Experimental Neurology最新文献

{"title":"RvE1/ChemR23 facilitates hematoma clearance and promotes M2 polarization of macrophages/microglia in intracerebral hemorrhage.","authors":"Mei Fang, Fan Xia, Bang Teng, Wanting Xia, Yunfei Yang, Jiayan Wang, Chuanyuan Tao, Xin Hu","doi":"10.1016/j.expneurol.2025.115173","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115173","url":null,"abstract":"<p><strong>Introduction: </strong>Previous studies have demonstrated the potent anti-inflammatory effects of RvE1 in various diseases, and recent research has shown that it can also promote macrophage phagocytosis. Given that hematoma clearance is crucial for intracerebral hemorrhage (ICH) treatment, while neuroinflammation significantly influences secondary injury, we hypothesize that RvE1/ChemR23 activation, by modulating the polarization of macrophages/microglia, promotes hematoma resolution and alleviates neuroinflammatory responses after ICH.</p><p><strong>Method: </strong>A total of 125 WT C57BL/6 and 67 ChemR23^-/- male mice were used. Western blot and immunofluorescence staining assessed the temporal and spatial expression of ChemR23 after ICH. T2WI, T2*WI and behavioral tests were obtained to assess the protective effect of the RvE1/ChemR23 pathway in ICH. Additionally, co-staining of M1 (iNOS) or M2 polarization (Arg-1) markers with Iba-1 was used to explore the polarization status of macrophages/microglia in the perihematomal region. Finally, Akt phosphorylation was validated as a downstream mediator of the RvE1/ChemR23 pathway using an Akt inhibitor.</p><p><strong>Results: </strong>ChemR23 is mainly expressed in activated microglia and infiltrating macrophages, with expression peaking 5-7 days post-ICH. Activation of the RvE1/ChemR23 pathway promotes hematoma resolution, reduces brain edema, and improves neurological deficits in ICH. These effects are likely mediated by promoting M2 polarization of macrophages/microglia after ICH. Furthermore, the use of an Akt inhibitor can counteract the protective effects of RvE1 in ICH.</p><p><strong>Conclusions: </strong>Our study provides the first evidence of the protective role of RvE1/ChemR23 signaling in ICH. This pathway might offer novel therapeutic targets for the clinical management of ICH.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115173"},"PeriodicalIF":4.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074411","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":"Exosomal irisin from FNDC5-engineered BMSCs improves ischemic stroke via inhibiting YAP/EGR1/ACSL4-mediated ferroptosis.","authors":"Cuini Fang, Lei Huang, Jiayi Gu, Tao Song","doi":"10.1016/j.expneurol.2025.115172","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115172","url":null,"abstract":"<p><strong>Background: </strong>BMSCs-derived exosomes play an important role in ischemic stroke. Irisin and its precursor fibronectin type III domain-containing protein 5 (FNDC5) are implicated in neuroprotective effect. We aimed to clarify the role of exosomal irisin from FNDC5-overexpressed BMSCs in ischemic stroke.</p><p><strong>Methods: </strong>Oxygen-glucose deprivation and reoxygenation (OGD/R) neuronal cells (HT-22 and Neuro-2 A cells) model and middle cerebral artery occlusion (MCAO) mice model were established. Exosomes were isolated from FNDC5-overexpressed BMSCs (BMSCs-FNDC5-exos). Cell viability was estimated with CCK-8. Fe²⁺, lactate dehydrogenase (LDH), glutathione (GSH) and malondialdehyde (MDA) were determined with commercial kits. Moreover, lipid reactive oxygen species (ROS) was analyzed using flow cytometry. Neurological dysfunction, infarct volume and mitochondria injury were estimated with modified neurological severity score (mNSS), TTC staining and transmission electron microscopy (TEM). Chromatin immunoprecipitation and dual luciferase assay were applied to verify the molecular interactions. Western blot, RT-qPCR and ELISA were performed for the detection of related genes and proteins.</p><p><strong>Results: </strong>YAP, EGR1 and ACSL4 were increased in OGD/R-subjected cells. Irisin from BMSCs-FNDC5-exos elevated cell viability and suppressed ferroptosis. EGR1 transcriptionally upregulated ACSL4 and promoted OGD/R-induced ferroptosis. Additionally, YAP transcriptionally upregulated EGR1 and promoted OGD/R-induced ferroptosis. EGR1 or YAP overexpression could reverse the effects of BMSCs-FNDC5-exos. EGR1 silencing or BMSCs-FNDC5-exos overturned the facilitated ferroptosis induced by YAP overexpression, meanwhile, EGR1 silencing further enhanced the effect elicited by BMSCs-FNDC5-exos. BMSCs-FNDC5-exos reduced cerebral infarction, improved neurological impairment, inhibited ferroptosis, downregulated YAP, EGR1, ACSL4 and up-regulated irisin in MCAO mice.</p><p><strong>Conclusion: </strong>Exosomal irisin from FNDC5-overexpressed BMSCs improves ischemic stroke via inhibiting YAP/EGR1/ACSL4-mediated ferroptosis, which shed light on discovering new strategy against ischemic stroke.