Microglial decline in the dentate gyrus is an important mechanism in the development of depression-like behaviors in stressed animals. Reversing this decline with low-dose lipopolysaccharide (LPS) can Show more
Microglial decline in the dentate gyrus is an important mechanism in the development of depression-like behaviors in stressed animals. Reversing this decline with low-dose lipopolysaccharide (LPS) can produce rapid antidepressant effects, yet the underlying mechanisms remain incompletely understood. Our previous work identified a critical role for astrocytic P2Y1 receptor (P2Y1R) activation and subsequent dentate gyrus extracellular signal-regulated kinase 1/2 (ERK1/2)-brain-derived neurotrophic factor (BDNF) signaling in the antidepressant effect of low-dose LPS. This study elucidates the signaling cascade linking astrocytic P2Y1R mobilization to the antidepressant effect of low-dose LPS. We found that low-dose LPS promoted glutamate release through ATP-triggered astrocytic P2Y1R signaling. Blockade of N-methyl-D-aspartic acid (NMDA) receptors, but not metabotropic receptors, and the GluN2B subtype of NMDA receptors abolished the antidepressant effect of low-dose LPS. GluN2B knockdown also abolished the reversal effect of low-dose LPS on CUS-induced depression-like behaviors and impairment of dentate gyrus ERK1/2-BDNF signaling. Moreover, chelating intracellular Ca Show less
Pathological neuroinflammation is a critical factor that disrupts neuronal activity and, when sustained, ultimately contributes to neuronal death. Among the primary mediators of neuroinflammation, mic Show more
Pathological neuroinflammation is a critical factor that disrupts neuronal activity and, when sustained, ultimately contributes to neuronal death. Among the primary mediators of neuroinflammation, microglia play a central role in modulating brain immunity. However, their overactivation is closely associated with neuronal damage and structural remodeling of brain tissue, leading to the onset and progression of various neurodegenerative diseases. We investigated the neuroprotective effects of avarol, a marine-derived sesquiterpenoid, focusing on its ability to inhibit lipopolysaccharide (LPS)-induced overactivation of BV2 microglial cells and its subsequent impact on neuronal activity in HT-22 hippocampal neuronal cells. Pretreatment with avarol significantly attenuated the LPS-induced release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), as well as oxidative stress markers such as reactive oxygen species (ROS) and nitric oxide (NO). These inhibitory effects were further substantiated by a dose-dependent reduction in nuclear translocation of nuclear factor-kappa B (NF-κB), a key transcription factor involved in the inflammatory signaling cascade. Regarding the interaction between microglia and neurons, both conditioned medium and co-culture systems demonstrated that avarol significantly attenuated alterations in neuronal plasticity-related molecules-such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)-induced by activated microglia. Overall, these findings suggest that avarol exerts neuroprotective effects through the modulation of microglia-mediated neuroinflammation. Importantly, avarol's capacity to traverse the blood-brain barrier highlights its potential as an effective pharmacological agent in mitigating neuroinflammation-associated neurological disorders. Show less