Neurochemical Research最新文献

Oxidative stress associated with neuronal death resulting from excitotoxicity represents a key pathophysiological mechanism contributing to the genesis and progression of neurofunctional alterations in epilepsy. Here, we evaluated the neuroprotective properties of GLE (300 mg/kg; i.g.) in the PTZ-induced Kindling model. Four groups of male Wistar rats were randomly assigned: control, PTZ, GLE-300, and Diazepam, each consisting of 8 rats. During the kindling process, 11 injections of PTZ (35 mg/kg; i.p.) were given every 48 h (21 consecutive days) to create a model of epilepsy. The 5-stage Racine scale was used to assess the severity of seizures. Moris water maze, Y maze test and novel object recognition was used to determine cognitive comorbidities. An assessment of oxidative stress biomarkers in the hippocampus was performed. Histological evaluation was also performed to quantify neuronal death in CA1 and CA3 using nissl staining. Our results show that supplementing animals with GLE attenuates PTZ-induced cognitive impairment and improves memory and learning deficits. In addition, GLE attenuated seizure severity and oxidative stress by decreasing lipid peroxidation and nitric oxide levels, and increasing superoxide dismutase and catalase activities in the hippocampus. Histopathological analysis also confirmed these results. These results indicate that GLE supplementation has therapeutic impacts on cognitive comorbidities and decreases PTZ damage, which may be associated with reduced oxidative stress in the hippocampus.

1,3,4-Oxadiazole derivatives have attracted substantial attention as promising therapeutic agents for neurodegenerative disorders due to their anti-inflammatory and neuroprotective properties. This study specifically examined a 1,3,4-oxadiazole derivative, i.e.,-{[5-(3-bromophenyl)-1, 3, 4-oxadiazol-2-yl] sulfanyl} ethan-1-ol (abbreviated as OX-1), in the context of multiple sclerosis (MS). Currently, approximately 2.8 million individuals worldwide are living with MS. The study demonstrates the therapeutic potential of OX-1 using the experimental autoimmune encephalomyelitis (EAE) model of MS. Neurobehavioral assessments indicate significant improvements in clinical scoring, motor deficits, muscular strength, and locomotor activity in EAE subjects. Imaging test reveal notable improvements in spinal deformity, further supporting the efficacy of the compound. Comprehensive analyses, including antioxidant assays, RT-PCR, and comet assays, confirm that OX-1 effectively reduces oxidative stress, accompanied by a significant decrease in cytokine expression. Histological examinations reveal critical pathological changes in the hippocampus, cortex, eyes, spinal cord, and optic nerve. The data demonstrate that this compound exhibits neuroprotective effects by activating the Nrf2/HO-1 pathway, thereby reducing oxidative stress and enhancing the antioxidant defense system. Additionally, it suppresses the TLR4/NF-κB pathway, significantly lowering pro-inflammatory cytokine production and immune cell infiltration. Furthermore, molecular docking and simulation studies demonstrate the binding interactions and potential modulatory effects of OX-1 on HO-1 and NF-κB. These results emphasize the therapeutic promise of OX-1 in effectively alleviating the clinical signs and symptoms associated with EAE-induced MS.

Graphical Abstract

The graphical abstract of EAE model of MS.

Non-coding RNA plays an important role in the occurrence and development of Parkinson’s disease (PD). This study only explores the diagnostic value of miR-431-5p in PD and its role in the development of PD. A total of 92 patients with PD were selected as the PD group, and 100 healthy individuals undergoing physical examinations were selected as the control group. The levels of serum miR-431-5p were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic value of serum miR-431-5p for PD. Multivariate Logistic regression was utilized to analyze the risk factors of PD with cognitive impairment. The in vitro PD cell model was constructed by inducing SH-SY5Y cells with MPP⁺, and the effects of miR-431-5p on the proliferation, apoptosis, inflammation, oxidative stress and autophagy of the cell model were explored. Luciferase reporter gene was used to evaluate the interaction between miR-431-5p and its downstream target genes. The expression of miR-431-5p in PD is decreased, and its expression in PD with cognitive impairment is lower than that in PD without cognitive impairment. The diagnostic value of miR-431-5p combined with α-Syn for PD is better than that of a single indicator. Logistics regression analysis demonstrated that total unified Parkinson’s disease rating scale (UPDRS) and miR-431-5p were the risk factors for the occurrence of PD with cognitive impairment. In vitro studies have shown that MPP⁺ induces the inhibition of proliferation and the promotion of apoptosis, autophagy, inflammation and oxidative stress. However, the above effects can be offset by the addition of miR-431-5p mimics. SOX9 is a direct target gene of miR-431-5p, which is upregulated in PD. miR-431-5p is down-regulated in PD and has clinical significance for the early diagnosis of PD. miR-431-5p may play a role in the progression of PD by targeting SOX9.