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115172"},"PeriodicalIF":4.6,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074408","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":"Early postnatal GABAB antagonist treatment normalizes inhibitory/excitatory balance in neonatal Ts65Dn mice, a genetic model of down syndrome.","authors":"Joshua Jin, James Doan, Cassandra Fernandez, Samuel Nguyen, Cole Spencer, Alexander M Kleschevnikov","doi":"10.1016/j.expneurol.2025.115171","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115171","url":null,"abstract":"<p><p>Brain abnormalities in Down syndrome (DS) most rapidly accumulate during the third trimester, a critical period for the formation of neural circuits in the hippocampus and neocortex. In mice, this stage roughly corresponds to the first 2.5 weeks after birth. We hypothesized that enhanced Girk2 channel signaling during this critical period profoundly contributes to the formation of faulty neural circuits in mouse genetic models of DS, with a key feature being an imbalance of excitatory and inhibitory neurotransmission favoring inhibition. Major predictions of this hypothesis were tested. We observed that hippocampal Girk2 levels are enhanced, GABAB/Girk2 signaling efficiency is increased, and intrinsic neuronal excitability of dentate gyrus (DG) granule cells is reduced in neonatal Ts65Dn mice. Given this, we tested if suppressing the enhanced GABAB/Girk2 signaling in the early postnatal period would affect the inhibitory/excitatory (I/E) balance in Ts65Dn mice. Remarkably, GABAB antagonist treatment from postnatal day 2 (P2) to P17 normalized the exaggerated IPSC/EPSC ratio in DG granule cells in Ts65Dn mice. Our findings show that GABAB/Girk2 signaling is increased in neonatal Ts65Dn mice, and that pharmacological suppression of GABAB receptors during the early postnatal period normalizes the I/E balance. These results suggest that early intervention targeting GABAB/Girk2 signaling could be a promising therapeutic approach to mitigate cognitive impairment in DS.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"115171"},"PeriodicalIF":4.6,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074415","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 dynamic duo: Decoding the roles of hypoxia-inducible factors in neonatal hypoxic-ischemic brain injury.","authors":"Rajnish Kumar Yadav, Amanda O Johnson, Eric S Peeples","doi":"10.1016/j.expneurol.2025.115170","DOIUrl":"10.1016/j.expneurol.2025.115170","url":null,"abstract":"<p><p>Neonatal hypoxic-ischemic encephalopathy (HIE) results in considerable mortality and neurodevelopmental disability, with a particularly high disease burden in low- and middle-income countries. Improved understanding of the pathophysiology underlying this injury could allow for improved diagnostic and therapeutic options. Specifically, hypoxia-inducible factors (HIF-1α and HIF-2α) likely play a key role, but that role is complex and remains understudied. This review analyses the recent findings seeking to uncover the impacts of HIF-1α and HIF-2α in neonatal hypoxic-ischemic brain injury (HIBI), focusing on their cell specific expression, time-dependant activities, and potential therapeutic implications. Recent findings have revealed temporal patterns of HIF-1α and HIF-2α expression following hypoxic-ischemic injury, with distinct functions for HIF-1α versus HIF-2α within the neonatal brain. Ongoing studies aimed at further revealing the relationship between HIF isoforms and developing targeted interventions offer promising avenues for therapeutic management which could improve long-term neurological outcomes in affected newborns.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115170"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064650","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":"Targeting the NLRP3 inflammasome in Parkinson's disease: From molecular mechanism to therapeutic strategy.","authors":"Jin-Yu Liang, Xiao-Lei Yuan, Jia-Mei Jiang, Ping Zhang, Kuang-Tan","doi":"10.1016/j.expneurol.2025.115167","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115167","url":null,"abstract":"<p><p>Parkinson's disease is the second most common neurodegenerative disease, characterized by substantial loss of dopaminergic (DA) neurons, the formation of Lewy bodies (LBs) in the substantia nigra, and pronounced neuroinflammation. The nucleotide-binding domain like leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome is one of the pattern recognition receptors (PRRs) that function as intracellular sensors in response to both pathogenic microbes and sterile triggers associated with Parkinson's disease. These triggers include reactive oxygen species (ROS), misfolding protein aggregation, and potassium ion (K⁺) efflux. Upon activation, it recruits and activates caspase-1, then processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, which mediate neuroinflammation in Parkinson's disease. In this review, we provide a comprehensive overview of NLRP3 inflammasome, detailing its structure, activation pathways, and the factors that trigger its activation. We also explore the pathological mechanisms by which NLRP3 contributes to Parkinson's disease and discuss potential strategies for targeting NLRP3 as a therapeutic approach.