Molecular Neurobiology最新文献

{"title":"Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.","authors":"Yogesh Mishra, Ashutosh Kumar, Ravinder Kumar Kaundal","doi":"10.1007/s12035-024-04412-0","DOIUrl":"10.1007/s12035-024-04412-0","url":null,"abstract":"<p><p>Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"6715-6747"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902349","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":"Plasma Metabolites as Mediators Between Gut Microbiota and Parkinson's Disease: Insights from Mendelian Randomization.","authors":"Jianzhun Chen, Liuhui Zhu, Fang Wang, Yangfan Zhu, Jieyu Chen, Chunyu Liang, Bin Liu, Ailan Pang, Xinglong Yang","doi":"10.1007/s12035-025-04765-0","DOIUrl":"10.1007/s12035-025-04765-0","url":null,"abstract":"<p><p>Recent evidence supports the causal role of both plasma metabolites and gut microbiota (GM) in Parkinson's disease (PD). However, it remains unclear whether GM are responsible for causing PD through plasma metabolites. Here, we used Mendelian randomization (MR) to investigate the intrinsic causal relationships among GM, plasma metabolites, and PD. Summary statistics were derived from a GWAS of 1400 metabolites (N = 8299), GM (N = 18,340), and PD (Ncase = 33,674 and Ncontrol = 449,056). We used two-step/mediation MR (TSMR) to study the mediating effect of plasma metabolites on the association between GM and the risk of developing PD. We detected 54 genetic traits that were causally associated with PD development. According to the TSMR analysis, ceramide had a mediating effect on the relationship between the genus Clostridium sensu stricto 1 and the risk of developing PD (15.35% mediation; 95% CI = 1.29-32.75%). 7-Alpha-hydroxy-3-oxo-4-cholestenoate had a mediating effect on the relationship between the genus Eubacterium xylanophilum group and the risk of developing PD (11.04% mediation; 95% CI = 0.11-27.07%). In the present study, we used MR analysis to investigate the connections among GM, plasma metabolites, and PD. This comprehensive investigation offers insights into the pathogenic mechanisms of PD and the roles of the intestinal microbiota and metabolites in this disease.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7945-7956"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441522","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":"Nrf2 Ameliorates Sevoflurane-Induced Cognitive Deficits in Aged Mice by Inhibiting Neuroinflammation in the Hippocampus.","authors":"Junhua Li, Jinfeng Li, Yafang Liu, Chuwen Hu, Hui Xu, Dong Cao, Rong Zhang, Kun Zhang","doi":"10.1007/s12035-025-04777-w","DOIUrl":"10.1007/s12035-025-04777-w","url":null,"abstract":"<p><p>Perioperative neurocognitive disorders (PND), common complications that occur after anesthetized surgery in elderly patients, are major challenges to our rapidly growing aging population. The transcription factor known as nuclear factor erythroid-2-related factor 2 (Nrf2) is an essential component of the cellular antioxidant response, purportedly contributing to the preservation of cognitive functions such as learning and memory. Nevertheless, the function and intracellular processes involving Nrf2 in PND remain largely unknown. Therefore, we evaluate the influence and fundamental mechanism of Nrf2 on PND in aged mice. To establish the postoperative neurocognitive dysfunction (PND) model, aged mice were subjected to anesthesia via inhalation of 3% sevoflurane for a duration of 2 h. The role of Nrf2 in PND was investigated by administering microinjections of either the adeno-associated virus (AAV)-Nrf2 vector or a null virus vector into the hippocampal CA1 region of aged mice 28 days before exposure to sevoflurane. Various assays including enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blotting were employed to assess levels of pro-inflammatory cytokines, microglial activation, and the oxidative stress response. Furthermore, synaptic plasticity was evaluated through long-term potentiation (LTP) recording and Golgi staining techniques. Elevated expression of Nrf2 within the hippocampal CA1 region ameliorated sevoflurane-induced cognitive deficits, synaptic plasticity anomalies, and the oxidative stress reaction in aged mice. Furthermore, the activation of microglia and the release of pro-inflammatory cytokines (including IL-6, TNF-α, and IL-1β) within the hippocampus post-sevoflurane exposure were modulated in an Nrf2-dependent fashion. Based on the findings from present research, we conclude that Nrf2 ameliorates sevoflurane-induced cognitive dysfunction by inhibiting hippocampal neuroinflammation, thereby proposing a potential therapeutic target for PND.