Intracerebral hemorrhage (ICH) is a life-threatening subtype of
cerebral stroke with high morbidity and mortality; however, effective treatment for ICH is still lacking.
Adiponectin (APN) is a a kind of fat-derived
plasma protein with beneficial effects in
cerebrovascular disorders. In this study, we aimed to investigate the protective effects of recombinant APN
peptide (APNp) on
brain injury after ICH in adult male C57BL/6J mice and further explored the underlying molecular mechanisms of these effects. APNp treatment exerted dose-dependent
neuroprotective effects including improved neurological function, decreased
brain edema, reduced neural apoptosis, and alleviated blood-brain barrier (BBB) disruption in ICH mice. We found the massive accumulation of APNp on reactive astrocytes around brain microvessels under
hemorrhage conditions by immunofluorescence analysis.
mRNA sequencing (
mRNA-seq) and transcriptome analysis indicated that APNp significantly attenuated the inflammatory response and mitochondrial respiratory dysfunction in astrocytes. Further study revealed that this process was, at least in part, reliant on the inhibition of Drp1-mediated excessive mitochondrial fission. More specifically, APNp increased
AMP-activated protein kinase (AMPK) activation-dependent Drp1
serine 637 (S637) phosphorylation, which inhibited the translocation of Drp1 to the mitochondrial membrane and reduced mitochondrial fragmentation and the production of mitochondrial
superoxide, ultimately attenuating inflammatory
brain injury induced by
hemorrhage. In conclusion, we propose APNp as a potential therapeutic agent for ICH. We provide the first mechanistic evidence that APNp can modulate Drp1-mediated mitochondrial fission, which then contributes to alleviating astrocyte-derived
inflammation.