Systemic treatment with GnRH agonist produces antidepressant-like effects in LPS induced depression male mouse model.

Gonadotropin-releasing hormone (GnRH) is at the head of the neuroendocrine reproductive axis. However, the non-reproductive functions of GnRH expressed in various tissues, including hippocampus, are still not known. Here, we unveil a previously unknown effect of GnRH, which mediates depression-like behaviors through the modulation of microglia function during immune challenge. Specifically, we found that either systemic treatment with GnRH agonist or over-expression of endogenous hippocampal GnRH via viral tool abolished the depression-like behavior after LPS challenges in mice. And the anti-depressant of GnRH was dependent on the hippocampal GnRHR signaling, since antagonizing GnRHR by drug treatment or by hippocampal GnRHR knockdown could block the antidepressant-effect of GnRH agonist. Interestingly, we found that the peripheral GnRH treatment prevented the microglia activation mediated inflammation in the hippocampus of mice. In light of the research findings presented here, we propose that, at least in the hippocampus, GnRH appears to act on GnRHR to regulate higher order non-reproductive functions associated with the microglia mediated neuroinflammation. These findings also provide insights into the function and cross-talk of GnRH, a known neuropeptide hormone, in neuro-immune response.

Hyperactivation of TRPV4 causes the hippocampal pyroptosis pathway and results in cognitive impairment in LPS-treated mice.

Pyroptosis, a newly discovered proinflammatory programmed cell death, is involved in the regulation of cognitive dysfunction, such as Alzheimer's disease. Exploring potential drug targets that prevent pyroptotic procedures might benefit the development of a cure for these diseases. In the present study, we explored whether the transient receptor potential vanilloid 4 (TRPV4) blocker HC067047 and knockdown of TRPV4 in the hippocampus could improve cognitive behavior through the inhibition of pyroptosis in a mouse model developed using systemic administration of lipopolysaccharide (LPS). We found that systemic administration of HC067047 or knockdown of hippocampal TRPV4 prevented the activation of canonical and noncanonical pyroptosis in the hippocampus of LPS-treated mice. Consistent with the inhibition of the hippocampal pyroptosis pathway, a knockdown of hippocampal TRPV4 lowered expression of TNF-α, IL-1ß, IL-18, and IL-6. Furthermore, we verified that the main pyroptosis cell type might be a neuron, indicated by reduced neuronal marker expression. Mechanically, we also found that knockdown of hippocampal TRPV4 might inhibit phosphorylation of CamkⅡα which results in NFκb mediated inflammasome reduction in the hippocampus of LPS-treated mice. More interestingly, mice intraperitoneally injected with HC067047 or the hippocampus injected with TRPV4 shRNA showed improved cognitive behavior, as indicated by the enhanced discrimination ratio in the NORT, NOPT, and SNPT. Collectively, we consider that HC067047 might be a small molecular drug that prevents pyroptosis, and TRPV4 could be an effective therapeutic target for preventing pyroptosis-induced cognitive dysfunction.

Alternate-day fasting for the protection of cognitive impairment in c57BL/6J mice following whole-brain radiotherapy.

NLRP3 inflammasome activation is implicated in irradiation-induced cognitive dysfunction. Alternate-day fasting (ADF) has been demonstrated to improve neuroinflammation as a non-pharmacological intervention. However, the exact mechanism and the anti-inflammatory effect in irradiation-induced cognitive dysfunction still need further in-depth study. The present study examined the effects of eight-week ADF on the cognitive functions of mice as well as inflammasome-mediated hippocampal neuronal loss following irradiation in mouse models of irradiation-induced cognitive deficits using seven-week-old male C57BL/6J mice. The behavioral results of novel place recognition and object recognition tasks revealed that ADF ameliorated cognitive functions in irradiation-induced cognitive dysfunction mice. ADF inhibited the expression of components of the NLRP3 inflammasome (NLRP3, ASC, and Cl.caspase-1), the downstream inflammatory factor (IL-1ß and IL-18), and apoptosis-related proteins (caspase-3) via western blotting. Furthermore, an increased number of neurons and activated astrocytes were observed in the hippocampus using immunohistochemistry and Sholl analysis, which was jointly confirmed by western blotting. According to our study, this is the first time we found that ADF improved cognitive dysfunction induced by irradiation, and the anti-inflammatory effect of ADF could be due to inhibition in NLRP3-mediated hippocampal neuronal loss by suppressing astrocyte activation.

CCDC26 rs4295627 polymorphisms associated with an increased risk of glioma: A meta-analysis.

BACKGROUND: Gliomas are the most common primary brain tumor in adults. Many studies have revealed associations between the rs4295627 polymorphism in the coiled-coil domain containing 26 (CCDC26) gene and the risk of glioma. However, the conclusions are still unclear because some studies have reported inconsistent results. OBJECTIVES: The aim of the present meta-analysis was to determine the relationship and quantitatively evaluate the effect of the rs4295627 polymorphism on the risk of glioma. MATERIAL AND METHODS: Data was extracted from PubMed, EMBASE and Google Scholar, with the most recent search up to December, 2015. Odds ratios (OR) and their 95% CIs were used to evaluate the effect of CCDC26 rs4295627 polymorphisms on glioma. A test of heterogeneity and an assessment of publication bias were also performed. RESULTS: A total of 11 studies (8292 cases and 12,419 controls) were selected for this meta-analysis. Significant associations were observed in all genetic analysis models (G vs T: OR = 1.26, 95% CI = 1.12-1.43; GG vs TT: OR = 1.72, 95% CI = 1.24-2.39; GT vs TT: OR = 1.33, 95% CI = 1.24-1.42; GG + GT vs TT: OR = 1.36, 95% CI = 1.20-1.53; GG vs GT + TT: OR = 1.65, 95% CI = 1.18-2.29, respectively). CONCLUSION: The results of the present study clearly show that the G allele of the rs4295627 polymorphism significantly increases the risk of glioma. Nevertheless, well-designed large-scale studies are needed to further evaluate the effect of the rs4295627 polymorphism on different types or degrees of glioma in different ethnic groups as well as to measure the combined effects on glioma risk.