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8048-8064"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449709","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 Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.","authors":"Patrick C Bradshaw, Jessa L Aldridge, Leah E Jamerson, Canah McNeal, A Catherine Pearson, Chad R Frasier","doi":"10.1007/s12035-024-04630-6","DOIUrl":"10.1007/s12035-024-04630-6","url":null,"abstract":"<p><p>Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7022-7040"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667487","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":"Milnacipran and Vanillin Alleviate Fibromyalgia-Associated Depression in Reserpine-Induced Rat Model: Role of Wnt/β-Catenin Signaling.","authors":"Nour A Kamaly, Ahmed S Kamel, Nermin Abdelhamid Sadik, Nancy N Shahin","doi":"10.1007/s12035-025-04723-w","DOIUrl":"10.1007/s12035-025-04723-w","url":null,"abstract":"<p><p>Fibromyalgia (FM) patients are highly susceptible to depression. Wnt/β-catenin signaling has shown a crucial role against depression in several studies. The FDA-approved FM drug, milnacipran (Miln), has shown antinociceptive potential against FM. Yet, no study has investigated its antidepressant potential in FM. Vanillin (Van), a well-known phytochemical often employed as flavoring agent, has been previously reported for its antidepressant and antinociceptive effects in several animal models, but has not been tested so far in FM. This study explored the antidepressant effect of Van and Miln in FM through investigating Wnt/β-catenin signaling. FM was induced in female Wistar rats by injecting reserpine (1 mg/kg/day s.c) for 3 days. Thereafter, animals received either Miln (30 mg/kg/day p.o) or Van (100 mg/kg/day p.o) for the subsequent 14 days. Results showed that both drugs demonstrated antidepressant effect in forced swimming test besides analgesic, and antiallodynic influences observed in Randall-Selitto, hot plate, cold allodynia, Von-Frey, and tail immersion tests. Biochemically, Miln and Van significantly enhanced serotonergic transmission in the hippocampus and upregulated the protein expression of the Wnt/GSK-3β/β-catenin signaling axis, including the downstream proteins, T cell factor, and dicer. This is followed by subsequent upregulation of the resilience micro ribonucleic acids (miRNAs) 124 and 135. Histopathological examinations corroborated the biochemical and molecular findings. Interestingly, these effects of Miln and Van were overturned via administration of the β-catenin inhibitor, XAV939 (0.1 mg/kg, i.p., daily). In conclusion, this study outlined the antidepressant aptitude of Miln and Van through activating Wnt/β-catenin signaling in the hippocampus in reserpine-induced FM.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7682-7705"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382628","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":"The Application of MicroRNAs in Traumatic Brain Injury: Mechanism Elucidation and Clinical Translation.","authors":"Hong Wang, Xiaolin Fan, Yuhao Zhang, Ning Ma, Liang Li, Qing Lu, Qi Wang, Boya Yu, Xiao Li, Junhong Gao","doi":"10.1007/s12035-025-04737-4","DOIUrl":"10.1007/s12035-025-04737-4","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a complex neurological disease caused by external forces impacting the head and is one of the leading causes of mortality and disability worldwide, exerting a significant impact on public health and socioeconomic conditions. Current research on TBI has focused primarily on assessing injury severity, determining clinical treatment, and improving patient prognosis. The timely and accurate diagnosis of TBI in clinical settings and the implementation of effective therapeutic strategies remain challenging. However, a deeper understanding of changes in gene expression and underlying molecular regulatory processes may alleviate this pressing issue. MicroRNAs (miRNAs), a class of short noncoding RNA molecules, play crucial roles in cellular physiology and pathology by regulating gene expression. With advancements in research, miRNAs have garnered increasing attention in TBI studies. This review summarizes the progress of miRNA research in TBI and explores the potential of miRNAs as diagnostic and prognostic