Experimental Neurology最新文献

{"title":"Harnessing the potential of long non-coding RNAs in the pathophysiology of Alzheimer's disease","authors":"Rasanpreet Kaur ,&nbsp;Swadha Pandey ,&nbsp;Saurabh Gupta ,&nbsp;Jitendra Singh","doi":"10.1016/j.expneurol.2024.115134","DOIUrl":"10.1016/j.expneurol.2024.115134","url":null,"abstract":"<div><div>Alzheimer's disease (AD), a diverse neurodegenerative disease, is the leading cause of dementia, accounting for 60–80 % of all cases. The pathophysiology of Alzheimer's disease is unknown, and there is no cure at this time. Recent developments in transcriptome-wide profiling have led to the identification of a number of non-coding RNAs (ncRNAs). Among these, long non-coding RNAs (lncRNAs)—long transcripts that don't seem to be able to code for proteins—have drawn attention because they function as regulatory agents in a variety of biological processes. Recent research suggests that lncRNAs play a role in the pathogenesis of Alzheimer's disease by modulating tau hyperphosphorylation, amyloid production, synaptic impairment, neuroinflammation, mitochondrial dysfunction, and oxidative stress, though their precise effects on the disorder are unknown. The biology and modes of action of the best-characterized lncRNAs in AD will be outlined here, with an emphasis on their possible involvement in the pathophysiology of the disease. As lncRNAs may offer prospective prognostic/diagnostic biomarkers and therapeutic targets for the treatment of AD, a greater comprehension of the molecular processes and the intricate network of interactions in which they are implicated could pave the way for future research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115134"},"PeriodicalIF":4.6,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909461","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":"Investigating the effect of metformin on chemobrain: Reports from cells to bedside","authors":"Evelyn Leddy ,&nbsp;Tanawat Attachaipanich ,&nbsp;Nipon Chattipakorn ,&nbsp;Siriporn C. Chattipakorn","doi":"10.1016/j.expneurol.2024.115129","DOIUrl":"10.1016/j.expneurol.2024.115129","url":null,"abstract":"<div><div>Chemobrain can be defined as the development of cognitive side effects following chemotherapy, which is increasingly reported in cancer survivor patients. Chemobrain leads to reduced patients' quality of life by causing different symptoms ranging from strokes and seizures to memory loss and mood disorders. Metformin, an antidiabetic drug, has been proposed as a potential treatment to improve the symptoms of chemotherapy-induced cognitive dysfunction. Several benefits of metformin on chemobrain have been suggested, including anti-inflammation, anti-oxidative stress, restoring impaired mitochondrial function, stabilizing apoptosis, ameliorating impairments to dendritic spine density, normalizing brain senescence protein levels, and attenuating reductions in cell viability, along with reversing learning and memory deficits. These benefits occur through various pathways of metformin, including adenosine monophosphate-activated protein kinase (AMPK), TAp73, and phosphatidylinositol 3-kinase/protein kinase B (Akt) pathways. In addition, metformin can exert neuroprotective effects and restore deficits in brain homeostasis caused by chemotherapy. Furthermore, activation of AMPK following metformin therapy promotes autophagy, stimulates energy production, and improves cell survival. Metformin's interaction with Tap73 and Akt pathways allows for regulated cell proliferation in adult neural precursor cells and cell growth, respectively. Although the negative effects on cerebral function induced by chemotherapeutics have been alleviated by metformin in several instances, further studies are required to confirm its beneficial effects. This research is essential as it addresses the pressing issue of chemobrain, which is on the rise alongside global increases in cancer. Exploring metformin's potential as a neuroprotective agent offers a promising avenue for mitigating these cognitive impairments and highlights the need for further studies to validate its therapeutic mechanisms. This review comprehensively summarises evidence from both <em>in vitro</em> and <em>in vivo</em> studies to demonstrate metformin's effects on cognitive function when co-administered with chemotherapy and identifies gaps in knowledge for further investigation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115129"},"PeriodicalIF":4.