Neurological Research最新文献

Purpose: The objective of this study is to investigate the mechanism of cuproptosis regulation in TMZ resistance in GBM, and provide an important theoretical basis for the rational design of combination therapy to block TMZ resistance.

Methods: The experimental participants were divided into four groups, including a control group (Control), a Control + CU-ES group, a TMZ group, and a TMZ + copper ion carrier (TMZ + CU-ES) group. TMZ-resistant U87 MG cell lines (U87 MG/TR) were established using a concentration gradient method. Cell proliferation rates were assessed using the CCK8 assay, apoptosis was analyzed via flow cytometry, and gene and protein expression levels of caspase-3 and caspase-9 were detected by using qRT-PCR and Western Blot. Differences in cell proliferation, apoptosis, and apoptosis-related molecule expression were compared across groups.

Results: The U87 MG/TR-resistant strain was established (IC50 =141.5 μM). Compared with the Control group, TMZ group showed a decrease in the cell proliferation rate but an increase in the apoptosis rate (p < 0.05). The TMZ + CU-ES group exhibited a further significant reduction in the cell proliferation rate and a significant increase in the apoptosis rate. The expression of caspase-3 and caspase-9 in the TMZ + CU-ES group was significantly higher than that in the TMZ group.

Conclusion: TMZ resistance in glioma cells was affectively reversed by the cuproptosis pathway, a mechanism likely involving the activation of the intrinsic apoptotic pathway. This finding offered a novel strategy for overcoming TMZ resistance.

Background: Epilepsy remains a major neurological disorder with high rates of drug resistance and cognitive decline. Repurposing neuroprotective drugs offers a promising approach. Metformin, a widely used antidiabetic agent, has shown anticonvulsant effects, yet its impact on nitric oxide synthase (NOS) isoforms in distinct brain regions remains unclear.

Methods: Adult male Wistar rats were allocated into control, pentylenetetrazole (PTZ), or metformin+PTZ groups. Metformin (200 mg/kg, i.p.) was administered for 7 days before induction of acute PTZ seizures (45 mg/kg, i.p.). Seizure severity and latency were assessed using Racine's scale, and cognition was evaluated by the passive avoidance test (PAT). Nitric oxide (NO) and the expression of its synthesizing enzymes, inducible (iNOS), neuronal (nNOS), and endothelial (eNOS), were quantified in the cortex and hippocampus via enzyme-linked immunosorbent assay (ELISA). In silico analyses included target prediction and molecular docking to assess metformin - NOS interactions.

Results: Metformin significantly reduced seizure severity, prolonged latency to the first myoclonic jerk, and prevented PTZ-induced memory impairment (all p < 0.001). These behavioral effects were accompanied by reductions in cortical and hippocampal nNOS and iNOS expression, decreased cortical eNOS levels, and lower NO accumulation. TargetNet predicted NOS isoforms among potential metformin targets, and docking indicated moderate binding affinity (-5.2 to -5.9 kcal/mol).

Conclusion: Metformin exerted seizure-suppressing and cognition-preserving effects in an acute PTZ model, associated with reductions in NOS isoform expression and NO levels, suggesting altered NOS/NO signaling and supporting its potential as an adjunctive candidate for mitigating seizure-related neuronal dysfunction.

Background: To investigate the effectiveness and safety of perioperative prophylaxis protocol for deep venous thrombosis (DVT) in patients undergoing surgery for treating glioblastoma.

Methods: A total of 428 patients were prospectively enrolled to undergo preoperative risk assessment, postoperative dynamic screening and prophylactic anticoagulation for DVT in the lower extremities. A 1:1 propensity-score matching was retrospectively performed to select controls who were hospitalized at the same time without perioperative DVT prophylaxis. Primary endpoint was the incidence of postoperative DVT during hospitalization. Secondary outcomes included pulmonary embolism (PE), length of hospital stay (LOS), delays in adjunctive chemoradiotherapy (CRT) and quality-adjusted life years (QALYs) within 3 months after discharge.

