Neuroreport最新文献

Objective: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive impairment and synaptic dysfunction. Despite substantial research efforts, effective therapeutic options remain limited. Tenuigenin (TEN), a principal bioactive constituent isolated from the traditional Chinese medicinal herb Polygala tenuifolia, has demonstrated promising neuroprotective effects.

Methods: This study adopted a comprehensive multitiered approach, combining network pharmacology, machine learning, molecular modeling, and in-vitro experiments, to elucidate the therapeutic targets and mechanisms of TEN in AD. Computational analyses identified mitogen-activated protein kinase kinase 1 (MAP2K1) as a critical target, mediating the effects of TEN. Gene set enrichment analysis indicated that TEN could activate the 26S proteasome pathway, promoting the degradation of neurotoxic proteins, such as amyloid-β (Aβ), thereby reducing their pathological accumulation.

Results: Immune infiltration analysis further revealed that TEN could modulate the distribution of activated natural killer cells and M0 macrophages, playing a role in restoring immune balance in the AD microenvironment. Molecular docking and dynamics simulations demonstrated strong binding affinity and structural compatibility between TEN and MAP2K1. Experimental validation using Aβ-treated SH-SY5Y cells indicated that TEN significantly enhanced cell viability and suppressed MAP2K1 protein expression.

Conclusion: In conclusion, this study provided the first integrated evidence that TEN exerts neuroprotective effects in AD by targeting MAP2K1. These findings highlight the multitarget, multipathway therapeutic potential of TEN and support its development as a natural agent for AD prevention and treatment.

Objective: To investigate the neuroprotective mechanism by which docosahexaenoic acid (DHA) promotes microglial autophagy via the miR-589-5p/toll-like receptor 4 (TLR4) axis in Alzheimer's disease.

Methods: In vitro, BV2 microglial cells were treated with Aβ25-35 to establish an Alzheimer's disease model and subjected to DHA treatment with or without miR-589-5p inhibition and TLR4 overexpression. Cytotoxic effects were assessed by methylthiazolyldiphenyl-tetrazolium bromide assays. Autophagy markers (LC3-II/I ratio, Beclin1, and p62) were evaluated by Western blot and immunofluorescence. The miR-589-5p/TLR4 interaction was assessed using dual luciferase assays. For clinical validation, peripheral blood samples from healthy controls, patients with mild Alzheimer's disease, and patients with severe Alzheimer's disease (n = 30 each) were analyzed for miR-589-5p and TLR4 mRNA expression via quantitative reverse transcription PCR (qRT-PCR).

Results: In cellular assays, DHA significantly enhanced autophagy by increasing the LC3-II/I ratio and Beclin1 expression while decreasing p62 levels (P < 0.05). Mechanistic validation showed that miR-589-5p inhibition abolished DHA's autophagy-promoting effects, while TLR4 overexpression reversed these benefits. Conversely, miR-589-5p mimic treatment rescued autophagy even under TLR4 overexpression conditions. Dual-luciferase assays confirmed that miR-589-5p directly targets TLR4. Clinically, qRT-PCR analysis revealed that miR-589-5p expression was downregulated and TLR4 expression was upregulated in Alzheimer's disease patients compared to healthy controls, and these alterations were correlated with disease severity (P < 0.05).

Conclusion: DHA enhances microglial autophagy via a novel miR-589-5p/TLR4 regulatory axis, a potential Alzheimer's disease therapy and biomarker for Alzheimer's disease progression.

Objectives: The medial septum modulates hippocampal oscillations, including ripples, which are critical for memory consolidation. While the role of the medial septum in theta rhythms is well-established, its specific contribution to hippocampal ripple activity remains poorly understood. This study sought to investigate the relationship between medial septal activity and hippocampal ripples in vivo .

Methods: This study aimed to characterize the in-vivo membrane potential dynamics of putative medial septal neuron subtypes and their contribution to hippocampal ripples in awake mice. We performed in-vivo whole-cell patch-clamp recordings from medial septal neurons in head-fixed, awake mice, while simultaneously acquiring hippocampal local field potentials.

Results: Medial septal neurons were classified into glutamatergic, cholinergic, and GABAergic subtypes using hierarchical clustering based on their intrinsic electrophysiological properties. We analyzed the firing rates and subthreshold membrane potential dynamics of these neurons during hippocampal ripple events and examined their correlations with ripple parameters (duration, frequency, and power). Our results revealed subtype-specific responses. Notably, putative glutamatergic neurons exhibited a slight decrease in firing rate, yet displayed a pronounced depolarization of their membrane potential approximately 100 ms before ripple onset, peaking at the initiation of ripples. This depolarization was inversely correlated with subsequent ripple amplitude and power. In addition, membrane hyperpolarization was positively correlated with ripple duration.

Conclusion: These findings elucidate the contribution of glutamatergic medial septal neurons to hippocampal ripple dynamics and suggest a tightly regulated interaction between the medial septum and hippocampus in shaping ripple activity.

