Neuroscience
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Mecamylamine, a noncompetitive blocker of nicotinic acetylcholine receptors (nAChRs), is the racemic mixture of two stereoisomers: S-(+)-mecamylamine (S-mec) and R-(-)-mecamylamine (R-mec), with distinct interactions with α4β2 nAChRs. It has been shown that mecamylamine increases glutamate release and excites serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN). In this study, we separately evaluated the effects of S-mec and R-mec on 5-HT neuron excitability. ⋯ Moreover, combining S-mec with TC-2559, a selective agonist of HS α4β2 nAChRs, increased firing frequency by 65 %, exceeding the effect of S-mec alone. To validate these findings, we evaluated the antidepressant effects of S-mec (1 mg/kg) combined with TC-2559 or RJR-2403, another α4β2 nAChR agonist. This combination successfully reduced depression-like behaviors, suggesting a potential treatment strategy for patients resistant to conventional antidepressants.
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Depression is a complex disorder with multiple contributing factors, and chronic stress has previously been recognized as a major causative factor, while gut microbes have also been found to be involved in depression recently. However, gene expression in depression models with different etiologies is unclear. Here, we compared the transcriptomes of the striatum in chronic social defeat stress (CSDS) model of C57BL/6J male mice and fecal microbiota transplant (FMT) model of Kumming male mice. ⋯ Further, the alternative splicing events of CSDS are more than FMT. Our results suggested models of depression induced by different etiologies differ significantly in gene expression and biological function. Our study also suggested us to pay attention to the characteristics of models of depression of different etiologies and provided a more comprehensive understanding of the heterogeneity of depression.
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Cerebral ischemia-reperfusion injury is frequently associated with neuroinflammation. The modulation of microglial polarization presents a promising approach for addressing cerebral ischemia-reperfusion injury. While electroacupuncture preconditioning has demonstrated efficacy in the management of ischemic stroke, the underlying therapeutic mechanisms remain inadequately understood. ⋯ After treatment, the number of M1-type microglia decreased, while the number of M2-type microglia increased. These results suggest that EA preconditioning may alleviate neurological deficits and neuronal apoptosis caused by cerebral I/R injury, while maintaining the integrity of the blood-brain barrier and promoting microglial polarization through the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway. Our findings establish a new molecular mechanism and theoretical foundation for electroacupuncture therapy of ischemic stroke.
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The blood-brain barrier's limited permeability to tenofovir restricts its ability to clear HIV from the brain. Probenecid acting as an adjuvant increases tenofovir concentrations in plasma and the kidneys thereby enhancing its therapeutic effect. However, the probenecid effect on brain tenofovir concentration and possible adverse effects remains poorly understood. ⋯ Furthermore, neither tenofovir nor probenecid affected dopamine concentration. In conclusion, probenecid enhances the concentration and retention of tenofovir in the brain, making it a possible pharmacokinetic enhancer. However, its anti-inflammatory effects may require a longer duration to fully manifest.
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This study aims to explore the neuroprotective effects of scalp Electroacupuncture (EA) on ischemic stroke, with a specific focus on the role of electrical stimulation (ES). Employing a rat model of middle cerebral artery occlusion (MCAO), we used methods such as Triphenyl tetrazolium chloride staining, micro-CT scanning, Enzyme linked immunosorbent assay (ELISA), and immunofluorescence to assess the impacts of EA. We further conducted RNA-seq analysis and in vitro experiments with organotypic brain slices and cerebral organoids to explore the underlying mechanisms. ⋯ This was further corroborated by in vitro experiments using organotypic brain slices and cerebral organoids, which showcased the efficacy of electrical stimulation in reducing neuroinflammation and protecting neuronal cells. The study highlights the potential of scalp EA, particularly its ES component, in treating ischemic stroke. It provides new insights into the mechanisms of EA, emphasizing its efficacy in neuroprotection and modulation of neuroinflammation, and suggests avenues for optimized treatment strategies in stroke therapy.