Filamin A (FLNA) is a key protein that binds actin filaments to transmembrane integrins and plays an important role in maintaining cell shape and signaling. In the brain, FLNA is emerging as a critical regulator of neurodevelopment, neuronal migration, actin organization, and neuromodulation. Mutations and/or aberrant expression of the FLNA gene are associated with various brain diseases, such as periventricular heterotopia, Ehlers-Danlos syndrome, and other disorders with impaired cognitive function and brain maldevelopment. Here, we discuss the critical role of FLNA in brain function; its interactions with receptors, integrins, and signaling molecules, as well as the implications of its activity for brain health and disease.
Stroke symptoms encompass sensory, cognitive, motor, and psychosocial dysfunctions, with motor impairment being the most prevalent. This impairment significantly contributes to functional incapacity and a diminished quality of life. Stroke rehabilitation strategies primarily aim to promote neural reorganization and motor skill recovery. Among these, motor imagery (MI) and action observation (AO) are distinct therapeutic techniques with unique mechanisms of action. This review begins by analyzing the strengths and limitations of each approach individually and argues that integrating MI and AO therapy could offer a more effective rehabilitation strategy. A thorough evaluation of relevant literature is presented, detailing methodologies, key findings, and implications. The objective is to elucidate the potential benefits and underlying mechanisms of combining these two therapies in stroke rehabilitation. In conclusion, the article advocates for the adoption of combined MI and AO therapy in neurorehabilitation.
The basolateral amygdala (BLA) is crucial for assigning emotional valence to sensory experiences, driving approach or avoidance behaviors during subsequent encounters. Particularly, the BLA plays a critical role in the coding, storage and retrieval of emotional learning. While traditionally viewed through the lens of memory consolidation, cholinergic signaling—mediated by dense inputs from the basal forebrain and abundant muscarinic receptors (mAChRs) in the BLA—plays a far more dynamic role. Acetylcholine, often described as a “memory molecule”, is central to this process, with scopolamine induced amnesia models underscoring its importance. Recent evidence suggests that cholinergic activity not only supports memory formation but also imparts emotional valence under specific conditions. This review examines the molecular and cellular mechanisms by which mAChR-mediated cholinergic signaling modulates BLA processing and the storage of emotional memories. We integrate psychopharmacological insights with loss and gain-of-function studies to demonstrate how cholinergic signaling in the BLA shapes approach and avoidance behaviors. Based on this evidence, we propose that acetylcholine’s influence in the BLA is highly context-dependent, reflecting its versatile role in emotional processing beyond mere memory consolidation.
Chronic pain frequently coexists with adverse emotions, including anxiety and depression, significantly affecting patients’ physical and psychological health as well as their quality of life. Changes in hippocampal synaptic architecture, neuronal injury, and diminished neurogenesis significantly contribute to pain-related emotions. Microglia in the hippocampus are implicated in these pathologies. Stimulation or injury leads to microglial activation, which causes pain; prolonged pain causes microglia to continuously release pro-inflammatory factors that induce astrocyte activation, which mediates the apoptosis of hippocampal neurons and abnormal neurogenesis. Concurrently, microglia exhibit aberrant phagocytosis and augmented pruning of hippocampal dendritic spines, which disrupts synaptic plasticity and influences hippocampal long-term potentiation, hence contributing to the emergence of negative emotions. Inflammatory responses in the brain are a prevalent pathological foundation for mood disorders and pain, and the activation or inhibition of microglia M1 polarization can influence pain-related emotions. This review elucidates the significance of hippocampal microglia activation, and their interactions with neurons in the hippocampus and astrocytes, in pain-related emotions.