Multiple sclerosis (MS) is a progressive, immune-mediated demyelinating disorder of the central nervous system (CNS). Kaempferol (KAM), a dietary bioflavonoid found in many edible and medicinal plants, exhibits significant neuroprotective effects in various immunological and neurological disorders; however, its therapeutic potential in MS remains largely unexplored. This study aimed to investigate the protective effects of KAM and the underlying molecular mechanisms using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. 40 female C57B1/6 mice were assigned to 4 groups: Normal control [saline (i.d.) + DMSO (i.p.)]; KAM [saline (i.d.) + KAM (50 mg/kg/d, i.p.)]; EAE [MOG^35–55 immunization (i.d.) + DMSO (i.p.)]; and EAE + KAM [MOG^35–55 immunization (i.d.) + KAM (50 mg/kg/d, i.p.)]. The brain and spinal cord were dissected for biochemical, molecular, histopathological, electron microscopic, and immunohistochemical analysis. KAM administration efficiently reduced clinical scores and ameliorated neural cytomorphological abnormalities. KAM profoundly combated iron overload and effectively upregulated ferroportin1 (Fpn1)-encoding gene expression. Furthermore, KAM valuably counteracted neuronal ferroptosis chiefly by restoring the Slc7A11/GSH/GPX4 axis. KAM considerably attenuated proinflammatory cytokine IL-17 and chemokine CCL-19. Intriguingly, KAM promoted axonal remyelination as indicated by an observable escalation in myelin basic protein content through activating the cAMP/CREB/ciliary neurotrophic factor (CNTF) axis. Collectively, for the first time, these findings demonstrated KAM’s neuroprotective potency against EAE, considering its antioxidant, anti-ferroptotic, immunomodulatory, anti-inflammatory, and neurotrophic properties, primarily mediated by inhibiting Fpn1-mediated ferroptosis, activating the cAMP/CREB/CNTF axis, and enhancing miRNA-367-3p expression. Accordingly, miRNA-367-3p has been proposed as an upcoming therapeutic target for MS, and KAM could be a promising treatment option for MS patients.

REM (rapid eye movement) sleep deprivation causes serious impairments in hippocampus-dependent learning and memory. This study examined whether the angiotensin II receptor blocker telmisartan, given at two different doses, could reduce cognitive deficits and affect molecular pathways related to chronic REM sleep deprivation. Thirty-two male Wistar-Albino rats (200–280 g, 3 months old) were randomly divided into four groups (n = 8): control, sleep deprivation (SD), telmisartan-treated SD groups at 1 mg/kg (SD+Tel1) and 3 mg/kg (SD+Tel3). Chronic REM sleep deprivation was induced for 21 days using the modified multiple platform (MMP) method. Telmisartan or distilled water was administered orally once daily. Cognitive performance was tested in the Morris water maze, assessing escape latency and time spent in the target quadrant. After behavioral tests, hippocampal and prefrontal cortex samples were analyzed for brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), glycogen synthase kinase-3 beta (GSK-3β), monocarboxylate transporter 2 (MCT2), and lactate dehydrogenase (LDH) levels, while plasma samples were analyzed for corticosterone (CORT) levels. Brain levels of malondialdehyde (MDA), reduced glutathione (GSH), nitrate, and glycogen were also measured. Sleep-deprived rats showed impaired learning and memory with longer escape latency and reduced time spent of target quadrant. Telmisartan-treated SD groups demonstrated significantly improved cognitive performance, increased BDNF and CREB expression, decreased GSK-3β levels, and balanced oxidative stress markers. In conclusion, telmisartan protected against cognitive and biochemical damage caused by chronic REM sleep deprivation, likely through modulation of GSK-3β/CREB/BDNF signaling and reduction of oxidative stress.

