CNS Neuroscience & Therapeutics最新文献

Aims: N-Demethylsinomenine (NDSM) demonstrates good analgesic efficacy in preclinical pain models. However, how NDSM exerts analgesic actions remains unknown.

Methods: We examined the analgesic effects of NDSM using both pain-evoked and pain-suppressed behavioral assays in two persistent pain models. Then western blot assay and immunofluorescence staining were used to investigate the effects of NDSM on the expression of the GABA_A receptor α2 subunit (GABRA2) and inflammatory factors in the spinal cord and brain tissues of male spared nerve injury (SNI) mice. Finally, the individual subtypes of GABA_ARs (α1, α2, α3, and α5) were respectively silenced by viral-mediated knockdown to explore the involvement of subtypes of GABA_ARs in the effects of NDSM on the pain-like behaviors in male SNI mice.

Results: NDSM demonstrated significant analgesic effects against chronic pain both in pain-evoked and pain-suppressed behavioral assays. NDSM treatment significantly reversed the SNI induced down-regulation of GABRA2 and up-regulation of TNF-α and IL-1β. The analgesic effects of NDSM were completely blocked by silencing GABRA2 or partially blocked by silencing GABRA3.

Conclusion: This study provided the first evidence that the analgesic effects of NDSM are mediated primarily by GABRA2 and partially by GABRA3, and the inhibition of neuroinflammation also contributes to the analgesic effects of NDSM.

Objective: This study aims to investigate how the E3 ubiquitin ligase LITAF influences mitochondrial autophagy by modulating MCL-1 ubiquitination, and its role in the development of epilepsy.

Methods: Employing single-cell RNA sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein-protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models.

Results: Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial autophagy by promoting MCL-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates MCL-1 ubiquitination, aggravating neuronal injury.

Conclusion: Our findings demonstrate that LITAF regulates MCL-1 ubiquitination, significantly impacting mitochondrial autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.

Aims: Stroke is a major public health concern leading to high rates of death and disability worldwide, unfortunately with no effective treatment available for stroke recovery during the repair phase.

Methods: Photothrombotic stroke was induced in mice. Adeno-associated viruses (AAV) were microinjected into the peri-infarct cortex immediately after photothrombotic stroke. Grid-walking task and cylinder task were used to assess motor function. Western blotting, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms.

Results: The ternary complex of neuronal nitric oxide synthase (nNOS), carboxy-terminal PDZ ligand of nNOS (CAPON) and dexamethasone-induced ras protein 1 (Dexras1) is structurally beneficial for S-nitrosylation of Dexras1 (SNO-Dexras1). In our previous study, uncoupling nNOS-CAPON interaction by Tat-CAPON-12C promoted functional recovery after stroke. Here, we show that ischemia elevated the levels of nNOS-Dexras1 complex and SNO-Dexras1 in the peri-infarct cortex in the days 4-10 after stroke induction, and as excepted, Tat-CAPON-12C, a peptide disrupting nNOS-CAPON interaction, significantly reversed these changes. The above information implies that repressed SNO-Dexras1 may mediate functional-promoting effects of Tat-CAPON-12C and SNO-Dexras1 could be the vital molecular substrate for post-stroke functional recovery in the repair phage. Inhibiting the ischemia-induced SNO-Dexras1 by AAV vector-mediated knockdown of Dexras1 or over-expression of dominant negative Dexras1 (Dexras1-C11S) produced sustained recovery of motor function from stroke. In contrast, up-regulation of SNO-Dexras1 by over-expressing Dexras1 worsened stroke outcome. Using electrophysiology recordings, we also observed that silence of Dexras1 in the peri-infarct cortex increased the spike number and the miniature excitatory postsynaptic currents (mEPSCs) frequency, suggesting enhancement of neuronal excitability. In addition, silence of Dexras1 increased dendritic complexity in cultured neuron and more importantly enhanced dendritic spine density in the peri-infarct cortex, implying dendritic remodeling.

Conclusion: Thus, inhibition of SNO-Dexras1 positively regulates post-stroke functional recovery via enhanced neuronal excitability and dendritic remodeling. Our results identify that SNO-Dexras1 may serve as a novel target for promoting motor functional restoration from stroke in the delayed phase, shedding light on stroke treatment.