Interferons (IFNs) are cytokines with diverse functions, possessing antiviral, antiproliferative, and immunomodulatory effects. IFN-α and IFN-β, key members of the type I interferon (IFN-I) family, are widely used in the treatment of diseases such as hepatitis and multiple sclerosis. In the nervous system, microglia, astrocytes, and neurons express IFN-I receptors. Beyond their classical transcriptional roles, IFN-Is can suppress neuronal activity and synaptic transmission through nongenomic mechanisms, producing potent analgesic effects. However, IFN-Is are active in signaling pathways such as phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and the MAPK-interacting serine/threonine-protein kinase (MNK)-eukaryotic initiation factor 4E (eIF4E) pathway, which can sensitize peripheral nociceptors and contribute to nociceptive responses. This narrative review explores recent advances in understanding the roles of IFN-I and the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling cascade in acute and chronic nociceptive responses, which are increasingly recognized but remain a subject of debate. Recent studies suggest that the STING–IFN-I pathway has complex, stage-dependent effects on nociception. In the middle to late stages of the nociceptive response, this pathway can activate signal transducer and activator of transcription (STAT) signaling, as well as microglial mediated STING pathways and tumor necrosis factor (TNF) receptor-associated factor (TRAF) family member-associated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB activator) collectively referred to as TANK. These pathways increase pro- and anti-inflammatory cytokine production, promote microglial M1 polarization, and inhibit endoplasmic reticulum-phagy (ER-phagy) in the central nervous system (CNS). These mechanisms contribute to central sensitization while modulating the analgesic effects of IFN-Is. Thus, the STING-IFN-I pathway plays a dual role in nociception, with both pro-nociceptive and analgesic effects that are dependent on the stage of the nociceptive response. Understanding the differential roles of STING–IFN-I signaling in nociceptors under physiological and pathological conditions could pave the way for the development of targeted nociceptive response management therapies.
Lumbar sympathectomy improves blood flow to the lower limbs and is widely used in clinical practice to treat lower limb pain and cold. However, the therapeutic mechanisms underlying lumbar sympathectomy for limb coldness resulting from nerve injury remain unclear. This study aimed to investigate the effect of lumbar sympathectomy on cold allodynia in rats with spared nerve injury (SNI) and identify potential target genes associated with its analgesic effects.
A rat model of SNI was established. Mechanical and cold pain thresholds were assessed in rats with SNI to explore the analgesic effects of lumbar sympathetic neurectomy on cold allodynia. Poly(A)-seq was used to analyze the transcriptional profile of the spinal cord. Differentially expressed genes (DEGs) were screened and analyzed using bioinformatics and validated by quantitative PCR analysis.
Lumbar sympathectomy improved mechanical pain, cold allodynia, and cold sensitivity in the ipsilateral hind paw of SNI rats (all p < 0.05). Poly(A)-seq identified 278 DEGs (177 upregulated and 101 downregulated) in the spinal cords of SNI model rats compared with control rats. We identified 174 DEGs in the gene expression profile of lumbar sympathectomized SNI rats, including 69 upregulated and 105 downregulated genes, compared with SNI model rats. Functional analysis of the DEGs revealed that the most significantly enriched pathways included immune-related pathways and cellular molecular components, which mediate neuroinflammation, central sensitization, and chronic pain. To explore the correlation among the DEGs, we used the STRING database to construct protein-protein interaction networks. Finally, quantitative PCR analysis revealed six potential target genes associated with cold analgesic effects epithelial mitogen gene (EPGN), histone cluster 2 H3 family member C2 (Hist2h3c2), small integral membrane protein 6 (Smim6), family with sequence similarity 187 member a (FAM187A), LOC108349650, and LOC102550818.
Lumbar sympathectomy may alleviate cold allodynia in SNI model rats. We identified key genes associated with pain mitigation, offering potential therapeutic targets. These genes may serve as targets for treating nerve injury-induced cold allodynia. These findings provide valuable insights for the development of new treatments for nerve-related pain disorders.
This study investigated cortical morphological changes in systemic lupus erythematosus (SLE) patients diagnosed with anxiety and/or depression, all of whom exhibited no major neuropsychiatric symptoms and had normal conventional magnetic resonance imaging (MRI) findings. We also further examined the correlation between these morphological alterations and clinical characteristics.
Employing advanced structural MRI (sMRI) techniques, we implemented a dual analytical approach combining voxel-based morphometry (VBM) and surface-based morphometry (SBM) to assess structural differences across three cohorts comprising 59 SLE patients with anxiety and/or depression (SLE-AD), 35 SLE patients with no anxiety and/or depression (SLE-NAD), and 48 age-matched healthy controls (HCs). Within the SBM-based analysis framework, we set a minimum clustering threshold of 50 vertices to secure robust outcomes and delineate significant brain regions. The study focused on whole-brain gray matter volume (GMV), cortical thickness (CT), depth of the sulci (SD), cortical gyrification index (GI), and fractal dimension (FD).