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902429","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":"Astrogliosis and glial scar in ischemic stroke - focused on mechanism and treatment","authors":"Wei Chen ,&nbsp;Gang Su ,&nbsp;Miao Chai ,&nbsp;Yang An ,&nbsp;Jinyang Song ,&nbsp;Zhenchang Zhang","doi":"10.1016/j.expneurol.2024.115131","DOIUrl":"10.1016/j.expneurol.2024.115131","url":null,"abstract":"<div><div>Ischemic stroke is a kind of neurological dysfunction caused by cerebral ischemia. Astrocytes, as the most abundant type of glial cells in the central nervous system, are activated into reactive astrocytes after cerebral ischemia, and this process involves the activation or change of a series of cell surface receptors, ion channels and ion transporters, GTPases, signaling pathways, and so on. The role of reactive astrocytes in the development of ischemic stroke is time-dependent. In the early stage of ischemia, reactive astrocytes proliferate moderately and surround the ischemic tissue to prevent the spread of the lesion. At the same time, reactive astrocytes release neuroprotective factors, ultimately relieving brain injury. In the late stage of ischemia, reactive astrocytes excessively proliferate and migrate to form dense glial scar tissue, which hinders the repair of damaged tissue. At the same time, reactive astrocytes in the glial scar release a large number of neurotoxic factors, ultimately aggravating ischemic stroke. In this paper, we focus on the molecular mechanism of astrogliosis and glial scar formation after cerebral ischemia, and explore the relevant studies using glial scar as a therapeutic target, providing a reference for the selection of therapeutic strategies for ischemic stroke and further research directions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115131"},"PeriodicalIF":4.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902449","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":"Unique infrared thermographic profiles and altered hypothalamic neurochemistry associated with mortality in endotoxic shock","authors":"Sean N. Curtis ,&nbsp;Catherine A. Mayer ,&nbsp;Tracey L. Bonfield ,&nbsp;Thomas M. Raffay ,&nbsp;Juliann M. DiFiore ,&nbsp;Richard J. Martin ,&nbsp;Adriana C. Hoffman ,&nbsp;Michael A. Folz ,&nbsp;Ryan W. Bavis ,&nbsp;Mathias Dutschmann ,&nbsp;Peter M. MacFarlane","doi":"10.1016/j.expneurol.2024.115130","DOIUrl":"10.1016/j.expneurol.2024.115130","url":null,"abstract":"<div><div>Neonatal sepsis results in significant morbidity and mortality, but early detection is clinically challenging. In a neonatal rat model of endotoxic shock, we characterised unique infrared thermographic (IRT) profiles in skin temperature that could identify risk of later mortality. Ten-day old rats were placed in a thermally stable isolette and IRT images of cranial (T_CR), scapula (T_SC) and rump (T_RU) skin temperature were obtained continuously for 8 h following an intraperitoneal injection of lipopolysaccharide (LPS) or saline. LPS resulted in ∼74 % mortality (designated as non-survivors, LPS_NS) between 4.5 and 7.5 h post-injection. LPS_NS and survivors of LPS (LPS_S) rats displayed hypothermic tendencies with T_CR, T_SC and T_RU decreasing at ∼80–100 min (T₈₀_–₁₀₀) post-injection. Compared to LPS_S rats, however, the hypothermia of LPS_NS rats occurred slightly earlier (T₈₀), was more severe, and failed to recover. The T_CR, T_SC and T_RU of LPS_S rats fully recovered by 4 h (T₂₄₀) post-injection. In separate rats, hypothalamic microglia and extracellular matrix (ECM) expression at T₂₄₀ post-injection were increased in putatively identified LPS_NS rats (but not LPS_S rats) and negatively correlated with IR temperatures. IRT could be a useful early identifier of infants at risk of death from endotoxic shock, which may be related to early failure of central nervous system (CNS) thermogenic mechanisms mediated by unique hypothalamic changes in inflammatory (microglia) and ECM neurochemistry.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115130"},"PeriodicalIF":4.