Brain Research Bulletin最新文献

{"title":"Bleomycin triggers chronic mechanical nociception by activating TRPV1 and glial reaction-mediated neuroinflammation via TSLP/TSLPR/pSTAT5 signals","authors":"","doi":"10.1016/j.brainresbull.2024.111081","DOIUrl":"10.1016/j.brainresbull.2024.111081","url":null,"abstract":"<div><p>Chronic pain is a universal public health problem with nearly one third of global human involved, which causes significant distressing personal burden. After painful stimulus, neurobiological changes occur not only in peripheral nervous system but also in central nervous system where somatosensory cortex is important for nociception. Being an ion channel, transient receptor potential vanilloid 1 (TRPV1) act as an inflammatory detector in the brain. Thymic stromal lymphopoietin (TSLP) is a potent neuroinflammation mediator after nerve injury. Bleomycin is applied to treat dermatologic diseases, and its administration elicits local painful sensation. However, whether bleomycin administration can cause chronic pain remains unknown. In the present study, we aimed to investigate how mice develop chronic pain after receiving repeated bleomycin administration. In addition, the relevant neurobiological brain changes after noxious stimuli were clarified. C57BL/6 mice aged five- to six-weeks were randomly classified into two group, PBS (normal) group and bleomycin group which bleomycin was intradermally administered to back five times a week over a three-week period. Calibrated forceps testing was used to measure mouse pain threshold. Western blots were used to assess neuroinflammatory response; immunofluorescence assay was used to measure the status of neuron apoptosis, glial reaction, and neuro-glial communication. Bleomycin administration induced mechanical nociception and activated both TRPV1 and TSLP/TSLPR/pSTAT5 signals in mouse somatosensory cortex. Through these pathways, bleomycin not only activates glial reaction but also causes neuronal apoptosis. TRPV1 and TSLP/TSLPR/pSTAT5 signaling had co-labeled each other by immunofluorescence assay. Taken together, our study provides a new chronic pain model by repeated intradermal bleomycin injection by activating TRPV1 and glial reaction-mediated neuroinflammation via TSLP/TSLPR/pSTAT5 signals.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002156/pdfft?md5=b09749f9a94f8305bbcf88ca702a7b95&pid=1-s2.0-S0361923024002156-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetin alleviates microglial-induced inflammation after traumatic brain injury via the PGC-1α/Nrf2 pathway dependent on HDAC3 inhibition","authors":"","doi":"10.1016/j.brainresbull.2024.111080","DOIUrl":"10.1016/j.brainresbull.2024.111080","url":null,"abstract":"<div><p>Inflammation and neuronal apoptosis play a key role in traumatic brain injury (TBI). Quercetin (Que) has been shown to exhibit a neuroprotective effect after TBI, but the underlying molecular mechanism remains unclear. In this study, We established a weight-drop mouse model to illustrate the effects of Que on microglial-induced inflammation in TBI. Mice were divided into four groups: the Sham group, TBI group, TBI+vehicle group, and TBI+Que group. The TBI+Que group was treated with Que 30 min after TBI. Brain water content, neurological score, and neuronal apoptosis were measured. Western blotting, TUNEL staining, Nissl staining, quantitative polymerase chain reaction, and immunofluorescence staining were performed to assess the activation of the PGC-1α/Nrf2 pathway and nuclear translocation of HDAC3 with Que treatment. The results showed that Que administration alleviated TBI-induced neurobehavioral deficits, encephaledema, and neuron apoptosis. Que also restrained TBI-induced microglial activity and the subsequent expression of the inflammatory factor in the contusion cortex. Moreover, Que treatment activated the PGC-1α/Nrf2 pathway, attributable to the inhibition of HDAC3 translocation to the nucleus. Overall, these results reveal the role of Que in protecting against TBI-induced neuroinflammation and promoting neurological functional recovery, which is achieved through the negative regulation of HDAC3.