Ginsenoside Rg1 ameliorates depressive-like behavior by inhibiting NLRP3 inflammasome activation in mice exposed to chronic stress.

Microglia-mediated inflammatory process is recognized as a target in the treatment of depression. Ginsenoside Rg1 (GRg1), the active ingredient of traditional ginseng, regulates microglial phenotypes to resist stress-induced inflammatory responses. Here we used a mouse model of stress-induced depression to investigate the involvement of microglial Nod-like receptor protein 3 (NLRP3) in the antidepressant effects of GRg1. Male C57BL/6J mice were exposed to chronic mild stress (CMS) for three weeks, followed by intraperitoneal injection of GRg1 (20 mg/kg) or the antidepressant imipramine (20 mg/kg) for another three weeks. Depressive-like behaviors were assessed by sucrose preference test, forced swimming test, and tail suspension test. Microglial phenotypes were assessed in terms of morphological features and cytokine profiles; inflammasome activity, in terms of levels of complexes containing NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1; and neurogenesis, in terms of numbers of proliferating, differentiating, and mature neurons identified by immunostaining. GRg1 reduced abnormal animal behaviors caused by CMS, such as anhedonia and desperate behaviors, without affecting locomotor behaviors. GRg1 also reduced the number of ASC-specks, implying inhibition of inflammasome activation, which was associated with weaker activation of pro-inflammatory microglia. At the same time, GRg1 rescued impairment of hippocampal neurogenesis in vivo and in vitro, which correlated with modulation of microglial phenotypes. GRg1 exert antidepressant effects by preventing stress from activating the NLRP3 inflammasome in microglia, promoting a proneurogenic phenotype and allowing adult hippocampal neurogenesis.

Patchouli alcohol ameliorates depression-like behaviors through inhibiting NLRP3-mediated neuroinflammation in male stress-exposed mice.

BACKGROUND: Microglia-mediated neuroinflammation contributes to major depressive disorder (MDD). Targeting microglia is a promising strategy for treating MDD. Patchouli alcohol (PA), an active component of Pogostemon cablin, has anti-inflammatory and neuroprotective effects. PURPOSE: In this study, we investigate the microglia-mediated neurogenesis pathway in which PA ameliorates depressive-like behaviors in stress-induced animal model of depression. METHODS: C57BL/6J male mice were exposed to chronic mild stress (CMS) for 4 weeks, then administered PA intraperitoneally at 10, 20 or 40 mg/kg once per day for 3 weeks. The antidepressant effects of PA were evaluated in the sucrose preference test, forced swimming test, and tail suspension test. Microglial phenotypes and activation of the NLRP3 inflammation were analyzed using RT-PCR, western blotting and immunofluorescence staining. Effects of PA on neurogenesis were analyzed in vitro and in vivo using immunofluorescence staining. RESULTS: Behavioral assessments showed that PA alleviated depressive-like behaviors in CMS-exposed mice. CMS induced microglial activation and pro-inflammatory profiles, which were blocked by PA treatment. PA attenuated the activation of NLRP3 inflammasome, leading to decreases in the levels of caspase-1, ASC, IL-1ß, and IL-18 in the hippocampus of CMS-exposed mice. In primary microglia cultures, PA inhibited LPS-induced NLRP3 inflammasome activation. PA rescued inflammation-inhibited neurogenesis in vivo and in vitro. CONCLUSIONS: Our results suggest that PA inhibits the NLRP3 inflammasome and ameliorates microglia-mediated neurogenesis impairment, contributing to antidepressant effects. Thus, PA may be a novel treatment for inflammation-driven mental disorders.

Pioglitazone alleviates maternal sleep deprivation-induced cognitive deficits in male rat offspring by enhancing microglia-mediated neurogenesis.

Maternal sleep disturbance in pregnancy causes cognitive impairments and emotional disorders in offspring. Microglia-mediated inflammatory processes contribute to prenatal stress-induced neurodevelopmental deficits. Peroxisome proliferator-activated receptor gamma (PPARγ) activation underlies the switching of microglial activation phenotypes, which has emerged as a pharmacological target for regulating neuroinflammatory responses in the treatment of neuropsychiatric disorders. Here we investigated the effects of PPARγ-dependent microglial activation on neurogenesis and cognitive behavioral outcomes in male rat offspring exposed to maternal sleep deprivation (MSD) for 72 h from days 18-21 of pregnancy. In the Morris water maze test, male MSD rat offspring needed more time than control offspring to escape to the hidden platform and spent less time in the target quadrant when the hidden platform was removed. In MSD rat offspring, microglial density as determined by immunofluorescence was higher, microglia showed fewer and shorter processes, and neurogenesis in the hippocampus was significantly reduced. Levels of mRNA encoding pro-inflammatory markers IL-6, TNFα, and IL-1ß were higher in male MSD offspring, whereas levels of anti-inflammatory markers Arg1, IL-4, and IL-10 were lower, as was PPARγ expression in the hippocampus. PPARγ activation by pioglitazone (30 mg/kg/day, i.p., 7 d) mitigated these negative effects of MSD, rescuing hippocampal neurogenesis and improving cognitive function. The PPARγ inhibitor GW9662 (1 mg/kg/day, i.p., 7 d) eliminated the effects of pioglitazone. Conditioned medium from pioglitazone-treated microglia promoted proliferation and differentiation of neural progenitor cells. These results suggest that MSD-induced deficits in spatial learning and memory can be ameliorated through PPARγ-dependent modulation of microglial phenotypes.