Experimental Neurology最新文献

{"title":"Intranasal administration of stem cell-derived exosome alleviates cognitive impairment against subarachnoid hemorrhage","authors":"Shuho Gotoh ,&nbsp;Masahito Kawabori ,&nbsp;Sho Yamaguchi ,&nbsp;Yo Nakahara ,&nbsp;Erika Yoshie ,&nbsp;Kohtarou Konno ,&nbsp;Yuki Mizuno ,&nbsp;Yoichiro Fujioka ,&nbsp;Yusuke Ohba ,&nbsp;Yuji Kuge ,&nbsp;Masahiko Watanabe ,&nbsp;Miki Fujimura","doi":"10.1016/j.expneurol.2025.115143","DOIUrl":"10.1016/j.expneurol.2025.115143","url":null,"abstract":"<div><h3>Introduction</h3><div>Brain damage caused by subarachnoid hemorrhage (SAH) currently lacks effective treatment, leading to stagnation in the improvement of functional outcomes for decades. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells (MSC), which effectively attenuate neuronal apoptosis and inflammation in neurological diseases. Due to the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a novel approach for targeting the brain. In this study, we investigate the effects of intranasally administered MSC-derived exosomes in a SAH animal model and elucidate their mode of action.</div></div><div><h3>Methods</h3><div>Exosomes were isolated from the cell supernatants of amnion-derived MSC. SAH was induced in 8-week-old Sprague-Dawley rats using an autologous blood prechiasmatic cistern injection model. A total of 1.2 × 10¹⁰ particles of exosomes in 200 μL of PBS or PBS alone were intranasally administered immediately and 24 h post-injury. Neurological function was assessed up to 7 days after injury, and histological analysis was performed to evaluate their anti-apoptotic and anti-inflammatory effects. The biodistribution of exosomes was assessed using PET/CT imaging of ⁶⁴Cu labeled exosome. In vitro analyses were performed using primary glial cells and cell lines to evaluate the anti-inflammatory effects of the exosomes.</div></div><div><h3>Results</h3><div>Animals treated with exosomes exhibited significant improvement in cognitive function compared with PBS treated animal. Apoptotic cells and inflammation were reduced for the exosome group in the hippocampal CA1 area and in cortex, resulting in better neuronal cell survival. Blood brain barrier permeability was also preserved in the exosome group. Nuclear imaging revealed that exosomes were primarily transferred to the olfactory nerve and cerebrum; furthermore, exosomes were also observed in the trigeminal nerve and brainstem, where exosomes were co-localized with microglia and with endothelial cells. In vitro assessment showed that exosome administration ameliorated inflammation and prevented the death of glial cells.</div></div><div><h3>Conclusions</h3><div>MSC-derived exosomes were successfully transferred into the brain through intranasal administration and alleviated brain damage following SAH.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115143"},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970259","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":"Molecular insights into Parkinson's disease and type 2 diabetes mellitus: Metformin's role and genetic pathways explored","authors":"Tingting Liu ,&nbsp;Haojie Wu ,&nbsp;Jianshe Wei","doi":"10.1016/j.expneurol.2025.115137","DOIUrl":"10.1016/j.expneurol.2025.115137","url":null,"abstract":"<div><div>Background To explore whether there is a bidirectional relationship between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM), study the common pathogenic mechanisms, screen relevant genes involved in the pathological process, and predict the potential targets of metformin (Met), so as to develop new therapeutic strategies.</div><div>Method A two-sample Mendelian randomization (MR) analysis was conducted to analyze the correlation between PD and T2DM. Common confounding genes identified in both PD and T2DM datasets were subjected to GO and KEGG analysis, PPI network analysis, and Hub gene identification. qPCR was used to verify the expression of hub genes in an animal model of T2DM complicated with PD. Subsequently, the analysis focused on whether metformin alleviates the behavioral and pathological manifestations of PD aggravated by T2DM. The intersection of metformin with T2DM and PD targets was identified, and the core targets and signaling pathways were analyzed. Finally, molecular docking analysis was performed between metformin and core proteins to identify the docking sites.