Experimental Neurology最新文献

{"title":"Zonisamide modulates cholinergic markers and alleviates levodopa-induced dyskinesia in a rat model of Parkinson's disease","authors":"Satoshi Morise ,&nbsp;Rie Tohge ,&nbsp;Mitsuaki Oki ,&nbsp;Norihiro Takenouchi ,&nbsp;Aya Murakami ,&nbsp;Masataka Nakamura ,&nbsp;Hirofumi Kusaka ,&nbsp;Yusuke Yakushiji ,&nbsp;Satoshi Kaneko","doi":"10.1016/j.expneurol.2025.115383","DOIUrl":"10.1016/j.expneurol.2025.115383","url":null,"abstract":"<div><div>Striatal cholinergic interneurons (ChIs) play a key modulatory role in basal ganglia circuits and is increasingly recognized as contributors to levodopa-induced dyskinesia (LID) development and expression in Parkinson's disease (PD). We aimed to investigate whether zonisamide (ZNS) exhibits the potential contribution of the cholinergic system to the antidyskinetic effects.</div><div>Unilateral PD model rats were treated with levodopa and/or ZNS. Two weeks post-treatment, LID severity was assessed, and striatal mRNA expression levels for muscarinic M1 (<em>Chrm1</em>) and M4 (<em>Chrm4</em>) receptors, and nicotinic α7 (<em>Chrnα7</em>) and β2 (<em>Chrnβ2</em>) subunits, as well as prodynorphin (<em>Pdyn</em>) and proenkephalin (<em>Penk</em>), were analyzed using real-time RT-PCR. Additionally, the proportion of striatal phosphorylated extracellular signal-regulated kinase (pERK)-positive ChIs was observed using immunohistochemistry.</div><div>LID was absent in ZNS (Group Z) or saline + DMSO-treated (Group N) rats but pronounced in levodopa-treated rats (Group I). Rats receiving both levodopa and ZNS (Group IZ) showed less-pronounced LID and increased locomotive activity compared with Group I. <em>Chrm1</em>, <em>Chrm4</em>, <em>Chrnα7</em>, and <em>Chrnβ2</em> receptor mRNA levels remained unchanged in Groups N and I. Conversely, <em>Chrm1</em>, <em>Chrm4</em>, and <em>Chrnβ2</em> receptor mRNA levels were reduced in Group Z, whereas all receptor mRNAs were downregulated in Group IZ. Additionally, the proportion of striatal pERK-positive ChIs significantly increased in Group I, whereas its reduction was observed in Group IZ.</div><div>These findings suggest that ZNS may serve as a dual-purpose therapy by potentially alleviating LID while maintaining locomotor function, possibly through the suppression of striatal ChI overactivity and downregulation of acetylcholine receptor expression.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115383"},"PeriodicalIF":4.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663288","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":"The development but not the maintenance of phrenic and sympathetic long-term facilitation after acute intermittent hypoxia requires nucleus tractus solitarii H2O2","authors":"Daniela Ostrowski ,&nbsp;Cheryl M. Heesch ,&nbsp;Allison C. Hollenbeck ,&nbsp;Alexis B. Graber ,&nbsp;David D. Kline ,&nbsp;Eileen M. Hasser","doi":"10.1016/j.expneurol.2025.115380","DOIUrl":"10.1016/j.expneurol.2025.115380","url":null,"abstract":"<div><div>Acute exposure to intermittent hypoxia (AIH) produces prolonged increases (long-term facilitation, LTF) in phrenic (PhrNA) and sympathetic (SNA) nerve activity (pLTF and sLTF, respectively) during non-hypoxic periods, and augments cardiorespiratory responses to hypoxia. We recently showed that neuronal activity in the nucleus tractus solitarii (nTS) is required for the induction and maintenance of LTF. However, the specific mechanisms involved were not determined. Because bouts of deoxygenation/reoxygenation produce reactive oxygen species and H₂O₂ contributes to plasticity in the nTS, we hypothesized that nTS H₂O₂ contributes to AIH-induced LTF and augmented hypoxic responses. We reduced H₂O₂ within the nTS acutely by nanoinjecting catalase or chronically by overexpressing catalase via an adenovirus vector. We then evaluated PhrNA and splanchnic SNA (SSNA) in animals subjected to AIH or time control. In control rats subjected to nTS nanoinjections of aCSF or overexpression of eGFP, AIH produced pLTF and sLTF, and augmented PhrNA responses to hypoxia. Reducing nTS H₂O₂ by either nTS nanoinjections or overexpression of catalase markedly attenuated the development of pLTF and sLTF. Augmented hypoxic responses due to AIH also were diminished. In contrast, after LTF had developed, nanoinjection of catalase had no effect on the magnitude of either PhrNA or SSNA although inhibiting nTS neuronal activity after LTF development reduced pLTF. The data indicate that nTS H₂O₂ is required for AIH-induced pLTF and sLTF, as well as augmentation of responses to hypoxia. Moreover, while nTS neuronal activity is essential to the maintenance of pLTF once developed, ongoing increases in H₂O₂ are not required.