Quantitative analyses revealed significant GMV reductions in the SLE-AD group compared with HCs and the SLE-NAD groups (gaussian random field (GRF) correction: pvoxel < 0.0005, pcluster < 0.0005). Additionally, we observed widespread decreases in the CT and SD, as well as reduced GIs across multiple regions (puncorr < 0.001, cluster size >50 vertices). The most prominent alterations were in the left temporal lobe, bilateral thalamus, prefrontal cortex cingulate gyrus, insula, postcentral gyrus, and fusiform gyrus. GMV in the left middle temporal gyrus (r = –0.288, p = 0.027) and CT in the left fusiform gyrus (r = –0.337, p = 0.009), along with CT in the right middle frontal sulcus (r = –0.306, p = 0.018) and right middle frontal gyrus (r = –0.356, p = 0.006), were inversely associated with SLE disease activity index (SLEDAI). However, neither GMV, CT, nor cortical complexity exhibited significant associations with Hamilton Anxiety Scale (HAMA) or Hamilton Depression Scale (HAMD) scores. Multivariate linear regression analysis indicated that the CT of left hemisphere-related brain areas—including the superior occipital gyrus, parieto-occipital sulcus, cuneus and opercular part of the inferior frontal gyrus—and the GI of the superior frontal gyrus significantly influenced HAMD/HAMA scores. CT of the left hemisphere’s intraparietal sulcus and transverse parietal sulci, along with SD of the right hemisphere’s central sulcus, were predictors of HAMA scores.
Our findings demonstrate that SLE patients presenting with anxiety and/or depression exhibit distinct neuroanatomical alterations, even without prominent neuropsychiatric manifestations. These morphological changes may represent the neurobiological substrate underlying the heterogeneous clinical spectrum of neuropsychiatric SLE (NPSLE), potentially serving as early neuroimaging biomarkers. Furthermore, these findings provide a structural framework for future studies investigating the causal relationships between these anatomical changes and the neurophysiological mechanisms underlying NPSLE.
It has been demonstrated that the cerebellum plays a critical role not only in motor function but also in cognitive function. Numerous studies have revealed that acute sleep deprivation (SD) alters the functional connectivity (FC) in the cerebral cortex associated with declining working memory (WM). However, the relationship between the altered cerebro-cerebellar FC and white matter damage following acute sleep deprivation remains elusive.
In this study, 26 healthy participants with regular sleep conducted an n-back task and had resting-state functional magnetic resonance imaging (fMRI) scans before and after 24 h of SD. The FC between the cerebrum and cerebellum and its relationship with WM function were analyzed in recruited participants.
Our results showed a significantly longer RT for the 1-back and 2-back tasks and lower accuracy of the 2-back task after SD. We found a marked reduction in FC between ten pairs of regions in the cerebellum and cerebrum after SD. Furthermore, a decline in WM performance was positively correlated with the changed FC between the left precentral gyrus and the right lobule X of the cerebellum.
Our findings indicate that the impaired FC between the cerebellum and cortical areas may contribute to the decline in WM after acute SD.
No: ChiCTR2000039858. Registered 12 November, 2020, https://www.chictr.org.cn/showproj.html?proj=63916.
Aging can cause degenerative changes in motor and cognition-related brain areas, presumably by interfering with gait performance in healthy aging populations. We aimed to assess the effects of transcranial direct current stimulation (tDCS) on single- and dual-task walking performances in healthy older adults using meta-analytic approaches.
Eleven studies were qualified based on the inclusion criteria: (a) healthy older adults, (b) treatment = tDCS protocols, (c) control = sham stimulation, (d) gait performance outcomes, and (e) randomized controlled trials using parallel or crossover designs. Effect sizes were estimated using standardized mean difference (SMD) to examine gait performances between active tDCS and sham stimulation. A separate random-effect meta-analysis was performed to determine the effects of tDCS protocols on gait performance during single- and dual-task walking tasks.
During single-task walking, the random-effects meta-analysis showed improvements in stride time variability (SMD = 0.203; p = 0.005) and functional mobility (SMD = 0.595; p < 0.001). Moreover, single-task walking performances were improved when the tDCS protocols targeted the primary motor cortex (SMD = 0.424; p = 0.005) and used off-line stimulation (SMD = 0.168; p = 0.008). During dual-task walking, tDCS improved gait speed (SMD = 0.177; p = 0.025) and dual-task cost for gait speed (SMD = 0.548; p < 0.001). Dual-task walking performances were advanced when the tDCS protocols targeted the dorsolateral prefrontal cortex (SMD = 0.231; p = 0.029) and multiple areas including prefrontal cortex (SMD = 0.382; p = 0.001), and applied off-line stimulation (SMD = 0.249; p < 0.001).