</div><div>Result Through MR analysis, a positive correlation between PD and T2DM was identified, indicating a mutual causal relationship. The hub genes RAC1, TPM2, MGA, and DENND3 are up-regulated in animal models of T2DM with PD. Met targets intersecting with T2DM and PD were analyzed, revealing 17 and 21 intersecting genes respectively, involved in various pathways related to oxidative stress, immune, and inflammation. PPI analysis identified hub genes for T2DM (MMP9, NCF1, CYCS, EIF4E, SOD2) and PD (GFAP, VIM, MOCOS, EIF1, TH, ACTA2, CDC42). Animal models validated the expression of these genes and pathways. Molecular docking analysis explored Met's binding sites on proteins, with lower binding energies indicating greater stability.</div><div>Conclusion This study contributes to a deeper understanding of the co pathogenesis of PD and T2DM, and provides new insights into the role of metformin in this disease.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115137"},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970258","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":"Transcription factor AP-2 Beta, a potential target of repetitive Transspinal magnetic stimulation in spinal cord injury treatment, reduced inflammation and alleviated spinal cord injury","authors":"Yang Yang ,&nbsp;Yang Shao ,&nbsp;Qi Dai ,&nbsp;Yuxi Zhang ,&nbsp;Yongxin Sun ,&nbsp;Kunpeng Wang ,&nbsp;Aihua Xu","doi":"10.1016/j.expneurol.2025.115144","DOIUrl":"10.1016/j.expneurol.2025.115144","url":null,"abstract":"<div><div>Spinal cord injury (SCI) is a neurodegenerative disease, with a high disability rate. According to the results of mRNA-seq, transcription factor AP-2 Beta (TFAP2B) is a potential target of repetitive Transspinal Magnetic Stimulation (rTSMS) in SCI treatment. Our results demonstrated that rTSMS significantly improved motor function and promoted neuronal survival post-SCI. The result showed that TFAP2B was downregulated following SCI, while significant upregulation after rTSMS treatment, suggesting its pivotal role in neuronal repair. Overexpression of TFAP2B improved Basso Beattie and Bresnahan (BBB) score and athletic ability, and decreased cell apoptosis in SCI rats. Additionally, overexpression of TFAP2B reduced the expression of Iba1 and GFAP in spinal cord, and the expression of PDGFrβ was also reduced in SCI rats after TFAP2B overexpression. Knockdown of TFAP2B reverses the effect of rTSMS treatment in SCI. We found that rTSMS alleviate osteoporosis caused by SCI, resulting in increased BMD, BV/TV, and Tb.Th. rTSMS treatment lowered the RANKL/OPG ratio. In all, our study illustrated TFAP2B is a downstream target of rTSMS for the treatment of SCI, and overexpression of TFAP2B enhanced the therapeutic effect of rTSMS.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115144"},"PeriodicalIF":4.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970260","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":"Indoleamine 2, 3-dioxygenase 1 inhibition mediates the therapeutic effects in Parkinson's disease mice by modulating inflammation and neurogenesis in a gut microbiota dependent manner","authors":"Chen-Meng Qiao ,&nbsp;Xiao-Yu Ma ,&nbsp;Lu-Lu Tan ,&nbsp;Yi-Meng Xia ,&nbsp;Ting Li ,&nbsp;Jian Wu ,&nbsp;Chun Cui ,&nbsp;Wei-Jiang Zhao ,&nbsp;Yan-Qin Shen","doi":"10.1016/j.expneurol.2025.115142","DOIUrl":"10.1016/j.expneurol.2025.115142","url":null,"abstract":"<div><div>Abnormal tryptophan metabolism is closely linked with neurological disorders. Research has shown that indoleamine 2,3-dioxygenase 1 (IDO-1), the first rate-limiting enzyme in tryptophan degradation, is upregulated in Parkinson's disease (PD). However, the precise role of IDO-1 in PD pathogenesis remains elusive. In this study, we administered 1-methyl-tryptophan (1-MT), an IDO-1 inhibitor, intraperitoneally at 15 mg/kg daily for 21 days to PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 30 mg/kg daily for 5 days. Our results show that IDO-1 inhibition improves behavioral performance, reduces dopaminergic neuron loss, and decreases serum quinolinic acid (QA) content and the aryl hydrocarbon receptor (AHR) expression in the striatum and colon. It also alleviates glial-associated neuroinflammation and mitigates colonic inflammation (decreasing iNOS, COX2) by suppressing the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Furthermore, IDO-1 inhibition promotes hippocampal neurogenesis (increasing doublecortin positive (DCX⁺) cells and SOX2⁺ cells), which have recently been recognized as key pathological features and potential therapeutic targets in PD, likely through the activation of the BDNF/TrkB pathway. We further explored the gut-brain connection by depleting the gut microbiota in mice using antibiotics. Notably, the neuroprotective effects of IDO-1 inhibition were completely abolished in pseudo-germ-free mice (administrated an antibiotic mixture orally for 14 days prior to 1-MT treatment), highlighting the dependency of 1-MT's neuroprotective effects on the presence of gut microbiota. Finally, we found IDO-1 inhibition corrects the abnormal elevation of fecal short chain fatty acids (SCFAs). Collectively, these findings suggest that IDO-1 inhibition may represent a promising therapeutic approach for PD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115142"},"PeriodicalIF":4.