Neuroreport最新文献

Background: Neuroinflammation plays a critical role in the pathogenesis and progression of Parkinson's disease. Verminoside (VMS) is a natural iridoid exhibiting anti-inflammatory properties. We aimed to investigate the effects of VMS on neuroinflammation and neuronal death in lipopolysaccharide (LPS)-treated BV2 microglial cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse models.

Methods: The production of inflammatory mediators, including nitric oxide, inducible nitric oxide synthase, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, were measured by Griess assay, ELISA, or real-time PCR. The protein levels of IκBα and nuclear factor kappa B (NF-κB) were determined by western blot. Cell viability and apoptotic rate were assessed using a cell viability assay and flow cytometry, respectively. Immunofluorescence was employed to label Iba-1-positive microglia and tyrosine hydroxylase-positive dopaminergic neurons. In addition, the motor function of mice was evaluated using the rotarod and traction tests.

Results: Our results demonstrated that VMS effectively suppressed the upregulation of inflammatory mediators induced by LPS in BV2 cells. VMS also inhibited the nuclear translocation of NF-κB and eliminated NF-κB activity. Moreover, VMS mitigated the toxicity of conditioned media from LPS-treated BV2 cells. In MPTP-treated mice, VMS decreased the number of Iba-1-positive microglia, reduced the production of inflammatory mediators, preserved tyrosine hydroxylase-positive dopaminergic neurons, and ameliorated motor deficits.

Conclusion: In summary, VMS prevents dopaminergic neuron degeneration and alleviates behavioral impairments by suppressing NF-κB-mediated neuroinflammation, highlighting its potential as a therapeutic drug for Parkinson's disease.

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.

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.

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.

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.

Purpose: Intracranial aneurysms represent the primary source of subarachnoid hemorrhage, ranking as the third most common cerebrovascular disorder after cerebral thrombosis and hypertension-related brain hemorrhage. As a member of the GATA family transcription factors, the role of zinc finger GATA-like protein 1 (ZGLP1) was unclear in intracranial aneurysm. In the present research, the specific effects of ZGLP1 on the proliferation and phenotypic transformation of human aerobic smooth muscle cells (HASMCs) were investigated.

Methods: Cell counting kit 8 and colony formation assays were performed to detect the growth of HASMCs. Cell migration was confirmed using transwell and wound healing assays. The apoptosis was analyzed using flow cytometry.

Finding: ZGLP1 knockdown inhibited the viability and colony formation ability of HASMCs. Importantly, ZGLP1 knockdown effectively promoted the apoptosis of HASMCs. The migration of HASMCs was remarkably inhibited by ZGLP1-specific small interfering RNA. Mechanistically, ZGLP1 knockdown inhibits the phosphorylation of protein kinase B (AKT) and cyclin D1 expression. In addition, ZGLP1 knockdown inhibited the expression of SMA and SM22α, while promoting the expression of OPN and MMP-2 in HASMCs, suggesting that ZGLP1 knockdown initiated the transformation from contractile phenotype to synthetic phenotype of HASMCs.

Conclusion: ZGLP1 knockdown induces apoptosis through the AKT pathway, and also induces the phenotypic transformation of HASMCs. ZGLP1 is a potential therapeutic target for intracranial aneurysm and deserves further research.

Objective: In this study, we investigated the interactions between brain regions at different scales in patients with mild cognitive impairment (MCI) to classify patients with MCI who may develop Alzheimer's disease (MCI-Converter (MCI-c)) and those with stable cognitive states (MCI-Stable (MCI-s)) at multiple spatial scales.

Methods: We divided the brain into 210, 40, and 12 regions, respectively, based on anatomical a priori, and then extracted six morphological features. Based on this, an intralayer structural brain network was constructed to detect connections between brain regions at different levels, and an interlayer network was constructed to explore connections between different spatial scales. Then these two networks were merged into a whole-brain network and trained the classifier after feature selection.

Results: Our study successfully identified meaningful connectivity features for precise classification, achieving an accuracy of 92.41%. In addition, some frequently reported abnormal brain regions were localized to more precise regions.

Conclusion: The human brain is a complex system with multiple spatial and temporal scales and multiple levels, showing a large number of emergent phenomena. Understanding the hierarchical relationship between brain structure and function is crucial. The network we constructed is not only important for MCI classification, but also holds promise for investigating other neurological conditions and elucidating brain development processes. Limitations include that model training and evaluation used only the Alzheimer's Disease Neuroimaging Initiative cohort; independent cohort validation is required to confirm generalizability. Moreover, integration with other imaging modalities (e.g. functional MRI and PET) may further improve prediction and will be explored in future work.

