Neuroreport最新文献

Objective: There has been less explanation for whether lumbar disc injury, particularly through puncture and nucleus pulposus (NP) aspiration, can influence chronic low back pain (LBP). We aim to investigate whether intradiscal injury modifies spine structure and contributes to behavioral alteration and peripheral neuronal hyperexcitability in a rat model.

Methods: Male Sprague-Dawley rats (n = 50) were subjected to lumbar disc (L4/5 and L5/6) puncture with nucleus pulposus aspiration (PUNCT) or sham surgery. Nociceptive processing was investigated through behavioral tests [dynamic weight bearing (DWB) and hindpaw withdrawal threshold], electrophysiological recordings of mechanosensitive single afferent nerves (MSAN), and calcium imaging of DiI-labeled dorsal root ganglion (DRG) neurons in response to capsaicin. Expression levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the disc and subchondral bone were quantified, and bone structure was assessed using ex vivo micro-computed tomography (µCT).

Results: The PUNCT group displayed significant behavioral changes, including increased forelimb dependency in DWB and decreased hindpaw withdrawal thresholds. Electrophysiological data indicated MSAN hyperexcitability with a reduced threshold to intradiscal pressure, and calcium imaging revealed heightened capsaicin (1 μM)-induced calcium influx in DiI-labeled DRG neurons from the PUNCT group. NGF and BDNF expression significantly increased in both the disc and subchondral bone of the PUNCT group. µCT analysis revealed hypertrophic bone volume, diminished trabecular bone quality, and localized bone erosion in the PUNCT group.

Conclusion: Intradiscal injury caused by puncture and NP aspiration induces spinal structural remodeling and peripheral neuronal sensitization, contributing to chronic LBP.

Background: Celastrol, a natural plant-derived compound with potent antioxidant and anti-inflammatory properties, demonstrates neuroprotective effects in various central nervous system disorders, though its impact on intracerebral hemorrhage (ICH) remains unexplored. This study examines whether celastrol modulates inflammation and necroptosis following ICH.

Methods: We established an ICH model in male C57BL/6 mice using collagenase IV and administered celastrol via intraperitoneal injection postinjury. Neurological function, Evans blue extravasation, brain water content, propidium iodide labeling, quantitative reverse transcription PCR, immunofluorescence staining, and Western blotting were employed to assess outcomes.

Results: Celastrol treatment markedly reduced cerebral edema and vascular leakage while improving neurological function post-ICH. The compound suppressed M1 microglial activation, evidenced by decreased Iba1 expression and reduced mRNA levels of tumor necrosis factor alpha, interleukin 1β, and inducible nitric oxide synthase. In addition, celastrol downregulated key necroptosis mediators receptor-interacting protein 3 and mixed lineage kinase domain-like protein, after ICH.

Conclusion: These findings suggest that celastrol mitigates ICH-induced injury by concurrently inhibiting necroptotic pathways and inflammatory responses.

Background: This study established three kainic acid-induced epileptic models via intraperitoneal, intranasal, and intravenous injections, comparing their behavioral and pathological differences to inform model selection in epilepsy research.

Methods: A total of 108 male C57BL/6J mice were randomized into six groups (intraperitoneal/intranasal/intravenous + kainic acid or PBS). Acute seizure severity (Racine scale), latency to stage IV-V seizures, status epilepticus duration, hippocampal neuronal degeneration (hematoxylin and eosin staining), apoptosis [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)], and glial activation (immunofluorescence for glial fibrillary acid protein/ionized calcium-binding adapter molecule 1) were assessed.

Results: The intravenous + kainic acid group showed the lowest mortality (10.0%) and highest success rate (96.3%), with shorter latency to severe seizures, longer status epilepticus duration, and milder Racine scores (P < 0.05). It also exhibited greater neuronal loss, morphological abnormalities, TUNEL-positive cells in CA3/dentate gyrus, and stronger glial activation. The intranasal + kainic acid group only showed increased dentate gyrus apoptosis.

Conclusion: The intravenous + kainic acid model exhibited low mortality, reduced dosage requirements, and inducible localized pathological damage, rendering it suitable for investigating localized neuronal injury. The intraperitoneal method, though simple with higher mortality, is preferable for systemic seizure models. The noninvasive intranasal approach is promising for trauma-sensitive research.

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: Anthraquinone derivative aloe-emodin, extracted from Chinese herbs has been confirmed with various pharmacological effects, including anti-inflammatory and neuroprotective properties, particularly in Alzheimer's disease, but the exact mechanism of action remains unclear.

Methods: In this study, the PC12 cells were induced by amyloid β-protein (Aβ) to establish an in vitro model of Alzheimer's disease. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine staining, transmission electron microscopy, real-time quantitative PCR, western blot, ELISA, coimmunoprecipitation (Co-IP), and immunofluorescence were employed to evaluate effect of aloe-emodin on the survival and expression of related genes and proteins in PC12 cells induced by Aβ.

Results: We found that 5 μM aloe-emodin significantly enhanced cell survival and proliferation. It also increased the mRNA and protein expression of Beclin-1 and LC3II, while decreasing the mRNA expression of P62, PI3K, AKT, mechanistic target of rapamycin (mTOR), NOD-like receptor protein 3 (NLRP3), and caspase-1, as well as the protein expression of P62, NLRP3, cleaved-caspase-1, p-PI3K, p-AKT, p-mTOR, interleukin-18 (IL-18), and IL-1β. Additionally, aloe-emodin reduced the intensity of p-tau fluorescence. The Co-IP results demonstrated a direct interaction between NLRP3 and LC3. Interestingly, aloe-emodin exhibited effects comparable to those of RAPA, an mTOR inhibitor.

Conclusion: These findings demonstrate that aloe-emodin offers neuroprotective benefits by reducing NLRP3-mediated inflammation and promoting autophagy, thereby providing a novel perspective on the treatment of Alzheimer's disease.

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: 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.

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.