markers and therapeutic targets for TBI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7846-7863"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408453","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 Effect of Picein on Inhibitory Avoidance Memory and Activity of Antioxidant Enzymes in Hippocampus of Male Rats with Scopolamine-Induced Injury.","authors":"Leila Elyasi, Jessica M Rosenholm, Mehrdad Jahanshahi, Fatemeh Jesmi","doi":"10.1007/s12035-025-04740-9","DOIUrl":"10.1007/s12035-025-04740-9","url":null,"abstract":"<p><p>Alzheimer disease (AD) is a common neurologic disorder, impairing memory and spatial perception. Consistent with the extensive search for its treatment, we investigated the effect of Picein on inhibitory avoidance memory, lipid peroxidation, and the activity of hippocampal antioxidant enzymes in rats. Forty adult male Wistar rats were randomized into control group (no intervention), model group (intraperitoneal injection of 3-mg/kg scopolamine), and three interventional groups (1.5-, 2.5-, and 5-mg/kg intraventricular Picein, once a day for 7 days, 24 h after scopolamine injection). After behavioral test, the rats' hippocampus was isolated for measuring oxidative stress markers, including enzymes superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC). One-way ANOVA was used for comparing numeric variables among the groups using SPSS v.21. The results showed scopolamine decreased SOD, GPX, and CAT enzymes, and TAC level, and increased MDA level, compared with the control group (P < 0.001) that confirmed the scopolamine-induced AD model. The two doses of 2.5- and 5-mg/kg Picein increased latency for entering the dark room, compared to the scopolamine group (P < 0.05), making them similar to the control group. The number of entries into the dark room in the 2.5-mg/kg Picein reduced and approached the control group (P < 0.05). The 2.5-mg/kg Picein decreased MDA and increased SOD, GPX, and TAC, more than 5 mg/kg Picein, both different than scopolamine; only 2.5-mg/kg Picein had different CAT, compared to scopolamine group (P < 0.05). In conclusion, by lowering oxidative stress in the hippocampus, Picein was able to prevent the scopolamine-induced impaired learning and avoidance memory in rats.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7835-7845"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408468","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":"IGF1R/ARRB1 Mediated Regulation of ERK and cAMP Pathways in Response to Aβ Unfolds Novel Therapeutic Avenue in Alzheimer's Disease.","authors":"Priyanka Sengupta, Debashis Mukhopadhyay","doi":"10.1007/s12035-025-04735-6","DOIUrl":"10.1007/s12035-025-04735-6","url":null,"abstract":"<p><p>IGF1R/INSR signaling is crucial for understanding Alzheimer's disease (AD) and may aid in the development of potent therapeutic strategies. This study investigated the expression and activity of these receptors and their potential to form functional hybrids in response to amyloid beta (Aβ). IGF1R, INSR, and ARRB1 were found to be upregulated in AD. The propensity for functional hybrid formation was also greater in the presence of Aβ. The association of IGF1R with ARRB1 reached a maximum at 60 min of Aβ treatment, which coincided with increased pERK activity at approximately the same time, indicating the importance of this association in pERK regulation. Knocking down IGF1R, INSR, and ARRB1 independently reduced cAMP, whereas overexpressing IGF1R significantly increased cAMP. Knocking down ARRB1 in IGF1R-overexpressing cells led to a reduction in cAMP, indicating that the interaction of ARRB1 and IGF1R possibly contributes to cAMP dysregulation. Since cAMP plays a crucial role in cognition and memory, alterations in cAMP after receptor hybridization could be significant in AD. Additionally, we noted hyperactivation of MAPK, which is associated with aberrant cellular activity, transcriptional control, and stress pathways. This finding highlights the importance of IGF1R and INSR dysregulation, which plays a major role in addition to conventional RTK signaling through multiple pathways. Here, we focused on the ARRB1 and IGF1R interaction and showed that picropodophyllin (PPP), an IGF1R-specific inhibitor, blocks this interaction and alters the ERK and cAMP status under disease conditions. Cell viability studies further revealed that the PPP substantially improved cell viability in the presence of Aβ. This highlights the role of the PPP in