Abstract
BackgroundMicroglia, 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.MethodsThis 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.ResultsIn 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.ConclusionBased 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.
Highlights
Perioperative neurocognitive disorders (PND), common complications that occur after surgery, have recently received significant attention
An agonist of Histamine 2 receptor (H2R) or Histamine 3 receptor (H3R) inhibits exploratory laparotomy-induced microglia activation and Toll-like receptor-4 (TLR4) expression in the rat hippocampus The effects of the H2R/H3R agonists on exploratory laparotomy-induced microglia activation were determined by immunostaining for Ionized calcium-binding adapter molecule 1 (Iba1), which is a marker of microglia
We demonstrated that TLR4 actively participated in the anti-inflammatory effects of H2R/H3R as follows: (i) the expression of TLR4 in the rat hippocampus significantly improved 1 day after exploratory laparotomy, while pretreatment with the H2R/H3R agonists inhibited the expression of TLR4, and (ii) the expression of TLR4 in primary microglia was upregulated by LPS, but pretreatment with the H2R/H3R agonists reduced the expression of TLR4 during LPS challenge
Summary
Perioperative neurocognitive disorders (PND), common complications that occur after surgery, have recently received significant attention. The principal resident immune cells of the central nervous system (CNS), are likely to play a vital role in promoting CNS pathology [4,5,6,7]. The principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). 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. We evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND
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