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Neuroinflammation has emerged as a crucial factor in the development of depression. Despite the well-known anti-inflammatory properties of 6-gingerol, its potential impact on depression remains poorly understood. This study aimed to investigate the antidepressant effects of 6-gingerol by suppressing microglial activation. In vivo experiments were conducted to evaluate the effect of 6-gingerol on lipopolysaccharide (LPS)-induced behavioral changes and neuroinflammation in rat models. In vitro studies were performed to examine the neuroprotective properties of 6-gingerol against LPS-induced microglial activation. Furthermore, a co-culture system of microglia and neurons was established to assess the influence of 6-gingerol on the expression of synaptic-related proteins, namely synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), which are influenced by microglial activation. In the in vivo experiments, administration of 6-gingerol effectively alleviated LPS-induced depressive behavior in rats. Moreover, it markedly suppressed the activation of rat prefrontal cortex (PFC) microglia induced by LPS and the activation of the NF-κB/NLRP3 inflammatory pathway, while also reducing the levels of inflammatory cytokines IL-1β and IL-18. In the in vitro experiments, 6-gingerol mitigated nuclear translocation of NF-κB p65, NLRP3 activation, and maturation of IL-1β and IL-18, all of which were induced by LPS. Furthermore, in the co-culture system of microglia and neurons, 6-gingerol effectively restored the decreased expression of SYP and PSD95. The findings of this study demonstrate the neuroprotective effects of 6-gingerol in the context of LPS-induced depression-like behavior. These effects are attributed to the inhibition of microglial hyperactivation through the suppression of the NF-κB/NLRP3 inflammatory pathway. [ABSTRACT FROM AUTHOR]

Several pathophysiological processes involve Hypoxia conditions, where the nervous system is affected as well. We postulate that the GABAergic system is especially sensitive. Furthermore, drugs improving the resistance to hypoxia have been investigated, such as the neurosteroid dehydroepiandrosterone sulfate (DHEAS) which has shown beneficial effects in hypoxic processes in mammals; however, at the cellular level, its exact mechanism of action has yet to be fully elucidated. Here, we used a chemical hypoxia model through sodium sulfite (SS) exposure in Caenorhabditis elegans (C. elegans), a nematode whose response to hypoxia involves pathways and cellular processes conserved in mammals, and that allows study the direct effect of DHEAS without its conversion to sex hormones. This work aimed to determine the effect of DHEAS on damage to the GABAergic system associated with SS exposure in C. elegans. Worms were subjected to nose touch response (Not Assay) and observed in epifluorescence microscopy. DHEAS decreased the shrinkage response of Not Assay and the level of damage in GABAergic neurons on SS-exposed worms. Also, the enhanced nuclear localization of DAF-16 and consequently the overexpression of chaperone HSP-16.2 by hypoxia were significantly reduced in SS + DHEAS exposed worms. As well, DHEAS increased the survival rate of worms exposed to hydrogen peroxide. These results suggest that hypoxia-caused damage over the GABAergic system was prevented at least partially by DHEAS, probably through non-genomic mechanisms that involve its antioxidant properties related to its chemical structure. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic–ischemic encephalopathy (HIE) is a major cause of lifelong disabilities worldwide, without effective therapies and clear regulatory mechanisms. MicroRNAs (miRNAs) act as a significant regulator in neuroregeneration and neuronal apoptosis, thus holding great potential as therapeutic targets in HIE. In this study, we established the hypoxia–ischemia (HI) model in vivo and oxygen–glucose deprivation (OGD) model in vitro. Zea-longa score and magnetic resonance imaging were applied to verify HI-induced neuronal dysfunction and brain infarction. Subsequently, a miRNA microarray analysis was employed to profile miRNA transcriptomes. Down-regulated miR-124 was found 24 h after HIE, which corresponded to the change in PC12, SHSY5Y, and neurons after OGD. To determine the function of miR-124, mimics and lentivirus-mediated overexpression were used to regulate miR-124 in vivo and in vitro, respectively. Our results showed that miR-124 overexpression obviously promoted cell survival and suppressed neuronal apoptosis. Further, the memory and neurological function of rats was also obviously improved at 1 and 2 months after HI, indicated by the neurological severity score, Y-maze test, open field test, and rotating rod test. Our findings showed that overexpression of miR-124 can be a promising new strategy for HIE therapy in future clinical practice. [ABSTRACT FROM AUTHOR]

We studied the effects of different modes of hypobaric hypoxia on the content of epigenetic factors acH3K24, meH3K9, and meDNA modulating conformational characteristics of chromatin and gene expression in neurons of associative complex of rat parietal neocortex. Severe destructive hypoxia dramatically reduced the level of acH3K24 in 3 h after the end of exposure and increased meH3K9 and meDNA content. By contrast, 3-fold (but not single) adaptive exposure to moderate hypobaric hypoxia that produced a neuroprotective effect enhanced neuronal acH3K24 expression and decreased both meH3K9 and meDNA levels. Elevated acH3K24 content facilitates, while increased content of meH3K9 hampers binding of transcription factors to the target genes. At the same time, increased expression of meDNA suppresses transcription. The role of modification of epigenetic mechanisms in the regulation of proadaptive genes under the effects of hypoxic exposure according to various protocols is discussed. [ABSTRACT FROM AUTHOR]

Mice infected with LP-BM5 develop a severe immunodeficiency accompanied by learning and memory deficits, gliosis, and neurotransmitter abnormalities. The neurochemical alterations are consistent with elevated excitotoxin levels, suggesting that infected mice may incur neuronal damage. Although the number of neocortical neurons was unchanged in mice 12 wk after LP-BM5 infection, the expression of cytoskeletal proteins declined, particularly in the frontal and parietal cortex as indicated by MAP2, NF-200, and synaptophysin immunoreactivity. In contrast, the number of striatal neurons decreased 19%. The remaining neurons were smaller, with fewer synaptic boutons, and showed decreased synaptophysin and NF-200, immunoreactivity. Immunoblots of cortex and striatum confirmed decreases in MAP2, NF-200 and synaptophysin expression. Finally, although NCAM expression decreased in the striatum, it increased in the cortex. These results indicate that LP-BM5-infected mice sustain significant neuronal damage, which may contribute to their behavioral deficits. Moreover, the increase in cortical NCAM expression suggests active synaptic remodeling to compensate for the persistent excitotoxic environment in these mice, whereas striatal neurons degenerate. These concurrent degenerative and compensatory processes may also occur in the brains of patients with AIDS dementia complex (ADC), who suffer extensive degeneration of the basal ganglia and cerebral cortex. [ABSTRACT FROM AUTHOR]