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115380"},"PeriodicalIF":4.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667465","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":"Cell-generated mechanical forces play a role in epileptogenesis after injury","authors":"Laya Dalir ,&nbsp;Svetlana Tatic-Lucic ,&nbsp;Yevgeny Berdichevsky","doi":"10.1016/j.expneurol.2025.115376","DOIUrl":"10.1016/j.expneurol.2025.115376","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is associated with a significantly increased risk of epilepsy. One of the consequences of severe TBI is progressive brain atrophy, which is frequently characterized by organized tissue retraction. Retraction is an active process synchronized by mechanical interactions between surviving cells. This results in unbalanced mechanical forces acting on surviving neurons, potentially activating mechanotransduction and leading to hyperexcitability. This novel mechanism of epileptogenesis was examined in organotypic hippocampal cultures, which develop spontaneous seizure-like activity in vitro. Cell-generated forces in this model resulted in contraction of hippocampal tissue. Artificial imbalances in mechanical forces were introduced by placing cultured slices on surfaces with adhesive and non-adhesive regions. This modeled imbalance in mechanical forces that may occur in the brain after trauma. Portions of the slices that were not stabilized by substrate adhesion underwent increased contraction and compaction, revealing the presence of cell-generated forces capable of shaping tissue geometry. Changes in tissue geometry were followed by excitability changes that were specific to hippocampal sub-region and orientation of contractile forces relative to pyramidal cell apical-basal axis. Results of this study suggest that imbalanced cell-generated forces contribute to development of epilepsy, and that force imbalance may represent a novel mechanism of epileptogenesis after trauma.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115376"},"PeriodicalIF":4.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144654899","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":"Protein kinase C gamma regulates Purkinje cell dendritic spine development in a mouse model of spinocerebellar ataxia","authors":"Zsófia Sziber ,&nbsp;Paula Torrents-Solé ,&nbsp;Aleksandar Kovacevic ,&nbsp;Josef P. Kapfhammer","doi":"10.1016/j.expneurol.2025.115377","DOIUrl":"10.1016/j.expneurol.2025.115377","url":null,"abstract":"<div><div>The formation and proper organization of synaptic connections in the Purkinje cell dendritic tree are essential for cerebellar function and are often disrupted in cerebellar diseases, particularly in spinocerebellar ataxia (SCA). In this study, we utilized two distinct mouse models of SCA14, a subtype of SCA caused by point mutations in the protein kinase C gamma (PKCγ) gene, which plays an important role in regulating the dendritic architecture in Purkinje cells. We investigated the development of Purkinje cell dendritic spines in organotypic slice cultures from control, PKCγ knockout (PKCγ-KO) mice, and the two SCA14 models to further elucidate the role of PKCγ activity in dendritic spine formation. Our results revealed that the loss of PKCγ had only minor effects on dendritic spines, likely due to compensatory mechanisms mediated by PKCα. In contrast, elevated PKCγ activity—either induced pharmacologically in control mice or resulting from the expression of mutated PKCγ in the SCA14 models—led to a significant loss of dendritic spines. Furthermore, increased PKCγ activity impaired spine enlargement and maturation by reducing the number of mature, mushroom-shaped spines. These findings demonstrate that PKCγ regulates dendritic spine formation, a crucial process for synapse establishment and the proper function of cerebellar Purkinje cells.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115377"},"PeriodicalIF":4.