Background: Epilepsy has a genetic predisposition, yet causal factors and the dynamics of the immune environment in epilepsy are not fully understood.

Methods: We analyzed peripheral blood samples from epilepsy patients, identifying key genes associated with epilepsy risk through Mendelian randomization, using eQTLGen and genome-wide association studies. The peripheral immune environment's composition in epilepsy was explored using CIBERSORT. An epilepsy mouse model was established to validated the expression of key genes at the transcriptomic and proteomic levels through single-cell analysis. Relevant pathways were verified. Finally, we developed a predictive model for antiepileptic drug response in epilepsy patients.

Results: We found that CDC25B, DNMT1, GZMA, MTX1, and SSH2 expression decreases epilepsy risk, whereas FGD3, RAF1, and SH3BP5L increase it. Epilepsy patients exhibited an altered peripheral immune profile, notably with increased activated mast cells and decreased CD4 memory activated T cells and γδ T cells. Eight genes were significantly related to this immune environment. In the animal model, FGD3, SSH2, and DNMT1 were upregulated at both mRNA and protein levels in the hippocampus. FGD3 and SSH2 are specifically elevated in microglia and are primarily associated with actin regulation. The trained predictive model was deployed on an online platform.

Conclusions: This study elucidates key genes linked to epilepsy, delineates the epilepsy immune landscape, and highlights the interaction between these domains, providing insights into potential epilepsy mechanisms and treatments.

Aims: Neuron death is caused primarily by apoptosis after spinal cord injury (SCI). Autophagy, as a cellular response, can maintain cellular homeostasis to reduce apoptosis. We aimed to investigate the effect and the mechanism of vimentin knockdown on autophagy and neural recovery after SCI.

Methods: The SD rats with T10 complete transection as SCI model were used. The vimentin RNAi adenovirus was constructed and transplanted into T10 rats with total transection injury of the spinal cord, and the recovery of neurological and motor functions after SCI was evaluated by BBB score, footprint analysis, electrophysiological tests, and immunofluorescence staining. Protein and gene expression were assessed by Western blotting, CO-IP, q-PCR, and immunofluorescence. In addition, neuron-like PC12 cells were infected with adenovirus to further elucidate the effect of vimentin on autophagy and the molecular mechanism of neuronal apoptosis after SCI.

Results: Inhibition of SCI induced-vimentin upregulation improved motor function, enhanced the recovery of autophagy flux, and reduced neuronal apoptosis. Notably, this may be related to the formation of vimentin-14-3-3-Beclin1 complex and PI3K class III complex.

Conclusion: Our results suggest that inhibition of vimentin expression may enhance autophagy and anti-apoptosis in neurons after SCI by affecting the formation of the vimentin-14-3-3-Beclin1 complex, thereby promoting neuronal recovery.

Background: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.

Results: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.

Conclusions: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.

Objective: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are common neurodegenerative diseases with distinct but overlapping pathogenic mechanisms. The clinical similarities between these diseases often result in high misdiagnosis rates, leading to serious consequences. Peripheral blood mononuclear cells (PBMCs) are easy to collect and can accurately reflect the immune characteristics of both DLB and AD.

Methods: We utilized time-of-flight mass cytometry (CyTOF) with single-cell resolution to quantitatively analyze peripheral PBMCs, identifying 1228 immune characteristics. Based on the top-selected immune features, we constructed immunological elastic net (iEN) models.

Results: These models demonstrated high diagnostic efficacy in distinguishing diseased samples from healthy donors as well as distinguishing AD and DLB cases. The selected features reveal that the primary peripheral immune characteristic of AD is a decrease in total T cells, while DLB is characterized by low expression of I-kappa-B-alpha (IKBα) in the classical monocyte subset.

Conclusions: These findings suggest that peripheral immune characteristics could serve as potential biomarkers, facilitating the diagnosis of neurodegenerative diseases.

Aims: To analyze the effect of APOE ε4 on fluid biomarkers and the correlations between blood molecules and CSF biomarkers in AD patients.

Methods: This study enrolled 575 AD patients, 131 patients with non-AD dementia, and 112 cognitively normal (CN) participants, and AD patients were divided into APOE ε4 carriers and non-carriers. Cerebrospinal fluid (CSF) biomarkers and blood-derived biomolecules were compared between AD and CN groups, between non-AD dementia and CN groups, as well as within APOE ε4 subgroups of AD patients. Utilizing Spearman's correlation analysis and quantile regression analysis, the relationships between blood-derived biomolecules and CSF biomarkers were analyzed in APOE ε4 carriers and non-carriers.