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893060","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 H4R antagonist, JNJ-7777120 treatments ameliorate mild traumatic brain injury by reducing oxidative damage, inflammatory and apoptotic responses through blockage of the ERK1/2/NF-κB pathway in a rat model","authors":"Ece Sağlam-Çifci ,&nbsp;İlker Güleç ,&nbsp;Aslıhan Şengelen ,&nbsp;Feyza Karagöz-Güzey ,&nbsp;Burak Eren ,&nbsp;Hüsniye Esra Paşaoğlu ,&nbsp;Evren Önay-Uçar","doi":"10.1016/j.expneurol.2024.115133","DOIUrl":"10.1016/j.expneurol.2024.115133","url":null,"abstract":"<div><div>Growing evidence reveals that microglia activation and neuroinflammatory responses trigger cell loss in the brain. Histamine is a critical neurotransmitter and promotes inflammatory responses; thus, the histaminergic system is a potential target for treating neurodegenerative processes. JNJ-7777120, a histamine H4 receptor (H₄R) antagonist, has been shown to alleviate inflammation, brain damage, and behavioral deficits effectively, but there is no report on its role in brain trauma. Herein, we investigated the neuroprotective effects of JNJ-7777120 (shortly JNJ) in a mild traumatic brain injury (mTBI). mTBI setup was performed using a weight-drop model in adult male Sprague-Dawley rats. JNJ (1 mg/kg, twice/day for 7 days) was intraperitoneally administered following mTBI. Modified neurological severity score and beam-walking test used to assess motor, sensory, reflex, and balance functions (post-TBI days-1/3/7) showed that JNJ had significantly improved these functions. HE-staining revealed reduced neurodegenerative cells after JNJ-treatments compared to vehicle (2.85 % DMSO) treated group. JNJ also decreased the injury-induced apoptosis (Bax/Bcl-2, cleaved-Cas-3, cleaved-PARP1), oxidative (4HNE, MDA), and inflammatory (IBA1, TNF-α, IL-1β, IL-6, and IL-10) responses. Furthermore, blocking the activation of the ERK1/2/NF-κB pathway was determined to be involved in its therapeutic mechanism. The network pharmacology analyses for JNJ-7777120 and TBI confirmed the importance of targeting neurotransmitter receptor activity, signaling receptor activity, and kinase activation. Our results provide the first proof of the efficacy of an H₄R antagonist in a mild TBI rat model and suggest that H₄R targeting by JNJ-treatment might be a promising therapeutic approach to clinically halt the progression of brain injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115133"},"PeriodicalIF":4.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893047","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":"Labeling and isolating cell specific neuronal mitochondria and their functional analysis in mice post stroke","authors":"Yanfeng Li ,&nbsp;Zheng Gang Zhang ,&nbsp;Michael Chopp ,&nbsp;Zhongwu Liu ,&nbsp;William Golembieski ,&nbsp;Julie Landschoot-Ward ,&nbsp;Yi Zhang ,&nbsp;Xian Shuang Liu ,&nbsp;Hongqi Xin","doi":"10.1016/j.expneurol.2024.115126","DOIUrl":"10.1016/j.expneurol.2024.115126","url":null,"abstract":"<div><div>Dendritic and axonal plasticity, which mediates neurobiological recovery after a stroke, critically depends on the mitochondrial function of neurons. To investigate, in vivo, neuronal mitochondrial function at the stroke recovery stage, we employed Mito-tag mice combined with cerebral cortical infection of AAV9 produced from plasmids carrying Cre-recombinase controlled by two neuronal promoters, synapsin-I (SYN1) and calmodulin-kinase IIa to induce expression of a hemagglutinin (HA)-tagged enhanced green fluorescence protein (EGFP) that localizes to mitochondrial outer membranes of SYN1 positive (SYN⁺) and CaMKIIa positive (CaMKIIa⁺) neurons. These mice were then subjected to permanent middle cerebral artery occlusion (MCAO) and sacrificed 14 days post stroke. Neuronal mitochondria were then selectively isolated from the fresh brain tissues excised from the ischemic core (IC), ischemic boundary zone (IBZ), as well as from the homologous contralateral hemisphere (CON) by anti-HA magnetic beads for functional analyses. We found that the bead pulled neuronal specific mitochondria were co-precipitated with GFP and enriched with mitochondrial markers, e.g. voltage-dependent anion channel, cytochrome C, and COX IV, but lacked the Golgi protein RCAS1 as well as endoplasmic reticulum markers: Heme‑oxygenase 1 and Calnexin, indicating that specific neuronal mitochondria have been selectively isolated. Western-blot data showed that oxidative phosphorylation (OXPHOS) components in SYN⁺ and CAMKII⁺ neuronal mitochondria were significantly decreased in the IBZ and further decreased in the IC compared to the contralateral tissue, which was associated with the significant reductions of mitochondrial function indicated by oxygen consumption rate (OCR) (<em>p</em> &lt; 0.05, respectively, for both neuron types). These data suggest dysfunction of neuronal mitochondria post stroke is present during the stroke recovery stage. Collectively, for