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144654897","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":"Morphological regulation of wound repair astrocytes by leucine zipper-bearing kinase-AKT signaling after spinal cord injury","authors":"Matin Hemati-Gourabi ,&nbsp;Tuoxin Cao ,&nbsp;Anna E. Mills ,&nbsp;Ellie P. Rice ,&nbsp;Lauren Baur ,&nbsp;Xiu Xu ,&nbsp;William K. Fenske ,&nbsp;Meifan Chen","doi":"10.1016/j.expneurol.2025.115379","DOIUrl":"10.1016/j.expneurol.2025.115379","url":null,"abstract":"<div><div>Following focal CNS injury, a salient feature of astrocytes lining the lesion is their remarkable morphological transformation into an interwoven cellular border that serves their protective function in wound closure. Despite the importance of morphology in determining function of lesion border astrocytes and injury outcome, there is sparse knowledge of how cell shape is regulated temporally and mechanistically in border-forming astrocytes. We report a transcriptional program of actin and microtubule reorganization that is induced in lesion border astrocytes after spinal cord injury in mice. By genetic gain- and loss-of-function analyses <em>in vivo</em>, we show that leucine zipper-bearing kinase (LZK) is a positive regulator of injury-responsive transcription of cytoskeleton remodeling genes in lesion border astrocytes, with consequences on morphological adaptation of border-forming astrocytes. Functional validation of LZK-dependent cytoskeleton rearrangement <em>in vitro</em> demonstrates its ability to enhance astrocytic process extension, cell movement, and associated structural reorganization of actin and microtubules. We further identify LZK-dependent activation of AKT in astrocytes <em>in</em> <em>vitro</em> and <em>in vivo</em>, which is required for transcriptional regulation of the cytoskeleton by LZK, and to a similar extent as STAT3. Lastly, loss of astrocytic LZK impairs motor recovery after spinal cord injury. Our findings define temporal and molecular regulation of morphological transformation of lesion border astrocytes that may be targeted for CNS repair.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115379"},"PeriodicalIF":4.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667463","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 dysfunction in Alzheimer's disease: Mechanisms, emerging therapies, and future directions","authors":"Mahir Azmal ,&nbsp;Jibon Kumar Paul ,&nbsp;Fatema Sultana Prima ,&nbsp;A.N.M. Shah Newaz Been Haque ,&nbsp;Meghla Meem ,&nbsp;Ajit Ghosh","doi":"10.1016/j.expneurol.2025.115374","DOIUrl":"10.1016/j.expneurol.2025.115374","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a severe neurodegenerative condition characterized by progressive cognitive decline and behavioral changes. These symptoms are primarily driven by the accumulation of amyloid-beta (Aβ) plaques, tau tangles, and persistent neuroinflammation. Microglia, the brain's resident immune cells, play a crucial role in the disease's progression. Initially, these cells protectively respond to Aβ deposits, working to clear plaques and support neuronal health. However, prolonged activation of microglia leads to a transition from a neuroprotective state to a pro-inflammatory one, ultimately contributing to neuronal damage and worsening disease progression. This review explores the molecular mechanisms responsible for microglial dysfunction in AD, with a particular emphasis on key inflammatory pathways, including NF-κB, MAPK, and TLR4 signaling. These pathways drive the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which further amplify neuroinflammation, disrupt synaptic plasticity, and contribute to neuronal loss. Additionally, emerging therapeutic strategies aimed at modulating microglial activity to reduce neuroinflammation and enhance Aβ clearance are examined. A key focus is placed on the future of AD research, emphasizing the importance of longitudinal studies to gain a deeper understanding of how microglia contribute to disease progression over time. The review also highlights the potential of personalized medicine, which seeks to tailor treatments based on an individual's unique genetic and environmental risk factors. Notably, genetic predispositions such as the APOE4 allele, along with environmental influences like air pollution and chronic infections, are identified as significant modulators of microglial activity. Given the complexity of AD, a comprehensive, multi-faceted approach will be essential for advancing research and developing more effective therapeutic interventions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115374"},"PeriodicalIF":4.