Results: The levels of CSF biomarkers and blood molecules exhibited significant differences between the AD and CN groups, including Aβ42, t-tau, p-tau 181, high-density lipoprotein, low-density lipoprotein (LDL), and uric acid. In AD patients, APOE ε4 carriers had increased levels of CSF t-tau, p-tau 181, and plasma LDL. In the correlation and regression analyses, the negative relationships between plasma TG and t-tau, between plasma TG and p-tau 181 levels, as well as the positive relationship between serum IgA and CSF Aβ42, were observed significantly in APOE ε4+ AD groups, but not in APOE ε4- AD group.

Conclusion: APOE ε4 is associated with accelerated progression of AD pathology. The blood-derived biomolecules correlated with CSF biomarkers in APOE ε4 carriers are related to neuroinflammation and lipid metabolism, which may indicate the role of APOE ε4 in AD pathophysiology and offer insights for diagnostic and therapeutic strategies for AD.

Trial registration: ClinicalTrials.gov identifier: NCT03653156.

Objective: Our aim was to research the neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features of the locus coeruleus (LC) in essential tremor (ET) patients of various cognitive states and to explore the relationships between these features and cognition.

Methods: We recruited three groups of participants, including 30 ET patients with mild cognitive impairment (ET-MCI), 57 ET patients with normal cognition (ET-NC), and 105 healthy controls (HCs). All participants underwent MRI scanning and clinical evaluation. Through NM-MRI images, we compared the contrast-to-noise ratio of LC (CNR_LC) between groups and evaluated the relationships between CNR_LC and cognitive scales.

Results: Compared to HCs, ET-MCI patients had a substantially lower CNR_LC value (p = 0.017). The CNR_LC of ET-NC patients was intermediate between that of ET-MCI patients and HCs. Furthermore, a partial correlation analysis in ET-MCI patients, controlling for age, gender, and education level, showed that higher CNR_LC values correlate with better performance on the Montreal cognitive assessment test and the trail making test A.

Conclusion: LC degeneration in ET patients may partially contribute to cognitive decline, suggesting that the LC norepinephrine system deserves further research on the mechanism of cognitive decline of ET patients as well as the development of targeted drugs.

Aims: Drug-refractory epilepsy (DRE) refers to the failure of controlling seizures with adequate trials of two tolerated and appropriately chosen anti-seizure medications (ASMs). For patients with DRE, surgical intervention becomes the most effective and viable treatment, but its success rate is unsatisfactory at only approximately 50%. Predicting surgical outcomes in advance can provide additional guidance to clinicians. Despite the high accuracy of invasive methods, they inevitably carry the risk of post-operative infection and complications. Herein, to noninvasively predict surgical outcomes of DRE, we propose the "source causal connectivity" framework.

Methods: In this framework, sLORETA, an EEG source imaging technique, was first used to inversely reconstruct intracranial neuronal electrical activity. Then, full convergent cross mapping (FCCM), a robust causal measure was introduced to calculate the causal connectivity between remodeled neuronal signals within epileptogenic zones (EZs). After that, statistical tests were performed to find out if there was a significant difference between the successful and failed surgical groups. Finally, a model for surgical outcome prediction was developed by combining causal network features with machine learning.

Results: A total of 39 seizures with 205 ictal EEG segments were included in this prospective study. Experimental results exhibit that source causal connectivity in α-frequency band (8~13 Hz) gains the most significant differences between the surgical success and failure groups, with a p-value of 5.00e-05 and Cohen's d effect size of 0.68. All machine learning models can achieve an average accuracy of higher than 85%. Among them, the SVM classifier with Gaussian kernel function and Bayesian optimization demonstrates the highest accuracy of 90.73%, with a PPV of 87.91%, an NPV of 92.98%, a sensitivity of 90.91%, a specificity of 90.60%, and an F1-score of 89.39%.

Conclusion: Our results demonstrate that the source causal network of EZ is a reliable biomarker for predicting DRE surgical outcomes. The findings promote noninvasive precision medicine for DRE.