Results: Postoperative DVT occurred in 7.0% of patients in the screening cohort, which was significantly lower than the 22.2% observed in the matched controls, showing a difference of 15.2% (95%CI: 10.6%, 19.8%). Fewer patients in the screening cohort experienced postoperative PE compared to controls (p = 0.018). The rates of major and minor bleeding events following pharmacological prophylaxis were similar between the two cohorts (both p > 0.05). Patients with DVT screening were associated with shorter LOS, lower rates of delayed CRT and higher QALYs scores at both 1- and 3-month follow-up visits. No deaths were observed in either cohort during hospitalization.

Conclusions: This perioperative prophylaxis protocol was more effective at detecting postoperative DVT, without increasing the risk of major bleedings after surgery. This benefit was associated with a significantly shorter LOS, a lower rate of delayed CRT and improved QALYs scores within a 3-month follow-up period.

Background: Cerebral infarction (CI) is associated with high incidence and mortality rates. This study aimed to investigate the role and molecular mechanism of arachidonate 15-lipoxygenase (ALOX15) in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced SK-N-SH cells.

Methods: An in vitro OGD/R model was established using SK-N-SH cells. The gene expression levels were assessed by RT-qPCR and western blotting. Cell proliferation and apoptosis were evaluated using the 5-Ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry. Ferroptosis-related markers, including reactive oxygen species (ROS), Fe²⁺, and malondialdehyde (MDA), were measured. Bioinformatics analysis, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP) assays were used to validate the transcriptional regulation of ALOX15 by SP1. The interaction between ELAV-like RNA-binding protein 1 (ELAVL1) and ALOX15 was analyzed using RNA-binding protein database analysis. In vivo, a middle cerebral artery occlusion (MCAO) model was used to assess the effects of ALOX15 silencing on cerebral infarct volume and neurological deficits.

Results: ALOX15 was upregulated in CI patient tissues and OGD/R-treated SK-N-SH cells. Silencing ALOX15 alleviated OGD/R-induced SK-N-SH cell injury and ferroptosis. Specificity protein 1 (SP1) transcriptionally activated ALOX15 expression, promoting cell damage and ferroptosis. Additionally, ELAVL1 stabilized ALOX15 mRNA, further enhancing its expression and contributing to OGD/R-induced injury and ferroptosis. In the MCAO model, ALOX15 knockdown reduced infarct volume and improved neurological outcomes.

Conclusion: SP1 and ELAVL1 regulated ALOX15 to drive OGD/R-induced SK-N-SH cell injury and ferroptosis. These findings highlight the SP1/ELAVL1-ALOX15 axis as a potential therapeutic target for mitigating brain injury in CI, providing a translational basis for future interventions.

Objectives: The safety and effectiveness of electroacupuncture (EA) in treating depression have been scientifically validated. Recent evidence indicates that the c-Jun N-terminal kinase (JNK) pathway is a therapeutic target for anti-depression. This study examines the effects and mechanisms of EA on middle cerebral artery occlusion (MCAO) surgery and chronic-stress-induced post-stroke depression (PSD) mice.

Methods: C57BL/6 mice were randomly divided into the sham, MCAO, MCAO+stress, and MCAO+EA+stress groups. After the behavior test, H&E staining was conducted to detect hippocampal changes. TUNEL assay was performed to detect apoptosis. Western blot and RT-PCR were performed to assess the protein levels. Immunohistochemistry was used to detect NF200 and 5-HT expressions.

Results: EA treatment was found to ameliorate depressive behavior in mice by inhibiting neuro-apoptosis and microglia-mediated neuroinflammation. Furthermore, EA protected the hippocampal synaptic plasticity through up-regulating the protein expression of 5-hydroxytryptamine (5-HT), neurofilament-200 (NF-200), postsynaptic density protein 95 (PSD95), synaptophysin (Syn), and brain-derived neurotrophic factor (BDNF), along with increasing the counts of hippocampal synapses. The JNK signaling pathway was continuously activated after MCAO and stress treatments, and EA inhibited the JNK signaling pathway by decreasing the JNK and c-Jun phosphorylation levels and the downstream AP-1 expression.