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964364","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":"Comparative lipid profiling reveals the differential response of distinct lipid subclasses in blast and blunt-induced mild traumatic brain injury","authors":"Seema Dhariwal ,&nbsp;Kiran Maan ,&nbsp;Ruchi Baghel ,&nbsp;Apoorva Sharma ,&nbsp;Megha Kumari ,&nbsp;Mohd Aleem ,&nbsp;Kailash Manda ,&nbsp;Richa Trivedi ,&nbsp;Poonam Rana","doi":"10.1016/j.expneurol.2025.115141","DOIUrl":"10.1016/j.expneurol.2025.115141","url":null,"abstract":"<div><div>Head trauma from blast exposure is a growing health concern, particularly among active military personnel, and is considered the signature injury of the Gulf War. However, it remains elusive whether fundamental differences exist between blast-related Traumatic Brain Injuries (TBI) and TBI due to other mechanisms. Considering the importance of lipid metabolism associated with neuronal membrane integrity and its compromise during TBI, we sought to find changes in lipidomic profiling during blast or blunt (Stereotaxically Controlled Contusison-SCC)-mediated TBI. In the current study, we have developed the mild TBI (mTBI) model of blast (130 ± 10 kPa) and SCC (1.5 mm dorsal-ventral) on C57BL/6 mice, followed by the serum collection on days 1 and 7. Lipidomics was performed via ultra-high performance liquid chromatography (UHPLC) quadrupole time-of-flight mass spectrometry (qTOF-MS). Additionally, neurobehavioral outcomes were estimated using a revised neurobehavioral severity score for mice (mNSS-R) and an open field test (OFT). The study found that blast-exposed group exhibited more lipid dysregulation, as evidenced by a higher number of significant lipids and associated pathways at both time points. However, the comparative investigation further reveals eight significantly common lipids that can characterize the mTBI regardless of the manner of induction (blast or blunt). Besides, modulated neurobehavioral, locomotor and anxiety functions were also observed post-mTBI. The study illustrates the distinct systemic lipid metabolism intended to preserve the brain's lipid homeostasis post-mTBI. This approach may provide novel insights into lipid metabolism and identification of individual lipid species that aids in understanding the pathophysiology of mTBI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115141"},"PeriodicalIF":4.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946639","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 role of clock control of DRP1 activity involved in postoperative cognitive dysfunction","authors":"Yin Cui ,&nbsp;Zhiying Zheng ,&nbsp;Qingyun Zhou ,&nbsp;Xue Han ,&nbsp;Shuai Liu ,&nbsp;Tianjiao Xia ,&nbsp;Xiaopin Gu ,&nbsp;Yun Zhang","doi":"10.1016/j.expneurol.2025.115140","DOIUrl":"10.1016/j.expneurol.2025.115140","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) is a prevalent clinical issue following anesthesia and surgery. The onset of POCD, which is closely linked to circadian rhythm disturbance in previous studies, yet the underlying mechanism remains elusive. There is increasing evidence showed that mitochondrial architecture is coordinated by the circadian clock which DRP1 playing a crucial role. Nonetheless, how DRP1's mediation of mitochondrial dynamics influences POCD through circadian rhythm disruption is still unclear. To investigate this, mice were subjected to 6 h of 1.5 % isoflurane anesthesia from Zeitgeber Time ZT 14 to ZT20 to induce POCD. HT-22 cells underwent prolonged exposure to isoflurane in vitro. Cognitive function was assessed using the Y-maze and fear conditioning tests. Q-PCR and Western blot analyses were performed to measure relative protein expression. Mice's gross movement rhythms were continuously monitored using Mini-Mitter. Mitochondrial morphology was examined via Mito-Tracker imaging. ATP and ROS level were measured to evaluate mitochondrial function. Isoflurane anesthesia compromised the clock control of DRP1 activity in the hippocampus. This disruption of DRP1 phosphorylation rhythm impaired circadian ATP production, affected mitochondrial morphology and function, exacerbated circadian rhythm disturbances, and ultimately led to cognitive deficits in mice. Pretreatment with Mdivi-1, a specific DRP1 inhibitor, managed to reconstruct mitochondrial morphology and function, restore circadian ATP production and rhythm, thereby alleviating the cognitive impairment induced by isoflurane anesthesia. This study suggests that circadian DRP1 activity's regulation of mitochondrial energy metabolism in the hippocampus may play a significant role in the pathogenesis of POCD in mice.