These findings indicate that the tDCS protocols may be a promising tool to support mobility and reduce gait-related challenges in the healthy aging population.
Exercise enhances overall health, playing an important role in protecting against diseases that impact brain function. Studies show that physical activity influences several key biological processes, including dopamine signaling, brain glucose metabolism (BGluM), and social behavior.
Male sedentary and chronic exercise rats were examined for dopamine signaling and social behavior. Tyrosine hydroxylase (TH) immunohistochemistry (IHC), and D1 and D2 receptor (D1R and D2R) autoradiography was used to assess dopamine signaling; [18F]-Fluorodeoxyglucose positron emission tomography (FDG PET) was used to measure brain functional connectivity; Crawley’s three-chamber sociability test was used to measure social behavior; and Pearson correlation was used to analyze correlations between social interaction and TH, D1R, and D2R binding.
Exercised rats demonstrated greater D1R binding within several regions of the caudate putamen and nucleus accumbens. PET image analysis showed significantly higher BGluM in the exercised rats compared with the sedentary controls across several brain regions. These regions are associated with enhanced functional connectivity related to movement, olfaction, cardiovascular function, and predator awareness. Exercise had no significant effect on social interaction. Pearson correlation analysis revealed a significant negative relationship between social interaction and D1R binding.
Chronic aerobic exercise did not significantly alter social interaction, TH, or D2R binding. D1R binding was enhanced in the exercise group compared with the sedentary group and was negatively correlated with social interaction. We speculate that approach behavior was attenuated by exercise due to social threat stimulation. Functional connectivity imaging data showed significant glucose metabolic activation within the cuneiform nucleus, which has been previously shown to be critical in defensive behavior. This may explain the lack of significant effect of exercise on approach or exploratory behavior. These findings support the potential of exercise in response to social behavior and the possible attenuation of social behavior towards a social threat or socially inappropriate behavior. Exercise can induce metabolic transience that may assist rats in detecting odors from larger predatory animals.
The repair technology of peripheral nerve injuries has made great progress, but the simultaneous repair and promotion of nerve regeneration in multiple distal nerves remains a challenging task. The current cylindrical nerve conduits are unsuitable for nerve transposition repair. This study aims to assess the effect of conical chitosan conduits (different inner diameters at both ends) on nerve transposition repair, in conjunction with methylcobalamin (MeCbl).
In this study, a conical chitosan conduit was used to bridge a 2 mm defect between the proximal common peroneal nerve and distal tibial nerve and common peroneal nerve in rats. Additionally, we administered MeCbl at various concentrations to evaluate post-surgical adjuvant treatment effect. At 16 weeks post-surgery, gait analysis, electrophysiology testing, transmission electron microscopy (TEM) observation, toluidine blue staining, immunofluorescence staining, muscle wet weight determination and Masson’s trichrome staining were performed to assess nerve regeneration and reinnervation of gastrocnemius.
Gross observations did not reveal the formation of neuromas after bridging the distal nerves in each group. In terms of motor function (**p < 0.01), compound muscle action potential (CMAP) amplitude and latency (**p < 0.01), the quantity of regenerated nerve fibers, muscle fiber morphology and other parameters (**p < 0.01), 200 μg/kg MeCbl administration as a supplementary treatment had a significant positive impact compared to the chitosan conduit+normal saline (Chi/NS) group.
Our findings demonstrated that conical chitosan conduits combined with MeCbl can effectively promote nerve transposition repair following multiple distal nerve injuries.
Intracerebral hemorrhage (ICH) is a critical form of stroke with limited treatment options, with secondary brain injury significantly affecting patient outcomes. This study investigated the neuroprotective benefits of idebenone (IDE) in ICH.
An ICH model was established in mice and the temporal progression of oxidative stress and neuroinflammation was evaluated. IDE was then administered intraperitoneally for 3 consecutive days to evaluate its therapeutic effects. Tissue histology was examined after staining with hematoxylin-eosin and TdT-mediated dUTP nick end labeling (TUNEL), while oxidative stress was assessed by western blotting and measurement of malondialdehyde (MDA) levels and neuroinflammation was examined using immunostaining, western blotting, and enzyme-linked immunosorbent assay (ELISA).