Background: Intracerebral hemorrhage (ICH) induces secondary brain injury, driven in part by oxidative stress caused by hemin, a toxic hemoglobin breakdown product. Cortical astrocytes, critical for maintaining redox homeostasis, are vulnerable to hemin-induced oxidative damage, exacerbating neuronal injury. Induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs) have shown therapeutic potential in brain injury models by promoting neural repair, but their ability to protect astrocytes against hemin toxicity remains unexplored. We hypothesized that iPSC-NPCs coculture mitigates hemin-induced oxidative stress in astrocytes by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway.

Materials and methods: Astrocytes were exposed to hemin with or without iPSC-NPC coculture. We assessed cell viability, reactive oxygen species (ROS) accumulation, apoptosis, and the role of the Nrf2/HO-1 pathway using small-interfering RNA.

Results: iPSC-NPC coculture significantly reduced hemin-induced oxidative damage by promoting Nrf2 nuclear translocation and upregulating HO-1, thereby decreasing ROS and apoptosis. Silencing Nrf2 abolished these protective effects.

Conclusion: Our findings demonstrate that iPSC-NPCs protect astrocytes from hemin toxicity via the Nrf2/HO-1 pathway, suggesting a novel therapeutic strategy for ICH-induced oxidative injury.

Objective: Sepsis-associated encephalopathy (SAE) is a common and serious neurological complication of sepsis. This study aimed to investigate the mechanism of methyltransferase-like 3 (METTL3) in SAE-induced microglial pyroptosis and to identify new therapeutic targets for SAE treatment.

Methods: A SAE cell model was established using lipopolysaccharide (LPS)-treated BV-2 cells. The expression of interleukin-1β, interleukin-18, cleaved caspase-1, gasdermin D (GSDMD)-N, NOD-like receptor protein 3 (NLRP3), transforming growth factor beta receptor 3 (TGFBR3), and METTL3 was detected by. METTL3 was silenced in LPS-treated BV-2 cells to validate the role of METTL3 in microglial pyroptosis. Total N6-methyladenosine (m6A) content was measured. The binding of primary miRNA (pri-miR)-101-3p to DGCR8 and the m6A level of pri-miR-101-3p were analyzed by methylated RNA immunoprecipitation-qPCR. The expression of pri-miR-101-3p and miR-101-3p was measured by reverse transcription quantitative PCR. The downstream targets of miR-101-3p were predicted by databases, and the binding relationship between miR-101-3p and TGFBR3 was verified. Rescue experiments were performed to verify the role of METTL3/miR-101-3p/TGFBR3 axis in microglial pyroptosis.

Results: LPS treatment decreased cell viability and promoted interleukin-1β, interleukin-18, METTL3, cleaved caspase-1, GSDMD-N, and NLRP3. Silencing METTL3 inhibited microglial pyroptosis. Mechanistically, METTL3 promoted the binding of pri-miR-101-3p to DGCR8 through m6A modification and increased mature miR-101-3p expression. miR-101-3p targeted TGFBR3 and inhibited TGFBR3 expression. miR-101-3p overexpression or TGFBR3 downregulation partially reversed the inhibitory effect of silencing METTL3 on LPS-induced microglial pyroptosis.

Conclusion: METTL3 is upregulated in SAE, enhances miR-101-3p expression through m6A modification, and inhibits TGFBR3 expression, finally leading to microglial pyroptosis in SAE.

Background: Mild cognitive impairment (MCI) represents a critical window for intervention before Alzheimer's disease progression. This study investigated whether high-definition transcranial direct current stimulation (HD-tDCS) targeting the left dorsolateral prefrontal cortex (L-DLPFC) could modulate white matter microstructure and thereby influence cognitive function.

Methods: Twenty-four patients with MCI received 10 sessions of active HD-tDCS over the L-DLPFC. White matter integrity was assessed using diffusion tensor imaging (DTI) to quantify fractional anisotropy in corticospinal tracts (CSTs) and anterior thalamic radiations (ATR). Cognitive function was evaluated with the trail making test B (TMT-B), mini-mental state examination (MMSE), and Montreal cognitive assessment (MoCA) at baseline and postintervention. Forty healthy controls provided baseline DTI data.

Results: At baseline, patients with MCI showed significantly reduced fractional anisotropy in the bilateral CST and ATR compared with healthy controls. Following HD-tDCS, increases in fractional anisotropy were observed in these tracts. While MMSE and MoCA scores showed no significant change, TMT-B performance appeared to improve. Notably, increased fractional anisotropy in the left ATR showed an association with improved TMT-B performance (r = 0.467, P < 0.05).

Conclusion: The findings suggest that HD-tDCS targeting the L-DLPFC may promote microstructural remodeling in white matter tracts, evidenced by elevated fractional anisotropy within the corticospinal and anterior thalamic pathways. While global cognitive measures remained stable, a trend toward improved executive function (TMT-B) was observed, potentially associated with left ATR fractional anisotropy enhancement. This positions HD-tDCS as a candidate neuromodulatory intervention for MCI, warranting further investigation to confirm functional outcomes.