Neurochemical Research最新文献

A ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that exerts antiepileptic effects by attenuating spontaneous recurrent seizures, ameliorating learning and memory impairments, and modulating the gut microbiota composition. However, the role of the gut microbiome in the antiepileptic effects of a KD on temporal lobe epilepsy (TLE) induced by lithium-pilocarpine in adult rats is still unknown. Our study provides evidence demonstrating that a KD effectively mitigates seizure behavior and reduces acute-phase epileptic brain activity and that KD treatment alleviates hippocampal neuronal damage and improves cognitive impairment induced by TLE. We also observed that the beneficial effects of a KD are compromised when the gut microbiota is disrupted through antibiotic administration. Analysis of gut microbiota components via 16S rRNA gene sequencing in fecal samples collected from TLE rats fed either a KD or a normal diet. The Chao1 and ACE indices showed decreased species variety in KD-fed rats compared to TLE rats fed a normal diet. A KD increased the levels of Actinobacteriota, Verrucomicrobiota and Proteobacteria and decreased the level of Bacteroidetes. Interestingly, the abundances of Actinobacteriota and Verrucomicrobiota were positively correlated with learning and memory ability, and the abundance of Proteobacteria was positively correlated with seizure susceptibility. In conclusion, our study revealed the significant antiepileptic and neuroprotective effects of a KD on pilocarpine-induced epilepsy in rats, primarily mediated through the modulation of the gut microbiota. However, whether the gut microbiota mediates the antiseizure effects of a KD still needs to be better elucidated.

Neuropsychiatric and neurological disorders pose a significant global health burden, highlighting the need for innovative therapeutic approaches. Fingolimod (FTY720), a common drug to treat multiple sclerosis, has shown promising efficacy against various neuropsychiatric and neurological disorders. Fingolimod exerts its neuroprotective effects by targeting multiple cellular and molecular processes, such as apoptosis, oxidative stress, neuroinflammation, and autophagy. By modulating Sphingosine-1-Phosphate Receptor activity, a key regulator of immune cell trafficking and neuronal function, it also affects synaptic activity and strengthens memory formation. In the hippocampus, fingolimod decreases glutamate levels and increases GABA levels, suggesting a potential role in modulating synaptic transmission and neuronal excitability. Taken together, fingolimod has emerged as a promising neuroprotective agent for neuropsychiatric and neurological disorders. Its broad spectrum of cellular and molecular effects, including the modulation of apoptosis, oxidative stress, neuroinflammation, autophagy, and synaptic plasticity, provides a comprehensive therapeutic approach for these debilitating conditions. Further research is warranted to fully elucidate the mechanisms of action of fingolimod and optimize its use in the treatment of neuropsychiatric and neurological disorders.

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.

Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic strategy that shows promise in ameliorating the clinical sequelae following traumatic brain injury (TBI). These improvements are associated with neuroplastic changes in neurons and their synaptic connections. However, it has been hypothesized that rTMS may also modulate microglia and astrocytes, potentially potentiating their neuroprotective capabilities. This study aims to investigate the effects of high-frequency rTMS on microglia and astrocytes that may contribute to its neuroprotective effects. Feeney’s weight-dropping method was used to establish rat models of moderate TBI. To evaluate the neuroprotective effect of high frequency rTMS on rats by observing the synaptic ultrastructure and the level of neuron apoptosis. The levels of several important inflammation-related proteins within microglia and astrocytes were assessed through immunofluorescence staining and western blot. Our findings demonstrate that injured neurons can be rescued through the modulation of microglia and astrocytes by rTMS. This modulation plays a key role in preserving the synaptic ultrastructure and inhibiting neuronal apoptosis. Among microglia, we observed that rTMS inhibited the levels of proinflammatory factors (CD16, IL-6 and TNF-α) and promoted the levels of anti-inflammatory factors (CD206, IL-10 and TNF-β). rTMS also reduced the levels of pyroptosis within microglia and pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, IL-1β and IL-18). Moreover, rTMS downregulated P75NTR expression and up-regulated IL33 expression in astrocytes. These findings suggest that regulation of microglia and astrocytes is the mechanism through which rTMS attenuates neuronal inflammatory damage after moderate TBI.