Oxidative stress and neuroinflammation peaked at 3 days post-ICH, with elevated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and significant microglial activation. IDE-treated mice had reduced hematoma volumes and improved neurological outcomes. IDE administration decreased Kelch-like ECH-associated protein 1 (Keap1) expression while increasing Nrf2 and NAD(P)H quinone oxidoreductase 1 (NQO1) levels, leading to reduced oxidative damage (p < 0.01, p < 0.05, and p < 0.05, respectively). Moreover, IDE attenuated microglial activation and neutrophil recruitment (p < 0.01, p < 0.01), reduced the levels of matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels (p < 0.05, p < 0.05, and p < 0.05, respectively), and increased IL-10 expression (p < 0.01). IDE also preserved the integrity of the blood-brain barrier (BBB) and reduced brain edema.
The results demonstrated that IDE exerts neuroprotective effects in ICH through the mitigation of oxidative stress and neuroinflammation during the acute injury phase. IDE may be a viable therapeutic intervention for ICH.
Alcohol use disorder (AUD) is a global health concern, with alcohol abuse leading to structural damage to white matter (WM) fiber tracts, which are crucial for cognitive and emotional functions. However, existing studies often lack systematic evaluations of these changes and their clinical correlations.
Using tract-based spatial statistics (TBSS), we analyzed diffusion tensor imaging (DTI) data from 20 AUD patients and 20 healthy controls. Correlations between fractional anisotropy (FA) values and clinical symptoms, including cognitive dysfunction, depression, and impulsivity, were examined.
AUD patients presented significantly decreased FA values in the right corpus callosum, right fornix, left inferior fronto-occipital fasciculus, and left cerebral white matter. The FA peak values of the right fornix and the left cerebral white matter were positively and significantly correlated with cognitive function scores in the AUD group after controlling for smoking status, age, and years of education.
Alcohol abuse significantly impairs WM integrity, particularly in regions related to cognitive and emotional regulation. These findings provide structural evidence for the neurobiological mechanisms of AUD and suggest that FA may serve as a potential biomarker for assessing brain damage, guiding therapeutic interventions.
Bone cancer pain (BCP) is a prevalent chronic pain condition and a common clinical symptom in patients with advanced cancer. It significantly affects the mobility and quality of life of patients; however, current treatments offer limited efficacy. Harmine, a beta-carboline alkaloid extracted from Peganum harmala, exhibits anti-inflammatory, anxiolytic, analgesic, and neuroprotective properties. However, its antinociceptive properties and mechanisms in BCP models remain unclear. This study aimed to systematically investigate the analgesic effects of Harmine in rats with BCP and explore its underlying molecular mechanisms.
Using databases such as SwissTargetPrediction and Polypharmacology Browser, molecular docking analysis, behavioral tests, and biochemical analysis, we comprehensively evaluated the effects of Harmine in the BCP model.
The results demonstrated that Harmine significantly alleviated BCP induced by Luciferin-Malignant Atypical Discrete Breast 106 cells (LUC-MADB106) in a dose-dependent manner. Intrathecal administration of Harmine significantly inhibited the upregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) expression and the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in the spinal cord dorsal horn (SCDH) of rats with bone cancer.
These findings suggest that Harmine has significant therapeutic potential for alleviating BCP hyperalgesia, providing a foundation for the future development of new drugs targeting BCP.
Aging alters estrogen receptor (ER) expression in distinctive hypothalamic loci, but information regarding potential adjustments in estradiol receptivity at the individual neuron population level remains incomplete. Estradiol controls glucostasis by action on ventromedial hypothalamic nucleus (VMN) targets. VMN growth hormone-releasing hormone (Ghrh) neurons exhibit sex-dimorphic ER variant and counterregulatory transmitter gene profiles in young adult rats.
Combinatory single-cell laser-catapult-microdissection/multiplex qPCR analyses was used to investigate whether aging changes nuclear versus cytoplasmic ER gene expression according to sex.
