Experimental Neurology最新文献

{"title":"A mouse model for cerebral/cortical visual impairment (CVI) impairs vision and disrupts the spatial frequency tuning of neurons in visual cortex","authors":"Dana K. Oakes ,&nbsp;Cecilia A. Attaway ,&nbsp;Wenxin Zeng ,&nbsp;Jun Cai ,&nbsp;William Guido ,&nbsp;Aaron W. McGee","doi":"10.1016/j.expneurol.2026.115648","DOIUrl":"10.1016/j.expneurol.2026.115648","url":null,"abstract":"<div><div>Cerebral/cortical visual impairment (CVI) is a visual disorder often associated with perinatal hypoxic injury. The pathophysiology of CVI is poorly understood in part because of the lack of an animal model. Here we developed a murine model of CVI from existing rodent early postnatal hypoxia models for periventricular leukomalacia. Exposure to hypoxia during the equivalent to the human third trimester did not perturb gross motor function but caused severe impairments in binocular depth perception and visual acuity measured with behavioral assays. Impaired vision was associated with normal retinal function assessed with electroretinograms, but reduced size of the visual thalamus, and aberrant tuning for spatial frequency by populations of excitatory neurons in primary visual cortex calculated from <em>in vivo</em> calcium imaging experiments. This murine model of CVI provides a framework for triangulating circuit deficits with the severity of visual impairment and testing potential therapeutic interventions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115648"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988838","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":"Molecular and biochemical insights into dysregulation of glycosphingolipid metabolism in a mouse model of lysosomal free sialic acid storage disorder","authors":"Marya S. Sabir ,&nbsp;Mahin S. Hossain ,&nbsp;Laura Pollard ,&nbsp;Petcharat Leoyklang ,&nbsp;Marjan Huizing ,&nbsp;William A. Gahl ,&nbsp;Frances M. Platt ,&nbsp;May Christine V. Malicdan","doi":"10.1016/j.expneurol.2026.115665","DOIUrl":"10.1016/j.expneurol.2026.115665","url":null,"abstract":"<div><div>Free sialic acid storage disorder (FSASD) is caused by pathogenic biallelic variants in <em>SLC17A5</em>, which encodes the lysosomal sialic acid exporter, sialin. FSASD is characterized by the accumulation of lysosomal free sialic acid, leading to either a severe, childhood-lethal form or a more slowly progressive neurodegenerative disorder associated with the p.Arg39Cys (p.R39C) variant, i.e., Salla disease. While dysregulated glycosphingolipid (GSL) metabolism has been observed in cellular models of FSASD, this study provides the first <em>in vivo</em> biochemical dissection of GSL metabolism in a knock-in mouse model harboring the <em>Slc17a5</em> p.R39C variant. We employed an integrated multi-modal approach, including sialic acid quantification, exploratory untargeted lipidomics, HPLC-based GSL profiling, bulk transcriptomics, and 4-MU-based lysosomal enzyme activity assays in brain and peripheral tissues (liver and kidney). Exploratory untargeted lipidomic screening revealed region-dependent lipid alterations, with more pronounced changes in the cerebellum than in the forebrain. Pathway-level analyses indicated enrichment of lipid classes related to sphingolipid and GSL metabolism. Targeted biochemical analyses demonstrated that several GSL species accumulate predominantly in the brain, with minimal changes in peripheral tissues, whereas glucosylceramide levels were significantly reduced in all brain regions analyzed. Transcriptomic profiling identified dysregulation of several genes involved in GSL and sialic acid metabolism. Enzyme activity assays corroborated the transcriptomic findings, demonstrating increased activity of several lysosomal glycohydrolases, including neuraminidase 1/3/4 and β-hexosaminidase. Collectively, these findings highlight dysregulated GSL metabolism as a prominent biochemical consequence of sialin deficiency <em>in vivo</em> and highlight its putative role in FSASD neuropathology.