P2X7R Signaling and Differential Regulation of Neuroinflammatory and Behavior Responses In male and Female Mice During Chronic Ethanol Exposure

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Abstract
Chronic alcohol exposure disrupts blood-brain barrier (BBB) integrity and promotes neuroinflammation, with P2X7 receptor (P2X7R) signaling playing a critical role. Our prior work in male mice linked P2X7R inhibition to reduced extracellular ATP (eATP) release, modulated extracellular vesicle (EV) cargo, and attenuated neuroinflammation in chronic intermittent ethanol (CIE)-exposed mice. However, sex specific roles of P2X7R signaling and EV-mediated mechanisms in alcohol-induced neuroinflammation remain unclear. Male and female mice were exposed to ethanol vapor for three weeks and treated with Brilliant Blue G (BBG), a P2X7R inhibitor. Compared to their respective CIE-unexposed controls, brain gene expression of Tnf-α, Il-1β, Il-6, Mcp-1, and Fasl sig-nificantly increased in CIE-exposed males, while only Il-1β increased in females. P2X7R inhibition significantly reduced these cytokines. Pericyte immunostaining was decreased by CIE (indicating BBB injury) in male mice only and restored by P2X7R inhibition with no difference between groups in females. Occludin staining (another BBB marker) did not differ between the treatment groups in male and female animals. Circulating cytokines (MIP-1α, TNF-α, IL-1β, and IL-27p28/IL-30) were significantly elevated in CIE-exposed males but not in females, with BBG treatment reducing cytokines in males. Circulating eATP, P2X7R, P-glycoprotein, EVs, and EV-mt-DNA that we identified in our previous study were increased in both sexes and partially decreased by P2X7R blockade. Spatial memory was impaired by CIE exposure in males but not females, and this deficit was reversed by BBG treatment. Our findings reveal sex differences in CIE-induced circu-lating cytokines, neuroinflammation, and memory impairment, with a stronger response in males. However, other markers of cell injury associated with CIE exposure were up-regulated in both sexes; P2X7R inhibition effectively mitigated these effects, highlighting the functional relevance of targeting P2X7R in alcohol-induced injury.

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