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115167"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064638","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":"Outcome measures in rodent models for spinal cord injury and their human correlates.","authors":"L A T Jones, E C Field-Fote, D Magnuson, V Tom, D M Basso, K Fouad, M J Mulcahey","doi":"10.1016/j.expneurol.2025.115169","DOIUrl":"10.1016/j.expneurol.2025.115169","url":null,"abstract":"<p><p>Pre-clinical research is intended to inform clinical research, however, communication between these researchers is lacking. A better understanding of what can be learned from animal and human models and what cannot, is essential. This includes a better understanding of where underlying constructs in outcome measures in rodents and humans align and where they diverge to improve dialogue between human and animal researchers. The goal of this review is to promote an understanding of similarities and differences in outcome measures and encourage consideration of these differences when planning, interpreting, and communicating findings from animal or human experiments. Seven individuals with a range of expertise in human and animal research and outcome measures reviewed rat and human measures focused on sensorimotor and functional outcomes. They then discussed where measures corresponded and where they did not, based on the underlying construct the assessment is intended to measure. Key findings are that measures of impairment (such as strength) often used in clinical trials are not commonly used in rodents. Measures such as speed and distance of locomotion are commonly assessed in humans and, while not commonly assessed in rodents, can be collected through existing outcome measures. Additional findings are that animal and human outcome measures are often developed and evaluated differently, with more standardized processes applied to human outcome measures. A deeper understanding and communication of similarities and differences in outcome measures, and where differences are necessary due to interspecies differences, may improve translation from animals to humans and humans to animals.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115169"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064634","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":"Behavioral, biochemical, and molecular characterization of MPTP/p-intoxicated mice.","authors":"Xiaolu Tang, Jinhua Xue, Rui Chen, Jiawei Xing, Xiaying Lu, Lili Cui","doi":"10.1016/j.expneurol.2025.115168","DOIUrl":"10.1016/j.expneurol.2025.115168","url":null,"abstract":"<p><p>The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most extensively utilized animal model for Parkinson's disease (PD). Treatment regimens are classified into three categories: acute, subacute, and chronic. Among these, the MPTP with probenecid (MPTP/p)-induced chronic mouse model is favored for its capacity to sustain long-term striatal dopamine depletion, though the resultant behavioral, biochemical, and molecular alterations require further validation. To systematically evaluate these abnormalities in the chronic MPTP/p mouse model, we conducted observations over a 12-month period. The results showed that these mice displayed reduced locomotor activity, minor gait abnormalities, and anxiety-like behavior within one week following the final MPTP/p injection. No significant motor disorders were observed from 1 to 12 months post-final injection, with exception of increased exploratory activity in the elevated plus maze from 2 to 8 months. One month after the final MPTP/p injection, there was a significant decrease in dopaminergic neurons in the ventral midbrain, which partially recovered after 12 months. A single MPTP/p injection temporarily increased striatal DA and its metabolites. Proteomics of ventral midbrain tissue indicated that the recovery of dopaminergic neurons might be linked to the upregulation of proteins like Bone morphogenetic protein type II receptor (Bmpr2) and Glutathione S-transferase mu 2 (Gstm2) once MPTP toxicity was removed. Our study indicated that the optimal time to evaluate behavioral abnormalities in chronic MPTP/p mouse model is within one week after modeling. Moreover, the upregulated expression of related proteins, such as Bmpr2 and Gstm2, in the ventral midbrain of the model mice after modeling may represent important targets for the future treatment of Parkinson's disease.