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115665"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043790","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":"Long-term continuous theta burst stimulation ameliorates L-DOPA-induced dyskinesia in Parkinsonian rats through modulation of the cerebello-thalamo-striatal circuit","authors":"Ling Wang,&nbsp;Yixuan Wang,&nbsp;Shuo Yang,&nbsp;Yihua Bai,&nbsp;Xiang Wu,&nbsp;Qingfeng Sun,&nbsp;Yanping Hui,&nbsp;Libo Li,&nbsp;Hongfei Qiao,&nbsp;Qiaojun Zhang","doi":"10.1016/j.expneurol.2026.115674","DOIUrl":"10.1016/j.expneurol.2026.115674","url":null,"abstract":"<div><div>Levodopa-induced dyskinesia (LID) is a debilitating complication of Parkinson's disease therapy. Emerging evidence suggests that the cerebellum is involved via cerebello -thalamo-striatal pathways.We first performed dual viral tracing to confirm cerebello-thalamo-striatal connectivity in a unilateral 6- hydroxydopamine rat model of LID. We then compared the efficacy of two cerebellar continuous theta burst stimulation (cTBS) protocols: a 2block protocol (14 days) and an intensified 3block protocol (10 days). Behavioral outcomes were assessed using the abnormal involuntary movement scale (AIMs). Local field potentials were recorded from the cerebellar dentate nucleus (DN) to characterize oscillatory variations. Striatal FosB expression was quantified as the molecular endpoint. Viral tracing confirmed the anatomical connectivity from the DN to the dorsolateral striatum via the parafascicular thalamus. Both the two protocols alleviated orolingual dyskinesia, with the 3block cTBS protocol demonstrated superior therapeutic efficacy (<em>p</em> &lt; 0.001). Electrophysiological analysis revealed that LID was associated with reduced δ-band power and enhanced low-γ power in DN. Notably, cTBS normalized these aberrant oscillatory patterns by increasing δ power and decreasing pathological low-γ activity. The magnitude of δ power was negatively correlated with orolingual AIMs scores (<em>r</em> = −0.467, <em>p</em> = 0.021), whereas low-γ power was positively correlated with total dyskinesia severity (<em>r</em> = 0.551, <em>p</em> = 0.005) and orolingual AIMs scores (<em>r</em> = 0.581, <em>p</em> = 0.003). At the molecular level, cTBS normalized pathologically elevated striatal FosB expression in LID rats (<em>p</em> &lt; 0.001). Collectively, these findings suggest that long-term cerebellar cTBS selectively ameliorates orolingual dyskinesia by modulating the cerebello-thalamo-striatal circuit.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115674"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075845","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 oligodendrocyte precursor cells triggers cognitive dysfunction and synaptic defects in SAE","authors":"You Wu ,&nbsp;Zhengdong Yang ,&nbsp;Huiqing Liu ,&nbsp;Jin Li ,&nbsp;Renhuai Liu ,&nbsp;Yi Li ,&nbsp;Yu Chen ,&nbsp;Binxiao Su","doi":"10.1016/j.expneurol.2026.115670","DOIUrl":"10.1016/j.expneurol.2026.115670","url":null,"abstract":"<div><div>Sepsis-associated encephalopathy (SAE) is defined as a diffuse neurological dysfunction that occurs secondary to sepsis, in the absence of direct central nervous system infection, and is associated with high rates of incidence, mortality, and disability. Despite its clinical significance, the neuropathological mechanisms underlying SAE are not yet fully understood, making its pathogenesis a focal point of ongoing research. Oligodendrocyte precursor cells (OPCs), which are the most proliferative cell type within the central nervous system, primarily contribute to the generation of mature oligodendrocytes and are integral to myelination and the maintenance of myelin. Nevertheless, the role and pathological changes of OPCs during the acute phase of SAE remain inadequately characterized. This study illustrates that OPCs in the hippocampal CA1 region may undergo immune activation under SAE conditions, characterized by significantly elevated inflammatory transcription and phagocytic capacity. Additionally, activated OPCs in SAE mice may contribute to the synaptic pruning of neurons. By generating PDGFRa-Cre/ERT transgenic mice and conducting stereotactic injections of pAAV-EGFP-flex-DTA virus into the hippocampal CA1 region to selectively ablate OPCs, we observed a significant enhancement in cognitive function in SAE mice. This improvement is likely due to the alleviation of synaptic structural and functional impairments in neurons. Our findings indicate that OPCs play a critical role in the pathogenesis of SAE, highlighting their potential as a novel therapeutic target for this condition.