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115140"},"PeriodicalIF":4.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946640","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":"Progesterone receptors regulate susceptibility to spreading depression","authors":"Suchitra Joshi ,&nbsp;John Williamson ,&nbsp;Serapio M. Baca ,&nbsp;Jaideep Kapur","doi":"10.1016/j.expneurol.2025.115139","DOIUrl":"10.1016/j.expneurol.2025.115139","url":null,"abstract":"<div><div>Migraine patients often experience sensory symptoms called auras accompanying the headaches. Cortical spreading depression (CSD), a slow-propagating wave of neuroglial depolarization followed by hyperpolarization is proposed to be the neurological mechanism underlying these auras. We have previously found that progesterone regulates susceptibility to migraine through progesterone receptor (PR) activation. Here, we determined if PR signaling also regulates susceptibility to CSD.</div><div>We used gonadally-intact and ovariectomized, estrogen-primed female mice expressing PRs or lacking them in the brain. CSDs were induced with dural application of KCl (1 M) and recorded using saline-filled glass electrodes placed in the cortex. PRs were modulated using agonist segesterone and antagonist RU-486. PR expression in the somatosensory cortex was evaluated using mice expressing a cre recombinase under the control of <em>Pgr</em> promoter, stereotaxically injected with adeno-associated virus (AAV) serotype 9 encoding flexed GFP. PR expression in excitatory or inhibitory neurons and distinctions in the cortical layer-specific expression were determined. The effect of chemogenetic silencing of PR-expressing somatosensory cortical neurons on CSD susceptibility was also evaluated using AAV9 expressing cre-driven hM4Di.</div><div>PRs were expressed in the excitatory neurons of the somatosensory cortex. Their expression was stronger in layer 4–6 cortical neurons than in layer 2/3 neurons. PR activation increased CSD frequency and accelerated their propagation speed. In contrast, PR antagonism or their genetic deletion suppressed CSDs. Chemogenetic silencing of PR-expressing somatosensory cortical neurons also reduced the CSD frequency.</div><div>These findings demonstrate the critical role of progesterone-PR signaling in regulating CSD and enhance our understanding of female hormonal regulation of migraine pathophysiological mechanisms.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115139"},"PeriodicalIF":4.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947072","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":"Virus-mediated delivery of single-chain antibody targeting TDP-43 protects against neuropathology, cognitive impairment and motor deficit caused by chronic cerebral hypoperfusion","authors":"Anna Ania Chami ,&nbsp;Claude Gravel ,&nbsp;Yuan Cheng Weng ,&nbsp;Jasna Kriz ,&nbsp;Jean-Pierre Julien","doi":"10.1016/j.expneurol.2025.115138","DOIUrl":"10.1016/j.expneurol.2025.115138","url":null,"abstract":"<div><div>Chronic cerebral hypoperfusion induced by permanent unilateral common carotid artery occlusion in mice was recently found to induce an age-dependent formation of insoluble cytoplasmic TDP-43 aggregates reminiscent of pathological changes found in human vascular dementia. In this model, the gradual deregulation of TDP-43 homeostasis in cortical neurons was associated with marked cognitive and motor deficits. To target the TDP-43-mediated toxicity in this model, we generated an adeno-associated virus vector encoding a single-chain antibody against TDP-43, called scFv-E6, designed for pan-neuronal transduction following intravenous administration. Injected prior to brain hypoperfusion, this tonic virus-mediated delivery of the scFv-E6 antibody reduced formation of cytoplasmic TDP-43 aggregates in cortical neurons, boosted levels of autophagy markers and attenuated microgliosis. Moreover, the novel object recognition and grip strength tests revealed that neuronal expression of scFv-E6 prevented the cognitive impairment and loss of motor performance caused by two-months of cerebral hypoperfusion. The robust protective effects of scFv-E6 antibody in this model suggest a key role of TDP-43 in neuronal damage and symptom phenotypes caused by chronic cerebral hypoperfusion. Accordingly, TDP-43 should be considered as a new therapeutic target in drug development, including antibody approaches, for treatment of vascular dementia.