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115168"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064628","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":"Relationship among depression, fatigue, and sleep after traumatic brain injury: The role of physical exercise as a non-pharmacological therapy.","authors":"Fernando da Silva Fiorin, Douglas Buchmann Godinho, Eduarda Bitencourt Dos Santos, Aderbal S Aguiar, Felipe Barreto Schuch, Marco Túlio de Mello, Zsolt Radak, Michele Rechia Fighera, Luiz Fernando Freire Royes","doi":"10.1016/j.expneurol.2025.115156","DOIUrl":"10.1016/j.expneurol.2025.115156","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a burdensome condition frequently associated with an increased risk of psychiatric disorders. Although the exact molecular signaling pathways have not yet been fully defined, the compromised integrity of functional brain networks in regions such as the prefrontal cortex and anterior cingulate cortex has been linked to persistent symptoms, including depression, fatigue, and sleep disorders. Understanding how TBI affects neural physiology enables the development of effective interventions. One such strategy may be physical exercise, which promotes neural repair and behavioral rehabilitation after TBI. However, there are caveats to consider when interpreting the effects of physical exercise on TBI-induced mental health issues. This review will highlight the main findings from the literature investigating how different physical exercise protocols affect the progression of TBI-induced depression, fatigue, and sleep disturbances. Furthermore, we aim to explore potential neurobiological pathways that explain how physical exercise influences depression, fatigue, and sleep following TBI.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115156"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045953","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":"An optogenetic mouse model of hindlimb spasticity after spinal cord injury.","authors":"Sara Goltash, Riham Khodr, Tuan V Bui, Alex M Laliberte","doi":"10.1016/j.expneurol.2025.115157","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115157","url":null,"abstract":"<p><p>Spasticity is a common comorbidity of spinal cord injury (SCI), disrupting motor function and resulting in significant discomfort. While elements of post-SCI spasticity can be assessed using pre-clinical SCI models, the robust measurement of spasticity severity can be difficult due to its periodic and spontaneous appearance. Electrical stimulation of sensory afferents can elicit spasticity-associated motor responses, such as spasms; however, placing surface electrodes on the hindlimbs of awake animals can induce stress or encumbrance that could influence the expression of behaviour. Therefore, we have generated a mouse model of SCI-related spasticity that utilizes optogenetics to activate a subset of cutaneous VGLUT2+ sensory afferents to produce reliable incidences of spasticity-associated responses in the hindlimb. To examine the efficacy of this optogenetic SCI spasticity model, a T9-T10 complete transection injury was performed in Islet1-Cre+/-;VGLUT2-Flp+/-;CreON-FlpON-CatCh+/- mice, followed by the implantation of EMG electrodes into the left and right gastrocnemius and tibialis anterior muscles. EMG recordings were performed during episodic optogenetic stimulation (1-2 sessions per week until 5 weeks post-injury (wpi); n = 10 females, 5 males). A subset of these mice (n = 3 females, 2 males) was also tested at 10 wpi. During each recording session, an optic fiber coupled to a 470 nm wavelength LED was used to deliver 9 × 100 ms light pulses to the palmar surface of each hind paw. The results of these recordings demonstrated significant increases in the amplitude of EMG responses to the light stimulus from 2 wpi to 10 wpi, suggesting increased excitability of cutaneous sensorimotor pathways. Interestingly, this effect was significantly greater in the female cohort than in the males. Incidences of prolonged involuntary muscle contraction in response to the stimulus (fictive spasms) were also detected through EMG and visual observation during the testing period, supporting the presence of spasticity. As such, the optogenetic mouse model developed for this study appears to elicit spasticity-associated behaviours in SCI mice reliably and may be valuable for studying SCI-related limb spasticity mechanisms and therapeutic.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115157"},"PeriodicalIF":4.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037754","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":"Editorial: COVID-19 and the central nervous system: Emerging insights from experimental neurology.","authors":"Takayoshi Shimohata","doi":"10.1016/j.expneurol.2025.115165","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115165","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115165"},"PeriodicalIF":4.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058519","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}