Stroke is a major cause of mortality and morbidity. It is known to induce gut dysbiosis, which can exacerbate brain injury by increasing systemic inflammation and disrupting the gut-brain axis. This study investigated the effects of probiotics on immunomodulation and brain regeneration in a post-stroke animal model, with a particular focus on gut-brain axis. In this study, Male Wistar rats were divided into three groups: Sham, Ischemia and Ischemia + Probiotic. Focal cerebral ischemia was induced by one-hour middle cerebral artery occlusion (MCAO). The probiotic group received 10⁹ CFU/ml probiotic solution via gavage for 14 days. After 14 days, behavioral outcomes and cerebral infarct volume were assessed. Molecular docking was performed to analyze the binding affinities of probiotic metabolites with TLR4 and FGFR2 which were further validated by RT-PCR gene expression analysis. Serum matrix metalloproteinase-9 activity was evaluated using zymography and oxidative stress was assessed by measuring malondialdehyde, total antioxidant capacity, and nitric oxide levels in the ischemic penumbra. According to the results, the probiotic group showed a significant reduction in infarct volume and improved behavioral deficits. Molecular analysis revealed that probiotics increased nitric oxide levels and total antioxidant capacity while decreasing malondialdehyde levels. Consistent with molecular docking, there was a significant increase in FGFR2 and TLR4 gene expression and matrix metalloproteinase-9 activity. These findings show probiotic supplementation reduces brain damage after stroke, likely via the modulation of FGFR2/TLR4 inflammatory pathway, which could originate from gut microenvironment dysregulation.

The endocannabinoid anandamide (AEA) and the related metabolite oleamide (ODA) have been demonstrated to possess anti-proliferative properties by recruiting apoptotic mechanisms in glioblastoma cells; however, the role of receptors other than the canonical cannabinoid receptors in their pattern of anti-proliferative mechanisms has been poorly investigated. Here, we evaluated the role of mitochondrial function and PPAR-γ membrane receptors in the anti-proliferative mechanisms induced by AEA and ODA in the glioblastoma cell lines C6 and RG2. Cell viability and lipid peroxidation assessments in both cell lines showed antiproliferative and pro-oxidant effects of the tested cannabinoids, respectively, compared to primary astrocyte cultures used as a non-tumor negative control. AEA and ODA also reduced mitochondrial membrane potential in C6, but not in RG2 cells, while impairing mitochondrial Complex I activity in C6. The PPAR-γ receptor antagonist GW9662 showed differential effects on the AEA- and ODA-induced loss of cell viability in both cell lines, as well as in mitochondrial membrane potential. The ontogenetic origin and metabolic differences between RG2 and C6 cell lines may establish differential responses evoked by endogenous cannabinoids and PPAR-γ receptor modulation. Combined, our results demonstrate that AEA and ODA modulate mitochondrial function in glioblastoma cells by inhibiting the activity of mitochondrial Complex 1, which in turn increases markers of oxidative damage and interferes with glioblastoma proliferation.

Graphical Abstract

The endocannabinoids AEA, and its related compound ODA, decrease cell viability and proliferation in C6 and RG2 glioblastoma cells by inducing mitochondrial stress. Depending on the phenotypic and metabolic features of the GB cell line, PPAR-γ receptor can induce anti-proliferative effects mediated by eCB. ODA and AEA exert different mechanisms depending on the cell line; in C6, lipoperoxidation, a decrease in mitochondrial membrane potential, and inhibition of mitochondrial complex I are predominant, while in RG2, sensitivity to PPAR-γ modulation and inhibition of mitochondrial complex I by ODA are more prominent.