrolled activation of SOCE is implicated in neurological disorders and CNS trauma, but underlying mechanisms remain unclear. We hypothesized that inhibiting SOCE enhances neurological recovery following contusive spinal cord injury (SCI). To investigate key SOCE effectors, stromal interaction molecules (STIM) and Orai channels on neurological recovery following spinal cord injury (SCI), we utilized male and female conditional neuronal <em>Stim1</em>KO mice to investigate the role of neuronal STIM1 in SCI outcome following a mild (30 kdyn) contusion at T13. To investigate Ca2+ store mediated Ca2+ store depletion, and SOCE-mediated refilling in SCI outcome, we inhibited the IP₃R with 2-APB, and uncoupled STIM/Orai activation with DPB162-AE, respectively. Intravital microscopy demonstrated that neuron specific <em>Stim1</em>KO increased axonal survival post-SCI. Likewise, pharmaceutical uncoupling of STIM1/Orai activation, alone or combined with IP₃R inhibition, enhanced axon survival 24 h after T13 contusion in male and female <em>Thy1</em>YFP+ mice. Behavioral evaluation of female C57BL/6 J mice revealed that DPB162-AE, alone or combined with 2-APB, improved neurological recovery 4–6 weeks following a moderate (50 kdyn) T9 contusion. Immunohistochemical analysis showed that combined treatment improves axonal sparing, increases astrogliosis, and reduces microglia/macrophage density at the injury epicenter 6 weeks post-SCI. These findings reveal a novel role for neuronal STIM1 in “bystander” secondary axonal degeneration, and introduce STIM/Orai functional uncoupler DPB162-AE, combined with IP₃R inhibitor 2-APB, as a novel therapeutic approach for improving neurological recovery following SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115178"},"PeriodicalIF":4.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143234417","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":"Neurochemical alterations in the cerebellum of Friedreich's Ataxia mouse models","authors":"Elizabeth Mercado-Ayón ,&nbsp;Ellarie Talgo ,&nbsp;Liam Flatley ,&nbsp;Jennifer Coulman ,&nbsp;David R. Lynch","doi":"10.1016/j.expneurol.2025.115176","DOIUrl":"10.1016/j.expneurol.2025.115176","url":null,"abstract":"<div><div>Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by frataxin deficiency. Neurological deficits remain the ubiquitous feature of FRDA and include progressive ataxia and dysarthria, both of which are controlled to a large degree by the cerebellum. The precise impact of frataxin deficiency on the cerebellum including Purkinje cells remains unclear. In the present work, we examined the biochemical and structural properties of the cerebellum and Purkinje cells in the doxycycline-inducible (FRDAkd) and the Knock-in/Knockout (KIKO) mouse models of FRDA. Acute systemic knockdown of frataxin in FRDAkd mice and chronic frataxin deficiency in KIKO leads to a significant decrease in levels of AMPA receptors, particularly GluR2, and an increase in glial glutamate transporters. Significant astroglial accumulation occurred in KIKO cerebellum but not in FRDAkd mice. Purkinje cell dendritic arbors in the molecular layer did not change compared to wildtype in either model. The Purkinje cell postsynaptic receptor NMDAR1 significantly decreased only in the FRDAkd cerebellum while other NMDA receptor subunits, largely found in non-Purkinje cells, did not change. Overall, we observed dysregulated levels of glutamate receptors and transporters in the KIKO and FRDAkd mice models of Friedreich ataxia, suggesting the importance of frataxin in maintaining Purkinje cells and cerebellar integrity along with synaptic properties. These results point to conserved but not identical synaptic features between the models that may represent markers or conceivably targets in human FRDA.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115176"},"PeriodicalIF":4.6,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187591","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":"Exercise-induced Sesn2 mediates autophagic flux to alleviate neural damage after ischemic stroke in mice","authors":"Yun Zhao ,&nbsp;Xinwang Ying ,&nbsp;Xiangxiong Pang ,&nbsp;Yao Lin ,&nbsp;Jiamen Shen ,&nbsp;Yanfang Zhao ,&nbsp;Weimin Shen ,&nbsp;Yuhan Yang ,&nbsp;Zhongqiu Hong ,&nbsp;Wen Wu ,&nbsp;Xiquan Hu ,&nbsp;Qingfeng Xie","doi":"10.1016/j.expneurol.2025.115174","DOIUrl":"10.1016/j.expneurol.2025.115174","url":null,"abstract":"<div><h3>Background</h3><div>We previously demonstrated that exercise pretreatment can suppress oxidative stress and neuroinflammation following ischemic stroke. However, the specific mechanisms underlying these effects are uncertain. Sestrin2 (Sesn2), a stress-responsive protein, has been reported to reduce neuroinflammation and protect against ischemic cerebral injury. Hence, this study aimed to verify whether Sesn2 can mediate the antineuroinflammatory and antioxidative effects of exercise pretreatment and explore the potential downstream mechanisms involved.</div></div><div><h3>Methods</h3><div>To assess infarction volume and neuronal morphology, we employed HE staining. Neurological functions following ischemic stroke were evaluated via modified neurological severity scores. Techniques such as immunofluorescence, TUNEL, Fluoro-Jade B, dihydroethidium staining, and Western blotting were utilized to investigate neuronal injury, oxidative stress, neuroinflammation, autophagic flux, and signaling pathway molecules.</div></div><div><h3>Results</h3><div>Our findings revealed that in a middle cerebral artery occlusion (MCAO) mouse model, administration of Sesn2 shRNA abolished the neuroprotective effects induced by exercise pretreatment. These effects include improvements in neurological dysfunction and impaired autophagy, as well as a reduction in oxidative stress and neuroinflammation. Mechanistically, the administration of AICAR to activate the AMPK/TFEB signaling pathway significantly reversed the aforementioned effects. Moreover, the inhibition of autophagic flux by chloroquine (CQ) in MCAO mice pretreated with exercise led to increased neuroinflammation.</div></div><div><h3>Conclusions</h3><div>Sesn2 contributes to the positive outcomes of exercise pretreatment for ischemic stroke. Sesn2 exerts neuroprotection by inhibiting oxidative stress and neuroinflammation, potentially through AMPK/TFEB-mediated autophagic flux in MCAO. Sesn2 may hold promise as a novel exercise-mimetic molecule and a potential target for therapeutic interventions in ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115174"},"PeriodicalIF":4.6,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188820","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}