Neurotrophin-3 (NT-3) is an important family of neurotrophic factors with extensive neurotrophic activity, which can maintain the survival and regeneration of nerve cells. However, the mechanism of NT-3 on macrophage phenotype transformation after sciatic nerve injury is not clear. In this study, we constructed a scientific nerve compression injury animal model and administered different doses of NT-3 treatment through osmotic minipump. 7 days after surgery, we collected sciatic nerve tissue and observed the distribution of macrophage phenotype through iNOS and CD206 immunofluorescence. During the experiment, regular postoperative observations were conducted on rats. After the experiment, sciatic nerve tissue was collected for HE staining, myelin staining, immunofluorescence staining, and Western blot analysis. To verify the role of the AMPK/NF-κB pathway, we applied the AMPK inhibitor Compound C and the NF-κB inhibitor BAY11-7082 to repeat the above experiment. Our experimental results reveal that NT-3 promotes sciatic nerve injury repair and polarization of M2 macrophage phenotype, promotes AMPK activation, and inhibits NF-κB activation. The repair effect of high concentration NT-3 on sciatic nerve injury is significantly enhanced compared to low concentration. Compound C administration can weaken the effect of NT-3, while BAY 11-7082 can enhance the effect of NT-3. In short, NT-3 significantly improves sciatic nerve injury in rats, promotes sciatic nerve function repair, accelerates M2 macrophage phenotype polarization, and improves neuroinflammatory response. The protective effects of NT-3 mentioned above are partially related to the AMPK/NF-κB signal axis.

Despite the increase in the prevalence of postpartum depression among maternal disorder, its treatment outcomes remain suboptimal. Studies have shown that exercise can reduce postpartum depressive episodes in the mother, but the effects of exercise during pregnancy on maternal behavior and the potential mechanisms involved remain poorly understood. From the second day of pregnancy to the day of birth, dams exercised for 1 h a day by running on a controlled wheel. The maternal behaviors of the dams were assessed on postpartum day 2 to postpartum day 8. Chronic restraint stress was applied from postpartum day 2 to day 12. Blood was collected on postpartum days 3 and 8, then subjected to ELISA to determine the serum concentration of prolactin. The weight of each dam and the food intake were recorded. Anxiety- and depression-like behavioral tests were conducted, and hippocampal neuroinflammation and prolactin receptor levels were measured. The dams exhibited elevated levels of anxiety and depression, decreased serum prolactin levels, decreased prolactin receptor expression, and activation of NLRP3-mediated neuroinflammation in the hippocampus following the induction of postpartum chronic restraint stress, which were reversed with controlled wheel running during pregnancy. Overall, the findings of this study revealed that the preventive effects of exercise during pregnancy on postpartum anxiety-and depression-like behaviors were accompanied by increased serum prolactin levels, hippocampal prolactin receptor expression and hippocampal NLRP3-mediated neuroinflammation.

Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.

The glucose analogue 2-deoxyglucose (2DG) has frequently been used as a tool to study cellular glucose uptake and to inhibit glycolysis. Exposure of primary cultured astrocytes to 2DG caused a time- and concentration-dependent cellular accumulation of 2-deoxyglucose-6-phosphate (2DG6P) that was accompanied by a rapid initial decline in cellular ATP content. Inhibitors of mitochondrial respiration as well as inhibitors of mitochondrial uptake of pyruvate and activated fatty acids accelerated the ATP loss, demonstrating that mitochondrial ATP regeneration contributes to the partial maintenance of the ATP content in 2DG-treated astrocytes. After a 30 min exposure to 10 mM 2DG the specific content of cellular 2DG6P had accumulated to around 150 nmol/mg, while cellular ATP was lowered by 50% to around 16 nmol/mg. Following such a 2DG6P-loading of astrocytes, glycolytic lactate production from applied glucose was severely impaired during the initial 60 min of incubation, but was reestablished during longer incubation concomitant with a loss in cellular 2DG6P content. In contrast to glycolysis, the glucose-dependent NADPH regeneration via the pentose phosphate pathway (PPP) was only weakly affected in 2DG6P-loaded astrocytes and in cells that were coincubated with glucose in the presence of an excess of 2DG. Additionally, in the presence of 2DG PPP-dependent WST1 reduction was found to have doubled compared to hexose-free control incubations, indicating that cellular 2DG6P can serve as substrate for NADPH regeneration by the astrocytic PPP. The data presented provide new insights on the metabolic consequences of a 2DG exposure on the energy and glucose metabolism of astrocytes and demonstrate the reversibility of the inhibitory potential of a 2DG-treatment on the glucose metabolism of cultured astrocytes.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-β-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-β. NFPS pretreatment prevented amyloid-β-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-β injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-β-induced hippocampal damage.

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