Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.