Ghrh neuron ER-alpha and G-protein-coupled estrogen receptor-1 (GPER) transcription was decreased in old versus young rats of each sex. Old animals lacked ER-alpha transcriptional reactivity to hypoglycemia, indicative of age-associated loss of response. Hypoglycemia had divergent effects on ER-beta transcription, with no effect found in old males versus an inhibitory effect in old female rats. Hypoglycemic inhibition of Ghrh neuron GPER gene expression in old male and female rats was similar to that which occurred in corresponding young animals. Ghrh gene silencing identified age-related loss of neuropeptide modulatory regulation of ER gene transcription. Ghrh signaling inhibited eu- and hypoglycemic Ghrh neuron aromatase/CYP19A1 mRNA profiles in old male and female rats; in each sex, this gene transcript was refractory to hypoglycemia regardless of age.
VMN Ghrh neuron neuroestradiol production may be up-regulated with age, but cellular sensitivity to this local steroid signal may differ between young and old rats due to differences in ER variant expression. Further research is warranted to examine how potential age-associated modifications in absolute and proportionate signaling by distinctive ER may affect Ghrh neuron glucose-regulatory neurotransmission in male versus female rats.
Freezing of gait (FOG) is a debilitating motor symptom of Parkinson’s disease (PD) that significantly affects patient mobility and quality of life. Identifying reliable biomarkers to distinguish between PD patients with freezing of gait (PDFOG+) and those without FOG (PDFOG–) is essential for early intervention and treatment planning. This study investigates the potential of electroencephalographic (EEG) signals, focusing on well-studied midfrontal beta oscillatory feature, to classify PDFOG+ and PDFOG– using machine learning (ML) and deep learning (DL) approaches.
Resting-state EEG data were collected from the midfrontal ‘Cz’ and nearby channels (Cz-cluster) from 41 PDFOG+ and 41 PDFOG– subjects. A range of ML and DL models, including logistic regression (LR), random forest (RF), extreme gradient boosting (XGBoost), categorical boosting (CatBoost), and long short-term memory (LSTM) models were evaluated using leave-one-subject-out (LOSO), 10-fold, and stratified cross-validation (CV).
Outcomes demonstrate that while LR achieved an area under the receiver-operating characteristic (AUC-ROC) score of 0.63, LSTM outperformed all models, achieving an AUC-ROC of 0.68 and accuracy of 0.63, particularly with the Cz-cluster configuration.
These findings support the potential of midfrontal beta oscillations, particularly in combination with LSTM temporal modeling, a promising EEG-based biomarker for distinguishing PDFOG+ from PDFOG–. This work contributes to the development of more effective diagnostic tools and treatment strategies for PD-related gait impairments.
Acute ischemic stroke (AIS) is one of the leading critical neurological conditions globally, resulting in significant adult mortality and disability. Previous studies have demonstrated a close relationship between AIS and the ferroptosis signaling pathway. Muscone, the primary active small-molecule component of musk, is a traditional Chinese medicine that exhibits significant pharmacological effects in reducing stroke injury. However, there is still only limited research on whether muscone can modulate ferroptosis-related injury in AIS, and on the underlying regulatory molecular mechanisms.
We utilized a transmission electron microscope and concurrently performed assays for glutathione peroxidase 4 (GPX4) activity, glutathione (GSH), reactive oxygen species (ROS), lipid peroxides, as well as cell viability and live/dead cell staining to investigate alterations in ferroptosis levels. RNA sequencing, bioinformatics analysis, and western blot (WB) assays were employed to evaluate the changes in synaptosome-associated protein 25 kDa (Snap25) expression levels. Furthermore, molecular docking, surface plasmon resonance (SPR) detection, and molecular dynamics (MD) simulation were implemented to examine the binding affinity and interaction between muscone and Snap25.
RNA sequencing technology, bioinformatics analysis, and WB assays revealed that Snap25 was specifically downregulated under simulated AIS conditions. Snap25 knockdown and overexpression experiments were also conducted to elucidate the molecular mechanism by which muscone modulates Snap25 expression, thereby mitigating ferroptosis injury in AIS. Additionally, the results of molecular docking, SPR detection, and MD simulations indicate that muscone has multiple binding sites that allow it to bind directly to the Snap25 protein, thereby stabilizing the protein structure.
Our findings suggest that muscone produces an anti-AIS effect in the context of AIS injury by increasing Snap25 protein expression, thus reducing ferroptosis. This investigation offers insight into the anti-stroke mechanism of muscone and introduces a promising new treatment option for clinical AIS management.