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115670"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075847","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":"Low-frequency TMS ameliorates neonatal hypoxia-ischemia injury by normalizing glutamatergic transmission in penumbra","authors":"Ivan Goussakov,&nbsp;Sylvia Synowiec,&nbsp;Alexander Drobyshevsky","doi":"10.1016/j.expneurol.2026.115669","DOIUrl":"10.1016/j.expneurol.2026.115669","url":null,"abstract":"<div><div>Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in term neonates. The current standard of care, therapeutic hypothermia, provides only partial neuroprotection. This study investigates the potential of low-frequency transcranial magnetic stimulation (LF-TMS) as a novel non-pharmacological adjunct therapy by targeting a key pathological mechanism of HIE: a persistent, pathological increase in glutamatergic synaptic transmission, or hypoxic long-term potentiation.</div><div>Using a neonatal mouse model of hypoxia-ischemia, we administered a single session of LF-TMS 30 min after the hypoxic event. We then evaluated its effects on synaptic function via slice electrophysiology and on brain injury volume using serial MRI. Our results show that hypoxia-ischemia induced significant and lasting synaptic potentiation in the perilesional region of the somatosensory cortex. LF-TMS treatment successfully reduced this elevated glutamatergic response to control levels, suggesting a therapeutic mechanism similar to long-term depression and/or depotentiation by downregulating AMPA receptors.</div><div>LF-TMS provided significant neuroprotection, as demonstrated by reductions in volumes of the ischemic core and penumbra 48 h after the injury. LF-TMS did not alter excitability in sham-treated mice, confirming its safety as a targeted intervention for pathological conditions without affecting normal brain function. This study supports that LF-TMS is a promising neuroprotective strategy that mitigates brain injury in a neonatal hypoxia-ischemia model.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115669"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146061048","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":"Neuropathic pain after spinal cord injury: Mechanisms, animal models and pain assessments","authors":"Zean Tao ,&nbsp;Xiaoling Zhou ,&nbsp;Lixia Jin ,&nbsp;Nixi Xu ,&nbsp;Yuanwu Cao ,&nbsp;Zhaoyi Wu ,&nbsp;Chang Jiang ,&nbsp;Zixian Chen","doi":"10.1016/j.expneurol.2026.115678","DOIUrl":"10.1016/j.expneurol.2026.115678","url":null,"abstract":"<div><div>Neuropathic pain after spinal cord injury (SCI-NP) often has lifelong and significant negative effects. Therefore, understanding its underlying mechanisms is a current research priority.</div><div>SCI-NP involves central sensitization, neuroinflammation and functional remodeling in the brain, hyperexcitability of primary sensory neurons, and peripheral–central interactions. The mechanism of SCI-NP at the spinal cord level is an important one to study. Glial cell activation and proinflammatory pathways in the spinal cord are the key drivers that lead to central sensitization at the spinal cord level, and they constitute the main mechanisms of current research. However, the mechanism of SCI-NP remains unclear, mainly because of the lack of standardized and uniform animal models in preclinical studies.</div><div>Animal models provide a basis for the mechanistic study of SCI-NP, but the stability and repeatability of these models pose problems. Behavioral evaluation of animal models of SCI-NP has focused on mechanical and heat-induced pain thresholds, but this phenotype is different from the clinical diagnostic criteria of SCI-NP in patients, which includes at least four positive signs according to the DN4 scale. Electrophysiological recordings, especially from spinal dorsal horn neurons and dorsal root ganglia neurons, provide important support for <span>SCI</span>-NP research.