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115138"},"PeriodicalIF":4.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947150","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":"Lactate improves postoperative cognitive function through attenuating oxidative stress and neuroinflammation in aged mice via activating the SIRT1 pathway","authors":"Li-Li Qiu ,&nbsp;Xiao-Xiang Tan ,&nbsp;Jiao-Jiao Yang ,&nbsp;Hui Zhang ,&nbsp;Ning Xu ,&nbsp;Chunjie Zhao ,&nbsp;Jie Sun","doi":"10.1016/j.expneurol.2024.115136","DOIUrl":"10.1016/j.expneurol.2024.115136","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) is a recognized clinical phenomenon characterized by cognitive impairment in patients following anesthesia and surgery, especially in the elderly. However, the pathogenesis of POCD remains unclear. In the last decades, lactate's neuroprotective properties have been increasingly mentioned. The study tested the hypothesis that lactate may attenuate the cognitive impairment induced by anesthesia and surgery in aged mice through SIRT1-dependent antioxidant and anti-inflammatory effects. We used 18-month-old C57BL/6 mice to establish the POCD animal model by exploratory laparotomy with isoflurane anesthesia. For the interventional study, mice were administered lactate, with or without the potent and selective SIRT1 inhibitor EX-527. Behavioral tests including open field (OF), Y maze and fear conditioning (FC) tests were performed from 4 to 7 days after anesthesia and surgery. Immunofluorescence staining and Western blot were employed to assess oxidative damage, activation of microglia and astrocytes, levels of proinflammatory cytokines, and the expression of plasticity-related proteins. Lactate treatment can ameliorate oxidative stress, neuroinflammation, and the decreased levels of plasticity-related proteins induced by anesthesia and surgery, ultimately improving cognitive impairment in aged mice. However, co-treatment with lactate and EX-527 diminished the beneficial effects. Our study indicates that the mechanisms underlying neuroprotective properties of lactate might be related to its antioxidant and anti-inflammatory effects, and improvement of hippocampal synaptic plasticity through activation of SIRT1 pathway.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115136"},"PeriodicalIF":4.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921469","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":"Astragaloside IV confers neuroprotection against radiation-induced neuronal senescence via the ERK pathway","authors":"Yanping Ding ,&nbsp;Chenxin Jiang ,&nbsp;Lili Chen ,&nbsp;Xin Liu ,&nbsp;Baoping Shao","doi":"10.1016/j.expneurol.2024.115135","DOIUrl":"10.1016/j.expneurol.2024.115135","url":null,"abstract":"<div><div>Various factors and mechanisms, including radiation, initiate cellular senescence and are concurrent with the progression of various neurodegenerative diseases. Radiation-induced chromosomal aberrations and DNA integrity damage impact the processes of cellular growth, maturation, and aging. Astragaloside IV (AS-IV) has been documented to display significant neuroprotective effects on inflammation, oxidative stress, and cellular apoptosis; however, the precise neuroprotective mechanism of AS-IV against neuronal aging remains unclear. In this study, radiation-induced senescence models in C57BL/6 mice, PC12 cells, and primary neuronal cells were established. SA-β-gal histochemistry, flow cytometric analysis, immunofluorescence technique, and Western blotting analysis were employed to investigate the underlying mechanism of AS-IV in mitigating the aging of the brain cells caused by exposure to radiation. Our findings revealed that radiation exposure may activate the ERK pathway, leading to an increase in SA-β-gal-positive cells, elevated p21 levels, and the arrest of neuronal cells in the G1/S phase. However, AS-IV has been observed to mitigate the radiation-driven proliferation of senescent cells, by downregulating p-ERK and CDK2 expression and upregulating p21 and RB expression in treatment, thereby alleviating the aging and cognitive impairment caused by radiation. Additionally, evidence of U0126 treatment further supports these findings. In summary, our study showed that AS-IV could protect mice from radiation-induced cognitive impairment and reduce cellular senescence by regulating the ERK pathway.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115135"},"PeriodicalIF":4.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921468","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}