the first time, we demonstrated that using a Mito-tag mouse line combined with AAV9 carrying Cre recombinase approach, neuronal specific mitochondria can be efficiently isolated from the mouse brain to investigate their functional changes post stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115126"},"PeriodicalIF":4.6,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885317","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":"Effects of ALS-associated 5’tiRNAGly-GCC on the transcriptomic and proteomic profile of primary neurons in vitro","authors":"Elisabeth Jirström ,&nbsp;Anna Matveeva ,&nbsp;Sharada Baindoor ,&nbsp;Paul Donovan ,&nbsp;Qilian Ma ,&nbsp;Elena Perez Morrissey ,&nbsp;Ingrid Arijs ,&nbsp;Bram Boeckx ,&nbsp;Diether Lambrechts ,&nbsp;Amaya Garcia-Munoz ,&nbsp;Eugène T. Dillon ,&nbsp;Kieran Wynne ,&nbsp;Zheng Ying ,&nbsp;David Matallanas ,&nbsp;Marion C. Hogg ,&nbsp;Jochen H.M. Prehn","doi":"10.1016/j.expneurol.2024.115128","DOIUrl":"10.1016/j.expneurol.2024.115128","url":null,"abstract":"<div><div>tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the <em>ANG</em> gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5’tiRNA^Gly-GCC, which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5’tiRNA^Gly-GCC revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5’tiRNA^Gly-GCC binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5’tiRNA^Gly-GCC is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115128"},"PeriodicalIF":4.6,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885311","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":"Microglial cell proliferation is regulated, in part, by reactive astrocyte ETBR signaling after ischemic stroke","authors":"John J. McInnis ,&nbsp;Matthew D. LeComte ,&nbsp;Leah F. Reed ,&nbsp;Emily E. Torsney ,&nbsp;Roxana del Rio-Guerra ,&nbsp;Matthew E. Poynter ,&nbsp;Jeffrey L. Spees","doi":"10.1016/j.expneurol.2024.115125","DOIUrl":"10.1016/j.expneurol.2024.115125","url":null,"abstract":"<div><div>Reciprocal communication between reactive astrocytes and microglial cells provides local, coordinated control over critical processes such as neuroinflammation, neuroprotection, and scar formation after CNS injury, but is poorly understood. The vasoactive peptide hormone endothelin (ET) is released and/or secreted by endothelial cells, microglial cells and astrocytes early after ischemic stroke and other forms of brain injury. To better understand glial cell communication after stroke, we sought to identify paracrine effectors produced and secreted downstream of astroglial endothelin receptor B (ETB_R) signaling. Using a genetic loss-of-function screen, we identified angiopoietin-2 (Ang-2) as a factor produced by reactive astrocytes in response to ET. In experiments with primary adult astrocytes stimulated by IRL1620, a specific ETB_R agonist, we found that ERK1/2 and NFkB mediated the effects of ET on Ang-2 production. To determine astroglial Ang-2 levels in vivo, reactive astrocytes expressing the high affinity glutamate transporter (GLAST, EAAT1) were isolated by magnetic-activated cell sorting 3 days after stroke. Astrocytes obtained from the ipsilateral hemisphere expressed significantly more Ang-2 compared with astrocytes isolated from the contralateral hemisphere, or from cortices of sham-operated (control) mice. Notably, analysis of microglia sorted from CX3CR1-eGFP mice demonstrated increased cell surface expression of Tie-2, the Ang-2 receptor, on cells obtained from ipsilateral versus contralateral tissue. Addition of recombinant Ang-2 to astrocyte-conditioned medium significantly increased the number of SIM-A9 murine microglial cells cultured under hypoxic conditions (1 % oxygen for 48 h). In transgenic GFAP-CreER™-<em>EDNRB</em>-^fl/fl mice with stroke, conditional knockout of astroglial ETB_R significantly decreased the number of proliferating cells in the peri-infarct area with a microglial phenotype (Ki67⁺/CD11b⁺). Our results indicate that Ang-2, and possibly other paracrine effectors functioning downstream of astroglial ETB_R signaling, are important mediators of microglial cell dynamics after stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115125"},"PeriodicalIF":4.6,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881730","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":"miR-135a-5p alleviates cerebral ischemia-reperfusion injury by inhibiting pyroptosis mediated through the DDX3X/NLRP3 pathway","authors":"Yong Liu ,&nbsp;Xin Jiang ,&nbsp;Yunfei