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002144/pdfft?md5=9f5ac149037d4f07fa11df7a94fbb158&pid=1-s2.0-S0361923024002144-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Projections from the ventral tegmental area to zona incerta regulate fear generalization in a mouse model of PTSD","authors":"","doi":"10.1016/j.brainresbull.2024.111079","DOIUrl":"10.1016/j.brainresbull.2024.111079","url":null,"abstract":"<div><p>Generalized fear is a maladaptive behavior in which non-threatening stimuli elicit a fearful response. The ventral tegmental area (VTA) has been demonstrated to play important roles in fear response and fear memory generalization, but the precious neural circuit mechanism is still unclear. Here, we demonstrated that VTA-zona incerta (ZI) glutamatergic projection is involved in regulating high-intensity threatening training induced generalization and anxiety. Combining calcium signal recording and chemogentics, our work reveals that VTA glutamatergic neurons respond to closed arm entering in the model of PTSD. Inhibition of VTA glutamatergic neurons or the glutamatergic projection to ZI could both relieve fear generalization and anxiety. Together, our study proves the VTA - ZI glutamatergic circuit is involved in mediating fear generalization and anxiety, and provides a potential target for treating post-traumatic stress disorder.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002132/pdfft?md5=1a3a27457bbf0fbde1b93b06854a7cca&pid=1-s2.0-S0361923024002132-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDNF facilitates cognitive function recovery following neonatal surgical-induced learning and memory impairment via activation of the RET pathway and modulation of downstream effectors PKMζ and Kalirin in rats","authors":"","doi":"10.1016/j.brainresbull.2024.111078","DOIUrl":"10.1016/j.brainresbull.2024.111078","url":null,"abstract":"<div><h3>Objective</h3><p>The aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions.</p></div><div><h3>Methods</h3><p>Newborn Sprague–Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (<em>n</em>=15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting.</p></div><div><h3>Results</h3><p>GDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594.</p></div><div><h3>Conclusion</h3><p>The effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002120/pdfft?md5=3beff9a5217a66fb993188060c8fcb4c&pid=1-s2.0-S0361923024002120-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium aescinate alleviates neuropathic pain through suppressing OGT-mediated O-GlcNAc modification of TLR3 to inactivate MAPK signaling pathway","authors":"","doi":"10.1016/j.brainresbull.2024.111077","DOIUrl":"10.1016/j.brainresbull.2024.111077","url":null,"abstract":"<div><p>Neuropathic pain results from damage to nerves or the brain, and is characterized by symptoms such as allodynia, spontaneous pain, and hyperalgesia. The causes of this type of pain are intricate, which can make it difficult to treat. Sodium aescinate (SA), a natural extract from horse chestnut tree seeds, has been shown to act as a neuroprotector by inhibiting microglia activation. This study aims to explore the therapeutic potential of SA for neuropathic pain and the molecular mechanisms regulated by SA treatment. Through in vivo animal models and experiments, we found that SA treatment significantly reduced mechanical allodynia and heat hyperalgesia in neuropathic pain models. Additionally, SA inhibited O-GlcNAc-transferase (OGT)-induced O-GlcNAcylation (O-GlcNAc) modification in neuropathic pain mice. OGT overexpression could impede the therapeutic effects of SA on neuropathic pain. Further investigation revealed that Toll-like receptor 3 (TLR3), stabilized by OGT-induced O-GlcNAc modification, could activate the Mitogen activated protein kinase (MAPK) signaling pathway. Further in vivo experiments demonstrated that TLR3-mediated p38 mitogen-activated protein kinase (p38MAPK) activation is involved in SA-mediated relief of neuropathic pain. In conclusion, this study uncovers a novel molecular pathway deactivated by SA treatment in neuropathic pain.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002119/pdfft?md5=b39776d4ea906cc2254572a35bb8b3e6&pid=1-s2.0-S0361923024002119-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuregulin-1 immunoreactivity in peripheral plasma is associated with rs6982890 polymorphism-mediated psychotic symptoms in schizophrenia","authors":"","doi":"10.1016/j.brainresbull.2024.111075","DOIUrl":"10.1016/j.brainresbull.2024.111075","url":null,"abstract":"<div><h3>Objectives</h3><p>Neuregulin 1 (<em>NRG1</em>) is a risk gene for schizophrenia and involved in neurodevelopment and synaptic plasticity. Polymorphisms in <em>NRG1</em> may affect psychotic symptoms in schizophrenia. This study investigated the effects of the single nucleotide polymorphism (SNP) rs6982890 on peripheral plasma NRG1 immunoreactivity, clinical symptoms and cognitive functions in schizophrenia patients.