Objective: The objective of this study is to investigate whether motor-evoked potentials (MEPs) amplitudes are associated nonlinearly with cold-water immersion-induced experimental pain in muscle.

Methods: The cortical representation area of the right abductor pollicis brevis muscle of 10 subjects was stimulated using a multi-locus transcranial magnetic stimulation device, and the resulting MEPs were recorded with electromyography. The stimulation was delivered with and without the cold-water immersion. A generalized additive model (GAM) was applied to study the association of different parameters with the MEP amplitudes.

Results: The GAM results indicated a nonlinear association between MEP amplitude and cold-water immersion-induced experimental pain, with a curved component at lower pain levels [up to approximately 5 on the numerical rating scale (NRS)], followed by a rising trend that peaked at the upper end of the NRS.

Conclusion: The formed GAM suggests a nonlinear association between the experienced pain level and the amplitudes of MEPs. These findings indicate that higher pain levels or prolonged cold-water exposure may be associated with changes in MEP amplitudes, though causality cannot be inferred.

Background: The neuronal pyroptosis exacerbated neurological injury in ischemic stroke. Indobufen (IND), a clinically used agent for reducing ischemic stroke risk, was shown to suppress neuronal pyroptosis in ischemic stroke. This study aimed to elucidate the precise mechanism by which IND regulates NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated neuronal pyroptosis.

Methods: SH-SY5Y cells underwent oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate ischemic damage. The binding of signal transducer and activator of transcription 1 (STAT1) at the NIMA-related kinase 7 (NEK7) promoter was assessed via chromatin immunoprecipitation and dual-luciferase reporter assay. Cell counting kit-8 was used to determine cell viability. The levels of inflammatory cytokines [interleukin (IL)-1β and IL-18] were evaluated using ELISA. Flow cytometry was employed to determine the rate of pyroptosis. The expression of NLRP3 was assessed by immunofluorescence. Quantitative real-time PCR or Western blot was utilized to detect the expression of STAT1, NEK7, GSDMD-N, cleaved caspase-1, and NLRP3.

Results: Treatment with IND significantly attenuated OGD/R-induced NLRP3 inflammasome activation and pyroptosis in neurons. STAT1 served as the direct molecular target through which IND exerted its antipyroptotic effects in ischemic stroke. Mechanistically, STAT1 transcriptionally activated NEK7 expression under the ischemic stroke condition. IND suppressed neuronal pyroptosis in ischemic stroke by inhibiting the STAT1/NEK7/NLRP3 signaling axis.

Conclusion: IND downregulated STAT1 to inhibit STAT1-mediated transcriptional activation of NEK7, thereby reducing NLRP3 inflammasome activation and ultimately mitigating neuronal pyroptosis in ischemic stroke.

Objective: This study investigated abnormal short- and long-range functional connectivity density (FCD) and resting-state functional connectivity (rsFC) within and outside the cortico-striatal-thalamic (CST) loop in patients with obsessive-compulsive disorder (OCD).

Methods: Ninety-two patients with OCD and 75 healthy controls underwent multimodal MRI. Clinical assessments included the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Anxiety Inventory, and Beck Depression Inventory. Voxel-based FCD analysis explored local and distant nodal changes, followed by seed-based rsFC analysis and correlation with clinical variables.

Results: Compared with healthy controls, patients with OCD showed decreased short-range FCD in the bilateral postcentral gyrus, left superior temporal gyrus, and right insula, but increased short-range FCD in the left caudate nucleus. Long-range FCD increased in the right orbitofrontal gyrus and left middle frontal gyrus. Seed-based analysis revealed enhanced rsFC between the right orbitofrontal gyrus and right calcarine fissure and surrounding cortex, and between the left middle frontal gyrus and right anterior cingulate and paracingulate gyri, as well as the right paracentral lobule. Left caudate FCD values negatively correlated with Y-BOCS scores, while left middle frontal gyrus FCD values positively correlated with illness duration.

Conclusion: Patients with OCD exhibit widespread connectivity abnormalities in multiple brain regions within and beyond the classic CST loop, involving sensorimotor networks, emotion-cognitive regulation, executive control, error monitoring, and visual processing systems. These findings suggest that OCD pathophysiology extends beyond the traditional CST loop, providing new insights into the neural mechanisms underlying this disorder.

Purpose: This study aimed to investigate the impairments in white matter microstructure and glymphatic function in patients with post-traumatic brain injury (TBI) who exhibit disorders of consciousness (DoCs), as well as their relationships with levels of consciousness and clinical outcomes.

Methods: We enrolled 30 patients diagnosed with TBI who exhibited DoCs and 30 healthy controls for MRI scanning. We compared intergroup differences in diffusion tensor imaging (DTI) metrics, the DTI analysis along the perivascular space (DTI-ALPS) index, and choroid plexus volume (CPV). The Pearson correlation analysis was conducted to examine the correlations among various indicators in the DoC group.