Zhang ,&nbsp;Guofeng Tong ,&nbsp;Kai Tang ,&nbsp;Yanlin Gui ,&nbsp;Lan Wen ,&nbsp;Changqing Li","doi":"10.1016/j.expneurol.2024.115127","DOIUrl":"10.1016/j.expneurol.2024.115127","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) are widely involved in signal transduction and regulation during cerebral ischemia-reperfusion injury (CIRI). This study investigates the molecular mechanisms of the specific miRNA/DDX3X/NLRP3 pathway in early-stage CIRI and explores its potential clinical applications. Through public database analysis, miR-135a-5p targeting DDX3X after CIRI was determined. The levels of DDX3X, NLRP3 inflammasome, and GSDMD-N were increased after MCAO/R. Upregulation of miR-135a-5p suppressed these protein levels. Upregulating miR-135a-5p also reduced infarct volume and neuronal pyroptosis, while improved neurological scores in MCAO/R mice. Co-IP confirmed protein interaction between DDX3X and NLRP3 in CIRI models. Furthermore, miR-135a-5p mimics alleviated pyroptosis and inhibited DDX3X/NLRP3 pathway activation after OGD/R cells, whereas miR-135a-5p inhibitor produced the opposite effect. The dual-luciferase reporter assay validated that DDX3X was a direct target of miR-135a-5p. Clinically, the serum level of miR-135a-5p was significantly lower in CIRI patients after thrombectomy compared to controls. The levels of DDX3X, NLRP3, and IL-18 were elevated in the CIRI group, while the difference of IL-1β levels between the two groups was not statistically significant (<em>p</em> = 0.055). Although an inverse correlation was observed between miR-135a-5p and DDX3X levels in CIRI patients, the linear regression analysis did not reach statistical significance (R² = 0.12, <em>p</em> = 0.061). This study indicated that miR-135a-5p/DDX3X/NLRP3 pathway is pivotal in early-stage CIRI. Upregulation of miR-135a-5p inhibits NLRP3-mediated neuronal pyroptosis by targeting DDX3X, thereby alleviating CIRI and improving neurological function. This signaling axis holds promise for future clinical applications in treating CIRI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115127"},"PeriodicalIF":4.6,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885322","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 alterations of functional connectivity, regional brain volumes and astrocyte markers in the beta-sitosterol beta-d-glucoside (BSSG) rat model of parkinsonism","authors":"C. Monnot ,&nbsp;M. Kalomoiri ,&nbsp;E. MacNicol ,&nbsp;E. Kim ,&nbsp;M. Mesquita ,&nbsp;P. Damberg ,&nbsp;J.M. Van Kampen ,&nbsp;D.G. Kay ,&nbsp;F. Turkheimer ,&nbsp;H.A. Robertson ,&nbsp;D. Cash ,&nbsp;P. Svenningsson","doi":"10.1016/j.expneurol.2024.115118","DOIUrl":"10.1016/j.expneurol.2024.115118","url":null,"abstract":"<div><div>The β-sitosterol-β-ᴅ-glucoside (BSSG) rat model of experimental parkinsonism develops pathological behaviour and motor changes that progress over time. The purpose of this study was to identify early changes in structure and function of the brain of rats treated with BSSG using both structural and resting-state functional MRI. BSSG and non-BSSG rats were fed five days a week for sixteen weeks, then underwent <em>in vivo</em> MRI scans and an assessment of motor performance 2 and 8 weeks later (18 and week 24 from BSSG). Groups of rats were killed at weeks 19 and 25, then imaged again with MR <em>ex vivo,</em> and immunostained for tyrosine hydroxylase (TH). Since BSSG may interfere with cholesterol metabolism in astrocytes, we also studied potential target engagement and measured levels of astrocyte markers GFAP and S100b. At both studied timepoints, functional connectivity (FC) between brain areas with intermediate connectivity was decreased, but brain volumes increased in the BSSG-treated rats. At week 18/19, fine movements were normal, whereas TH and GFAP were decreased in the striatum, but not in the substantia nigra. At week 24/25, fine movements were impaired, and TH was decreased both in the striatum and the substantia nigra and S100b was increased in the substantia nigra. Astrogliosis may contribute to the increased brain volume found after BSSG exposure. Using the BSSG model of parkinsonism, the results demonstrate <em>early</em> functional and structural alterations in MRI imaging that occur <em>before</em> the appearance of detectable motor symptoms.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115118"},"PeriodicalIF":4.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881719","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}