</p></div><div><h3>Material and methods</h3><p>We recruited subjects from the Han population of northern China from 2010 to 2022. We first genotyped and analyzed 6 NRG1 SNPS in 1304 patients with schizophrenia and 871 healthy controls. Then, 91 patients with schizophrenia and 40 healthy controls were selected to detect the peripheral plasma NRG1 immunoreactivity by ELISA. Among them, 84 patients were divided into rs6982890 genotypes to analyze the correlation between NRG1 immunoreactivity and clinical symptoms.</p></div><div><h3>Results</h3><p>Rs6982890 allelic frequencies were statistically significant between patients and controls. Baseline peripheral plasma NRG1 immunoreactivity in patients were significantly lower than controls. NRG1 immunoreactivity in patients were significantly increased after 8 weeks of antipsychotic treatment and significantly correlated with clinical symptoms and cognitive function. Genotyping of patients with SNP rs6982890 indicated NRG1 immunoreactivity in CC genotype increased significantly after treatment, while CT genotype had no significant change. Baseline NRG1 immunoreactivity with the CT genotype were significantly higher than CC genotype.</p></div><div><h3>Conclusions</h3><p><em>NRG1</em> SNP rs6982890 is significantly associated with schizophrenia in the Han population of northern China, and it may affect the effect of antipsychotic drug treatment by regulating the peripheral plasma NRG1 immunoreactivity.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002090/pdfft?md5=f95059a27ca47425033f386d9c067055&pid=1-s2.0-S0361923024002090-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142172938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction models of the aphasia severity after stroke by lesion load of cortical language areas and white matter tracts: An atlas-based study","authors":"","doi":"10.1016/j.brainresbull.2024.111074","DOIUrl":"10.1016/j.brainresbull.2024.111074","url":null,"abstract":"<div><h3>Objective</h3><p>To construct relatively objective, atlas-based multivariate models for predicting early aphasia severity after stroke, using structural magnetic resonance imaging.</p></div><div><h3>Methods</h3><p>We analyzed the clinical and imaging data of 46 patients with post-stroke aphasia. The aphasia severity was identified with a Western Aphasia Battery Aphasia Quotient. The assessments of stroke lesions were indicated by the lesion load of both the cortical language areas (Areas-LL) and four white matter tracts (i.e., the superior longitudinal fasciculus, SLF-LL; the inferior frontal occipital fasciculi, IFOF-LL; the inferior longitudinal, ILF-LL; and the uncinate fasciculi, UF-LL) extracted from human brain atlas. Correlation analyses and multiple linear regression analyses were conducted to evaluate the correlations between demographic, stroke- and lesion-related variables and aphasia severity. The predictive models were then established according to the identified significant variables. Finally, the receiver operating characteristic (ROC) curve was utilized to assess the accuracy of the predictive models.</p></div><div><h3>Results</h3><p>The variables including Areas-LL, the SLF-LL, and the IFOF-LL were significantly negatively associated with aphasia severity (p &lt; 0.05). In multiple linear regression analyses, these variables accounted for 59.4 % of the variance (p &lt; 0.05). The ROC curve analyses yielded the validated area under the curve (AUC) 0.84 both for Areas-LL and SLF-LL and 0.76 for IFOF-LL, indicating good predictive performance (p &lt; 0.01). Adding the combination of SLF-LL and IFOF-LL to this model increased the explained variance to 62.6 % and the AUC to 0.92.</p></div><div><h3>Conclusions</h3><p>The application of atlas-based multimodal lesion assessment may help predict the aphasia severity after stroke, which needs to be further validated and generalized for the prediction of more outcome measures in populations with various brain injuries.