</div><div>In summary, the development of SCI-NP involves a complex pathological process, and its mechanisms remain incompletely understood. Existing models and detection methods require refinement. This review focuses on the research progress in this field and looks forward to future research directions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115678"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131738","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":"Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy","authors":"Tao Yang ,&nbsp;Rajat Banerjee ,&nbsp;Mirte Scheper ,&nbsp;Mi Jiang ,&nbsp;Steven Dai ,&nbsp;Eleonora Aronica ,&nbsp;Yu Wang","doi":"10.1016/j.expneurol.2026.115668","DOIUrl":"10.1016/j.expneurol.2026.115668","url":null,"abstract":"<div><div>Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that <em>Slc6a5</em> (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out <em>Depdc5</em> and <em>Slc6a5</em> in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that <em>SLC6A5</em> plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115668"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050958","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":"β-1, 3-galactosyltransferase 2 promotes cerebral angiogenesis and neurological recovery during the ischemic repair phase through glycosylation modification of TGF-βR(II)/ALK1","authors":"Chang Liu ,&nbsp;Yao Ma ,&nbsp;Jiachen Li ,&nbsp;Yunhao Xu ,&nbsp;Meixuan Li ,&nbsp;Hong Li ,&nbsp;Zongze Li ,&nbsp;Zhanyou Wang ,&nbsp;Jia Liang ,&nbsp;Peng Wang","doi":"10.1016/j.expneurol.2026.115651","DOIUrl":"10.1016/j.expneurol.2026.115651","url":null,"abstract":"<div><div>β-1,3-galactosyltransferase 2 (B3galt2) has been increasingly recognized as an essential mediator in the pathogenesis of ischemic stroke (IS); nonetheless, its exact functional role has not been fully elucidated. This research aimed to clarify the regulatory mechanisms by which B3galt2 influences cerebral angiogenesis during the repair phase following ischemic injury. A mouse model of cerebral ischemia/reperfusion (I/R) injury was generated by subjecting animals to 1-h middle cerebral artery occlusion (MCAO), succeeded by reperfusion for varying time intervals. Recombinant human B3galt2 (rh-B3galt2) was administered intranasally beginning on day one post-injury and continued until tissue collection. Experimental outcomes revealed that rh-B3galt2 substantially diminished brain atrophy and enhanced neurological recovery during the repair phase of ischemia. Furthermore, rh-B3galt2 facilitated angiogenesis through increased expression of vascular endothelial growth factor A (VEGFA) and the tight junction proteins, occludin and claudin 5. Moreover, rh-B3galt2 activated the TGF-βR(II)/ALK1/Smad1/5 pathway. The galactosylation levels of TGF-βR(II) and ALK1 were increased after rh-B3galt2 treatment, suggesting that B3galt2 may regulate TGF-βR(II) and ALK1 through glycosylation modification. Moreover, the advantageous impacts of rh-B3galt2 on reducing brain atrophy and alleviating neurological deficits were reversed upon treatment with the ALK1 inhibitor, ML347. ML347 also counteracted the angiogenic promotion induced by rh-B3galt2, demonstrating that inhibition of ALK1 abolishes the protective benefits mediated by rh-B3galt2. Collectively, the results indicated that rh-B3galt2 significantly promotes angiogenesis and neurological function recovery during the cerebral ischemic repair stage, likely by regulating TGF-βR(II)/ALK1/Smad1/5 signaling pathway through glycosylation modification.