Results: Significant group differences were found in DTI metrics, the DTI-ALPS index, and CPV (P < 0.05). In the DoC group at baseline, fractional anisotropy (FA) and mean diffusivity (MD) values correlated with Coma Recovery Scale-Revised, DTI-ALPS, and CPV (P < 0.05). At 3-month follow-up, Glasgow Outcome Scale-Extended (scores were positively correlated with FA and DTI-ALPS, but negatively correlated with MD and CPV (P < 0.05).

Conclusion: This study suggested that TBI may cause brain structural damage, impair glymphatic function, and subsequently affect patients' levels of consciousness. These findings further indicate that glymphatic dysfunction could play an important role in the pathogenesis and prognosis of DoCs.

Background: Diabetes significantly elevates the risk of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, indicating shared pathophysiological mechanisms. While ferroptosis is increasingly implicated in neurodegeneration, microglia - highly vulnerable to ferroptosis - may mediate this link. However, it remains unknown whether high glucose (HG) directly induces microglial ferroptosis.

Methods: Using HG-treated BV2 microglia, we integrated multiomics profiling (RNA-seq and targeted lipidomics), functional assays, and genetic manipulation of pyruvate dehydrogenase kinase 4 (PDK4) to investigate its role in HG-associated ferroptosis.

Results: HG-induced microglial ferroptosis, characterized by iron overload, elevated malondialdehyde and mitochondrial reactive oxygen species, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial damage, including loss of membrane potential and ultrastructural disintegration. This was accompanied by upregulated PDK4 expression. PDK4 overexpression attenuated ferroptosis by preserving GPX4, reducing lipid peroxidation, and maintaining mitochondrial integrity; these protective effects were reversed by n-6 polyunsaturated fatty acid (PUFA) supplementation. Conversely, PDK4 knockdown exacerbated ferroptosis via amplified n-6 PUFA synthesis and oxidative stress. Mechanistically, PDK4 acts as a metabolic gatekeeper by restricting acetyl-CoA availability for the synthesis of pro-ferroptotic PUFAs, thereby curtailing iron-dependent lipid peroxidation.

Conclusion: PDK4 is a critical regulator of HG-induced microglial ferroptosis, thereby bridging hyperglycemia-induced metabolic dysfunction and neurodegeneration. Our findings nominate PDK4 as a promising therapeutic target for diabetes-linked neurodegenerative diseases.

Objective: Butyrate, a short-chain fatty acid produced by intestinal microbial fermentation of dietary fiber, serves as an endogenous ligand for the G protein-coupled receptors. Previous studies have confirmed the neuroprotective effects of sodium butyrate (NaB) in ischemic stroke, but its role in subarachnoid hemorrhage (SAH) remains unclear. Here, we investigated the potential therapeutic efficacy and underlying mechanisms of NaB in a rat SAH model.

Methods: NaB was administered intranasally 1 h post-SAH, and neurological function and neuronal apoptosis were evaluated 24 h post-SAH.

Results: During the early brain injury (EBI) phase after SAH, GPR41 was predominantly expressed in neuronal cells, and its expression levels increased significantly, peaking at 24 h post-SAH. NaB treatment attenuated neurological deficits after SAH, reduced brain edema, and alleviated neuronal damage and apoptosis. Furthermore, NaB elevated the levels of GPR41, phosphorylated Akt, and the antiapoptotic protein Bcl-2, while suppressing the expression of the proapoptotic protein Bax. Notably, the neuroprotective effects of NaB were partially reversed by GPR41 siRNA knockdown and pharmacological inhibition of PI3K with LY294002.

Conclusions: These findings suggest that NaB may mitigate EBI after SAH by inhibiting neuronal apoptosis, with the underlying mechanism potentially involving activation of the GPR41/PI3K/Akt signaling pathway.

Objectives: Acid-sensing ion channels (ASICs) are rapidly inactivated following activation by acidic extracellular pH. Consequently, mechanisms beyond ASICs are likely involved in modulating neuronal excitability under sustained acidic conditions. Therefore, this study investigated the impact of sustained acidic pH on neuronal excitability.

Methods: Membrane current and voltage changes induced by acidic pH were recorded from acutely isolated rat medullary dorsal horn neurons using the whole-cell patch-clamp technique.

Results: The steady-state inactivation relationship for extracellular pH revealed that most ASICs were completely inactivated at pH ≤ 6.5. Acidic pH depolarized medullary dorsal horn neurons with high affinity (EC50 of pH 6.9), a process mediated by ASIC activation. Acidic pH (≤6.9) also generated instantaneous action potentials; however, they immediately disappeared owing to the inactivation of voltage-gated Na⁺ channels. Action potentials reemerged depending on pH level, even under sustained acidic conditions. This reappearance of action potentials correlated with the extent to which acidic pH inhibited the persistent Na⁺ current mediated by voltage-gated Na⁺ channels.

Conclusion: These findings suggest that under pathological conditions characterized by sustained extracellular pH reduction, such as inflammation, a persistent Na⁺ current may serve as a sensor for modulating neuronal excitability in response to prolonged acidic pH levels.