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002089/pdfft?md5=b5a2f92693bae2f36046063e025c08f6&pid=1-s2.0-S0361923024002089-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of glutathione peroxidase 4 in neuronal ferroptosis and its therapeutic potential in ischemic and hemorrhagic stroke","authors":"","doi":"10.1016/j.brainresbull.2024.111065","DOIUrl":"10.1016/j.brainresbull.2024.111065","url":null,"abstract":"<div><div>Ferroptosis is a type of cell death that depends on iron and is driven by lipid peroxidation, playing a crucial role in neuronal death during stroke. A central element in this process is the inactivation of glutathione peroxidase 4 (GPx4), an antioxidant enzyme that helps maintain redox balance by reducing lipid hydroperoxides. This review examines the critical function of GPx4 in controlling neuronal ferroptosis following ischemic and hemorrhagic stroke. We explore the mechanisms through which GPx4 becomes inactivated in various stroke subtypes. In strokes, excess glutamate depletes glutathione (GSH) and products of hemoglobin breakdown overwhelm GPx4. Studies using genetic models with <em>GPx4</em> deficiency underscore its vital role in maintaining neuronal survival and function. We also consider new therapeutic approaches to enhance GPx4 activity, including novel small molecule activators, adjustments in GSH metabolism, and selenium supplementation. Additionally, we outline the potential benefits of combining these GPx4-focused strategies with other anti-ferroptotic methods like iron chelation and lipoxygenase inhibition for enhanced neuroprotection. Furthermore, we highlight the significance of understanding the timing of GPx4 inactivation during stroke progression to design effective therapeutic interventions.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024001990/pdfft?md5=5a7a61a0f3c30ab8c7e928a068a6f43d&pid=1-s2.0-S0361923024001990-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keap1-independent GSK-3β/Nrf2 signaling mediates electroacupuncture inhibition of oxidative stress to induce cerebral ischemia-reperfusion tolerance","authors":"","doi":"10.1016/j.brainresbull.2024.111071","DOIUrl":"10.1016/j.brainresbull.2024.111071","url":null,"abstract":"<div><h3>Purpose</h3><p>Cerebral ischemia-reperfusion (CIR) injury is a devastating consequence of stroke characterized by oxidative stress-induced neuronal damage. Electroacupuncture (EA) has emerged as a potential therapeutic intervention for ischemic stroke, but its underlying mechanisms remain incompletely understood. This study aimed to elucidate whether EA exerts anti-oxidative stress effects against CIR injury by modulating the GSK-3β/Nrf2 pathway.</p></div><div><h3>Methods</h3><p>CIR mouse models were established using the suture-occluded method and underwent EA pretreatment. Cognitive and neurologic function, cerebral infarct volume, and neuronal damage were assessed in mice. Oxidative stress levels and the expression of components of the GSK-3β/Nrf2 pathway in the cerebral cortex were measured. The regulatory effect of GSK-3β on Nrf2 and its role in electroacupuncture to alleviate oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury were investigated by modulating GSK-3β expression in HT22 hippocampal neuronal cells and electroacupuncture serum intervention. Ultimately, Nrf2 knockout mice, GSK-3β knockout mice, and wild-type mice treated with TBHQ (an Nrf2 activator) were utilized for further validation.</p></div><div><h3>Results</h3><p>EA pretreatment improved cognitive impairment and neuronal damage induced by CIR injury. Mechanistically, EA inhibited oxidative stress in the cerebral cortex, manifested by reduced levels of reactive oxygen species and malondialdehyde, along with increased superoxide dismutase activity. Furthermore, EA upregulated the expression of Nrf2 and its downstream antioxidant enzymes HO-1 and NQO1, while Keap1 expression remained unaffected. <em>In vitro</em>, GSK-3β overexpression inhibited the protective effects of EA serum on OGD/R-induced neuronal damage. <em>In vivo</em>, knockout of either Nrf2 or Gsk-3β genes abolished the neuroprotective effects of EA, and TBHQ exerted effects similar to EA, confirming the significant role of GSK-3β/Nrf2 in mediating EA antioxidative effects.</p></div><div><h3>Conclusion</h3><p>EA exerts antioxidative stress effects against CIR injury by activating the GSK-3β/Nrf2 signaling pathway, independent of Keap1 regulation.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002053/pdfft?md5=55c1884e133ec2fa4026461e364d4b57&pid=1-s2.0-S0361923024002053-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling","authors":"","doi":"10.1016/j.brainresbull.2024.111072","DOIUrl":"10.1016/j.brainresbull.2024.111072","url":null,"abstract":"<div><p>Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1–14, 3–14, 5–14, or 7–14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1–3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.</p></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0361923024002065/pdfft?md5=3bc2c2bc98e021affcaf45aa8ce0fc1f&pid=1-s2.0-S0361923024002065-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}