Conclusion: To summarize, EA effectively suppresses the activation of the JNK signaling pathway, thereby improving PSD-related depressive behavior by enhancing synaptic plasticity and reducing neuro-apoptosis and neuro-inflammation. This study lays a foundation for the clinical application of EA in alleviating PSD-related depressive behaviors, positioning it as a potential alternative therapy for addressing depressive symptoms in PSD.

Kenpaullone is known for its neuroprotective and anti-inflammatory properties. We explored the potential of a specific intervention to influence cognitive abilities and disease-related brain changes in a mice model replicating key aspects of Alzheimer's disease (AD). We employed 5XFAD transgenic mice, which develop Aβ plaques and cognitive impairments that mirror those observed in individuals with Alzheimer's disease (AD). The animals were treated with Kenpaullone (1 mg/kg, 3 mg/kg, and 5 mg/kg) or a vehicle (DMSO). The study evaluated memory using the Morris water maze (MWM) and the novel object recognition (NOR) task. This study employed immunohistochemistry, ELISA, and Western blot to analyze Aβ plaques and proinflammatory factors, investigating neurodegeneration. In contrast, the expression of genes related to neurodegeneration and apoptosis was evaluated using polymerase chain reaction (PCR). Administration of Kenpaullone yielded significant improvements in cognitive performance in the 5XFAD mice. Mice that received the 5 mg/kg treatment demonstrated the highest improvement in spatial learning and recognition memory. Furthermore, Kenpaullone decreased the burden of amyloid-beta plaques in key brain regions associated with memory (hippocampus and cortex), along with decreased levels of proinflammatory cytokines. Furthermore, Kenpaullone treatment resulted in a downregulation of genes related to neurodegeneration and apoptosis, suggesting a potential therapeutic benefit in mitigating neural apoptosis in AD. Our results suggest that Kenpaullone holds promise for improving cognitive function and mitigating neuropathological changes in AD, warranting further exploration as a potential medicinal substance.

Objective: Inflammatory and lipid biomarkers are increasingly recognized for their role in acute ischemic stroke (AIS). This study evaluated the predictive value of composite indicators, focusing on the hsCRP/HDL-C ratio.

Methods: A prospective study included 183 AIS patients and 194 controls from Sichuan Provincial People's Hospital (July 2023-July 2024). Venous blood samples assessed inflammatory and lipid markers. Primary outcome was 3-month functional prognosis (mRS 0-2 vs. 3-6); secondary outcomes included hemorrhagic transformation, NIHSS scores, and mortality.

Results: Significant baseline differences included hypertension, hyperlipidemia, atrial fibrillation, hsCRP, MHR, and hsCRP/HDL-C ratio (all p < 0.001). The hsCRP/HDL-C ratio showed high predictive accuracy (AUC analysis). Higher ratios correlated with atrial fibrillation, worse NIHSS scores, and poor 3-month prognosis (p < 0.001), but not hemorrhagic transformation or TOAST classification. After multivariate adjustment, higher quartiles of the hsCRP/HDL-C ratio remained an independent predictor of poor outcomes [quartile_4 (OR = 5.14, 95% CI: 1.03-25.81, p = 0.047)] and were also associated with increased NIHSS scores at admission, day 3, and day 7 [quartile_4 (0 h: B = 2.92, p = 0.016; 3d: B = 3.30, p = 0.004; 7d: B = 3.91, p = 0.001)].

Conclusion: The hsCRP/HDL-C ratio is strongly associated with AIS occurrence and predicts both short-term neurological deficits and long-term prognosis, offering clinical utility in risk stratification.

Background: Spinal cord injury (SCI) is a destructive neuropathological condition. Cinnamaldehyde (CA), a major bioactive component in Cinnamon essential oil, is known for its neuroprotective effects by inhibiting neuroinflammation, oxidative stress, and apoptosis. However, CA specific role in SCI remains unclear. The purpose of this study was to examine the impact of CA on SCI.