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605499","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":"Elucidating the mechanistic role of Rip3 in post-thalamic hemorrhage neurological deficits","authors":"Yinggang Xiao ,&nbsp;Yaqun Li ,&nbsp;Yang Zhang ,&nbsp;Yali Ge ,&nbsp;Shuai Han ,&nbsp;Zi Wang ,&nbsp;Ju Gao ,&nbsp;Tianfeng Huang","doi":"10.1016/j.expneurol.2025.115373","DOIUrl":"10.1016/j.expneurol.2025.115373","url":null,"abstract":"<div><div>Thalamic hemorrhage (TH), a critical subtype of intracerebral hemorrhage, often leads to central post-stroke pain (CPSP) and neurological deficits, yet its molecular mechanisms remain poorly understood. This study investigated the role of Rip3 in TH pathophysiology by constructing <em>Rip3</em>-knockout (KO) mice and integrating behavioral assessments, transcriptomic sequencing, and molecular experiments. Results demonstrated that TH induced motor dysfunction, mechanical pain hypersensitivity, working memory impairment, and anxiety-like behaviors in wild-type (WT) mice, while Rip3 knockout significantly alleviated pain sensitivity and anxiety and reduced hemorrhage volume. Transcriptomic analysis identified 956 Rip3-related candidate genes, among which Tac1, Gal, and Pdyn were validated as key downstream genes through protein-protein interaction networks and experimental assays. RT-qPCR and Western blot revealed significant upregulation of these genes in WT mice post-TH, with reduced expression in KO mice. Functional enrichment analysis implicated these genes in pathways such as NEUREXINS_AND_NEUROLIGINS and DOPAMINERGIC_NEUROGENESIS. Drug prediction identified potential therapeutic candidates, including Nizatidine, Ginger Allergenic Extract, Paregoric, and Estradiol 3-Benzoate, with the latter showing promise in modulating synaptic plasticity and pain signaling. Inhibition of Pdyn and Tac1 alleviated mechanical allodynia, while all three inhibitors, including Gal's, exhibited significant anxiolytic effects in the TH-induced CPSP model. This study reveals, for the first time, a correlative link between Rip3 and post-TH neurological injury and CPSP, potentially mediated via Tac1, Gal, and Pdyn regulation, providing novel targets for therapeutic intervention. Future research should validate direct <em>Rip3</em>-gene interactions and the efficacy of predicted drugs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115373"},"PeriodicalIF":4.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595577","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":"Ischemic stroke altered the expression profiles of super enhancer RNAs in mouse brain in a sexually dimorphic manner","authors":"Hadjer Namous ,&nbsp;Vijay Arruri ,&nbsp;Thomas Galleske ,&nbsp;Raghu Vemuganti","doi":"10.1016/j.expneurol.2025.115372","DOIUrl":"10.1016/j.expneurol.2025.115372","url":null,"abstract":"<div><div>Super enhancer RNAs (seRNAs) serve as vital regulators of gene expression, yet their role in ischemic stroke remains unexplored. Using microarrays, we profiled seRNAs and their target mRNAs in the peri-infarct cortex of male and female C57BL/6 J mice at 6 h and 24 h of reperfusion after transient focal ischemia. The seRNA expression profiles altered in a temporal and sex-specific manner with a more pronounced dysregulation in males. Gene ontology analysis showed that stroke-responsive seRNA-associated mRNAs involved in critical pathways, including neurogenesis, angiogenesis, and immune responses. Weighted Gene Co-expression Network Analysis showed that the upregulated driver seRNAs are associated with leukocyte proliferation and inflammation, and the downregulated driver seRNAs are linked to nucleosome organization, RNA stability, neuronal apoptosis, and mTOR signaling after focal ischemia. Several stroke-responsive seRNAs are also observed to be associated with transcription factors. These results suggest that seRNAs are pivotal regulators of post-stroke brain damage and recovery, providing potential targets for therapeutic intervention.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115372"},"PeriodicalIF":4.