Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice

Background: Neuroinflammation is a crucial factor contributing to neurological injuries after intracerebral hemorrhage (ICH). C1WINF-related protein 9 (CTRP9), an agonist of adiponectin receptor 1 (AdipoR1), has recently been shown to reduce inflammatory responses in systemic diseases. The objective of this study was to investigate the protective role of CTRP9 against neuroinflammation after ICH in a mouse model and to explore the contribution of adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor kappa B (NF kappa B) pathway in AdipoR1-mediated protection. Methods: Adult male CD1 mice (n = 218) were randomly assigned to different groups for the study. ICH was induced via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administered intranasally at 1 h after ICH. To elucidate the underlying mechanism, AdipoR1 small interfering ribonucleic acid (siRNA) and selective phosphorylated AMPK inhibitor Dorsomorphin were administered prior to rCTRP9 treatment. Brain edema, short- and long-term neurobehavior evaluation, blood glucose level, western blot, and immunofluorescence staining were performed. Results: Endogenous CTRP9 and AdipoR1 expression was increased and peaked at 24 h after ICH. AdipoRl was expressed by microglia, neurons, and astrocytes. Administration of rCTRP9 reduced brain edema, improved short- and long-term neurological function, enhanced the expression of AdipoRl and p-AMPK, and decreased the expression of phosphorylated NF kappa B and inflammatory cytokines after ICH. The protective effects of rCTRP9 were abolished by administration of AdipoR1 siRNA and Dorsomorphin. Conclusions: Our findings demonstrated that administration of rCTRP9 attenuated neuroinflammation through AdipoR1/AMPK/NF kappa B signaling pathway after ICH in mice, thereby reducing brain edema and improving neurological function after experimental ICH in mice. Therefore, CTRP9 may provide a potential therapeutic strategy to alleviate neuroinflammation in ICH patients.