Methods: We established a rat model of SCI and assessed nerve damage in rats using the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test and Tarlov Scale. Neuronal loss was evaluated with Nissl and NeuN staining. Apoptotic damage was assessed using TUNEL staining and caspase3 analysis. The level of M1-type microglia activation was explored using Iba1. Additionally, TNF-α and IL-Iβ concentrations were measured to examine inflammation. Poly (ADP-ribose) polymerase (PARP) and proliferating cell nuclear antigen (PCNA) were used to assess DNA damage.

Results: The results demonstrated that CA effectively improves behavioral scores measured by the BBB assay, inclined plane test, and Tarlov trial after SCI. NeuN and Nissl staining showed that CA significantly increases the number of NeuN-stained neurons and Nissl bodies. Apoptosis detection revealed that CA markedly reduces caspase3 production and the number of TUNEL-positive cells. Moreover, CA not only reduced Iba1 levels but also significantly decreased the production of TNF-α and IL-Iβ. Additionally, CA notably decreased PARP levels and promoted PCNA expression.

Conclusions: CA regulates pathways involved in anti-neuroinflammation, anti-apoptosis, and DNA repair to improve neurological deficits and pathological conditions after SCI. CA therapeutic effect of CA may depend on the dosage.

Objectives: Glioblastoma (GBM) is one of the most aggressive brain tumors, with a poor prognosis. Brain tumor stem cells (BTSCs) play a central role in GBM progression and recurrence. This study aimed to identify key BTSC-related genes associated with GBM prognosis and explore their potential biological functions.

Methods: BTSC-related differentially expressed genes (DEGs) were identified by integrating gene expression data from public databases. Functional enrichment analyses were conducted to explore their biological relevance in GBM. The key variables associated with GBM risk and prognosis were selected using the machine learning method. Immune cell infiltration in GBM was explored through CIBERSORT. Finally, the effects of MMRN1 on cell stemness and macrophage polarization were investigated using in vitro experiments.

Results: A total of 26 upregulated BTSC-related DEGs in GBM were identified, which were enriched in immune response and pathways in cancer. MMRN1 and age were the key variables associated with GBM risk and prognosis. Higher MMRN1 expression and older age indicated a poor prognosis. MMRN1 expression was significantly elevated in GBM tissues, especially in BTSCs. Mechanistically, MMRN1 activated the TLR7/8/9-IRF5 signaling pathway and promoted M2 macrophage polarization. In vitro validation confirmed that MMRN1 overexpression enhanced GBM cell stemness and induced macrophage M2 polarization.

Discussion: MMRN1 is a critical BTSC-related biomarker that contributes to GBM progression by enhancing tumor stemness and modulating the immune microenvironment. Targeting MMRN1 May represent a promising therapeutic approach for GBM treatment.

Background: Psychostimulants induce neuroplastic changes in the mesocorticolimbic system associated with the expression of the D2 receptor, which has two isoforms: D2long (D2L) and D2short (D2S). These isoforms seem to participate differentially in the plasticity changes induced by psychostimulants; however, the expression changes of this receptor induced by these substances remain unclear. Psychostimulants have a mechanism that involves the participation of monoamines, and there is evidence that the dopamine activation by modafinil (MOD) in combination with the serotonin activation by citalopram (CIT) enhances psychostimulant-like effects for this combination.

Objetive: The present study was designed to characterize the expression of the D2S, D2L isoforms and tyrosine hydroxylase in the medial prefrontal cortex, ventral tegmental area, nucleus accumbens and ventral pallidum of rats previously treated with modafinil alone or in combination with citalopram.

Results: Results show that MOD alone and co-administered with CIT induce overexpression of D2S and D2L in the ventral pallidum, and only the pretreatment with 60 mg MOD + 3 mg CIT generated a higher expression of D2L in the medial prefrontal cortex and ventral tegmental area. Tyrosine hydroxylase expression was reduced only with 60MOD +5 mg CIT in the nucleus accumbens.

Conclusion: These findings suggest that MOD, alone or co-administered with CIT, produces differential changes in the D2R isoforms that coincide with the psychostimulant effects of these substances. This research highlights the importance of further exploring the expression and function of D2 receptors and their two isoforms, as such analyses will allow us to infer the pre- and post-synaptic modulation of these receptors on the reward system.