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616912","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":"KIF23 inhibition protects against perioperative neurocognitive disorders by hindering ROS/caspase-3/GSDME-mediated pyroptosis","authors":"Shaoqun Tang ,&nbsp;Xi Yu ,&nbsp;Lei Zhang,&nbsp;Xueshan Bu,&nbsp;Wei Wang,&nbsp;Zhongyuan Xia","doi":"10.1016/j.expneurol.2025.115371","DOIUrl":"10.1016/j.expneurol.2025.115371","url":null,"abstract":"<div><div>The activation of caspase-3 and gasdermin E (GSDME)-mediated pyroptosis is a key driver of perioperative neurocognitive disorders (PND). Kinesin family member 23 (KIF23), a constituent of the kinesin superfamily of microtubule-associated motor proteins, governs NLRP3 inflammasome-mediated pyroptosis and is essential for dendritic differentiation and development. This study sought to ascertain whether KIF23 influences PND by affecting caspase-3/GSDME-dependent pyroptosis. The PND mouse model was established through laparotomy under isoflurane (Iso) anesthesia following recombinant adeno-associated virus 9 (AAV9)-mediated knockdown of KIF23, with or without the intraperitoneal administration of the caspase-3 agonist Raptinal. HT22 cells were transfected with either pcDNA3.1-KIF23 or siKIF23, followed by exposure to Iso and lipopolysaccharide (LPS). Cognitive performance, TUNEL staining, and pyroptosis-related parameters were assessed. KIF23 protein was upregulated in the hippocampus of aged mice following anesthesia and surgery. AAV9-shKIF23 ameliorated postoperative memory decline, suppressed reactive oxygen species (ROS) production and diminished the levels of cleaved caspase-3, N-GSDME, IL-1β and IL-18, which were reversed by Raptinal. KIF23 silencing enhanced neuronal viability and antioxidant capacity, blocked the cleavage of caspase-3 and N-GSDME, and repressed the release of IL-1β, IL-18, and LDH. Conversely, KIF23 overexpression exerted opposing effects on pyroptosis in response to Iso + LPS, which was abrogated by the caspase-3 inhibitor Ac-DEVD-CHO. These findings suggest that KIF23 could serve as a promising therapeutic target for PND through its positive modulation of pyroptosis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115371"},"PeriodicalIF":4.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607888","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":"Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures","authors":"Kakulavarapu V. Rama Rao,&nbsp;Victor L. McLean,&nbsp;Donna M. Wilder,&nbsp;Shataakshi Dahal,&nbsp;Malavika Kattuparambil,&nbsp;Joseph B. Long,&nbsp;Venkatasivasai Sujith Sajja","doi":"10.1016/j.expneurol.2025.115375","DOIUrl":"10.1016/j.expneurol.2025.115375","url":null,"abstract":"<div><div>Blast wave (BW)-associated brain injury criteria to assess risk of Warfighters are currently inadequate due to lack a suitable animal model that does not represent human blast injury pathology. We hypothesize that animal models with brain structures more closely resemble the human brain (e.g. gyrencephalic models) could better translate to recreate and identify human blast pathology. As a one-of-a kind evaluation, this study compared the blood brain barrier (BBB) integrity, gliovascular changes and neuroinflammation in lissencephalic (rats) and gyrencephalic (ferrets) models exposed to blast waves at varying overpressures (10, 15 and 20 psig) with a validation study in non-human primates exposed to a single BW at 20 psig. BBB disruption was measured by Evans blue extravasation. The extent of gliosis in brain sections was measured by immunofluorescence analysis of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba-1), and neurodegeneration was determined by silver staining. Ferrets exposed to BW had a statistically significant increase in extravasation of Evans blue in different brain regions while a no such changes were observed in the rat model. Blast also induced a significant reactive astrogliosis and microglial activation in ferrets. NHPs exposed to a single BW at 20 psig showed a significant increase in EB extravasation in only thalamus. These results suggest that gyrencephalic brain structures may be more vulnerable to vascular disruption compared to lissencephalic models and these models may have better translatability to human blast injuries and potentially better suited to identify injury thresholds.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115375"},"PeriodicalIF":4.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580750","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}