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115651"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006504","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":"DLK inhibition has sex-specific effects on neuroprotection and locomotor recovery after spinal cord injury","authors":"John C. Aldrich ,&nbsp;Samantha M. Alman ,&nbsp;Sydney E. Lee ,&nbsp;Ashley R. Scheinfeld ,&nbsp;Chelsea C. Zhang ,&nbsp;Averi L. Pike ,&nbsp;Fiona C. Bremner ,&nbsp;Olivia Calderon ,&nbsp;Sunil Goodwani ,&nbsp;William J. Ray ,&nbsp;Andrew D. Gaudet","doi":"10.1016/j.expneurol.2026.115681","DOIUrl":"10.1016/j.expneurol.2026.115681","url":null,"abstract":"<div><div>Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. Dual leucine zipper kinase (DLK) is a neuron-enriched kinase that responds to cellular stress by activating the c-Jun N-terminal kinase (JNK) pathway, driving both stress-responsive gene expression and neuronal apoptosis. We hypothesized that SCI would robustly activate DLK signaling and that acute pharmacological inhibition of DLK would suppress JNK pathway activation, thereby enhancing neuroprotection and locomotor recovery in our mouse model of moderate contusion SCI. Using western blotting, we observed that SCI induced strong and sustained activation of the JNK pathway in the injured spinal cord starting at 4 h post-injury through 7 days. Complementary analysis of single-nucleus RNA-seq revealed that DLK expression is highly enriched in neurons across all injury phases. Following SCI, neurons exhibited robust, time-dependent upregulation of multiple DLK-responsive transcripts, consistent with sustained pathway activation during the acute and subacute periods. Systemic treatment with the selective DLK inhibitor IACS-52825 effectively suppressed intraspinal JUN activation in a dose-dependent manner. However, unexpectedly, treatment delayed functional recovery and expanded lesion volume by 71% in male mice with no significant effect in females. These findings highlight the complex roles of DLK signaling after SCI, revealing a need to understand the sex-specific molecular mechanisms that modulate injury outcomes. Future studies should further optimize timing, location, and cellular targeting of DLK therapeutic strategies to improve neuroprotection and neurologic recovery after SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115681"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156546","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":"Exosomes-mediated delivery of miR-27a-3p antagomir alleviates white matter injury by regulating PPARγ/PRDX1/JNK pathway after subarachnoid hemorrhage in rats","authors":"Zhaosi Zhang ,&nbsp;Fuming Liang ,&nbsp;Daochen Wen ,&nbsp;Hong Chen ,&nbsp;Nina Gu ,&nbsp;Zhao Li ,&nbsp;Lin Wang ,&nbsp;Yingwen Wang ,&nbsp;Qiuling Pan ,&nbsp;Yajun Zhu ,&nbsp;Dan Xu ,&nbsp;Xiaochuan Sun ,&nbsp;Chongjie Cheng ,&nbsp;Jin Yan","doi":"10.1016/j.expneurol.2026.115667","DOIUrl":"10.1016/j.expneurol.2026.115667","url":null,"abstract":"<div><div>White matter injury (WMI) is a critical factor contributing to poor neurological outcomes following subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are key regulators of WMI-related pathology and can be delivered via exosomes, yet their mechanisms and therapeutic potential remain largely unexplored. In this study, miRNA sequencing revealed a significant upregulation of miR-27a-3p in peripheral blood exosomes after SAH, which was further confirmed in white matter tissue. BV2 cell–derived exosomes loaded with miR-27a-3p antagomir were administered intranasally and effectively targeted oligodendrocytes. Treatment with these exosomes alleviated WMI by reducing oligodendrocyte apoptosis and promoting the proliferation and differentiation of oligodendrocyte precursor cells, leading to improved neurological and electrophysiological recovery. Mechanistically, miR-27a-3p inhibited PPARγ, resulting in downregulation of PRDX1 and activation of the JNK pathway, which triggered oligodendrocyte apoptosis. These findings demonstrate that exosome-mediated delivery of miR-27a-3p antagomir mitigates SAH-induced WMI through modulation of the PPARγ/PRDX1/JNK axis, providing a promising noninvasive therapeutic approach for enhancing white matter repair and functional recovery after SAH.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115667"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046363","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}