regulating these cascades and opens the arena for further therapeutic development for AD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8065-8083"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449706","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":"Critical Role of Rho Guanine Nucleotide Exchange Factor 4 in Brain Function.","authors":"Hee Jeong Kim, Kina Lee, Kiseo Yoo, Jeong Eun Kim, Heeju Kim, Chae-Seok Lim, Young Seok Park, Hyong Kyu Kim","doi":"10.1007/s12035-025-04734-7","DOIUrl":"10.1007/s12035-025-04734-7","url":null,"abstract":"<p><p>Although Rho guanine nucleotide exchange factor 4 (Arhgef4) is highly expressed in the brain, its function remains poorly understood. Our previous study showed that Arhgef4 negatively regulates excitatory postsynaptic regional activity. This study investigated the effects of Arhgef4 deletion in postnatal forebrain-specific knockout mice on brain function, synaptic proteins, and behaviors. We generated a knockout mouse with Arhgef4 deleted from the forebrain and analyzed gene expression and protein levels by RT-PCR and western blot. Synaptic function was assessed through electrophysiological recordings, and behavioral tests evaluated memory and anxiety. In these conditional knockout (cKO) mice, we observed a significant decrease in the expression of a 75-kDa brain-enriched isoform of Arhgef4 in the forebrain. In KO mice, pre- and post-synaptic protein levels were unchanged. However, in cultured hippocampal neurons from KO mice, the levels of postsynaptic density protein 95 (PSD-95) in the postsynaptic regions were significantly increased from the pre-mature stage to the fully mature stage during neuronal development. In contrast, the number of dendritic protrusions decreased during the early mature stage of the cultured neurons. Electrophysiological recordings of hippocampal neurons from KO mice showed a significant increase in miniature excitatory postsynaptic currents (mEPSC) frequency. Furthermore, Arhgef4 KO mice exhibited enhanced long-term memory and reduced anxiety-related behaviors. These findings suggest that Arhgef4 plays a role in regulating brain functions such as learning, memory, and anxiety.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7647-7663"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370881","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":"Enterococcus faecalis Exerts Neuroprotective Effects via the Vagus Nerve in a Mouse Model of Parkinson's Disease.","authors":"Xian Shao, Tao Wu, Mengyun Li, Matao Zheng, Hui Lin, Xuchen Qi","doi":"10.1007/s12035-025-04741-8","DOIUrl":"10.1007/s12035-025-04741-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common neurodegenerative disease worldwide. Current treatment methods for PD are unable to halt disease progression. The gut microbiota contributes to the neurodevelopment of PD; however, the gut-brain connections and underlying neural bases that regulate this complex behavior are not yet clear. Enterococcus faecalis (EF) is a common commensal bacterium of the gut and a common pathogen associated with hospital-acquired infections. Here, we demonstrated the significant therapeutic effects of a non-pathogenic strain of EF (EF ATCC19433) on PD. In this study, we established a mouse model of PD by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that EF treatment alleviated behavioral impairment, dopaminergic neuronal loss, blood-brain barrier damage, and neuroinflammation induced by MPTP in the mice. Additionally, 16S rRNA sequencing revealed that dysbiosis of PD-related microbial communities induced by MPTP was reversed by EF treatment. Moreover, EF treatment relieved gastrointestinal dysfunction in the mice. The therapeutic efficacy of EF in MPTP-induced PD mice is markedly diminished when the activity of EF is lost. Further mechanistic studies indicated that the neuroprotective effects of EF in PD were associated with the vagus nerve pathway. Following the surgical severance of the vagus nerve through subdiaphragmatic vagotomy, the protective effects of EF on PD were markedly diminished. Our study suggests that EF can alleviate neurofunctional impairments and gastrointestinal disorders associated with PD, indicating that gut-derived microbes influence brain function through the vagus nerve pathway.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"7875-7891"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425420","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}