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

Abstract

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.

Histamine, Neuroinflammation and Neurodevelopment: A Review

“…the release of the anti-inflammatory cytokine interleukin-10 (IL-10). This is further supported by both Chen et al (2020) who found that H 2 and H 3 receptor agonism inhibited laparotomyor LPS-induced microglial activation, pro-inflammatory cytokine production and cognitive decline and by Fang et al (2020) whereby H 4 receptor antagonism reduced microglial activation and TNF-α release in a rat model of Parkinson's disease. Along with histamine's ability to induce microglial activation and the subsequent release of both anti-and pro-inflammatory factors, it can also promote phagocytosis via H 1 receptor activation and the production of reactive oxygen species (Rocha et al, 2016) and prostaglandin E2 (Lenz et al, 2018).…”

Galectin‐1 ameliorates perioperative neurocognitive disorders in aged mice

“…Emerging emphasis has been put on the role of neuroinflammation in the progression of PND 24,25 . Characterized by producing inflammatory mediators that facilitate the development and severity of PND, microglia play a crucial role in the progression of PND 26,27 . In a mouse model of PND, we investigate the correlation between galectin‐1 treatment and neurocognitive dysfunction.…”

The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

“…Changes in microglial signature induced by peripheral inflammation can translate into alterations in neuronal and synaptic functions. For instance, postoperative cognitive dysfunction is associated with microglia-induced neuroinflammation triggered by operation-induced peripheral inflammation [ 105 , 106 , 107 ]. TNF, IL-6 and IL-1β generated by microglia can profoundly affect synaptic transmission and plasticity and underlie cognitive and behavioral alterations occurring in peripheral inflammatory disease [ 108 , 109 , 110 , 111 , 112 ].…”