Recombinant adiponectin peptide promotes neuronal survival after intracerebral haemorrhage by suppressing mitochondrial and ATF4-CHOP apoptosis pathways in diabetic mice via Smad3 signalling inhibition.

OBJECTIVE:Low levels of adiponectin (APN), a biomarker of diabetes mellitus, have been implicated in the poor outcome of intracerebral haemorrhage (ICH). Herein, we aimed to demonstrate the neuroprotective effects of a blood-brain barrier-permeable APN peptide (APNp) on ICH injury in diabetic mice and explore the underlying mechanisms. MATERIALS AND METHODS:Recombinant APNp was administrated intraperitoneally to mice with collagenase-induced ICH. Neurological deficits, brain water content and neural apoptosis were assessed. Western blotting, immunofluorescence staining, quantitative RT-PCR and transmission electron microscopy were used to determine the signalling pathways affected by APNp. RESULTS:Adiponectin peptide significantly alleviated neural apoptosis, neurological deficits and brain oedema following ICH in diabetic mice. Mechanistically, APNp promoted the restoration of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α related mitochondrial function and suppressed activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)-induced neural apoptosis. Furthermore, Smad3 signalling was found to play a regulatory role in this process by transcriptionally regulating the expression of PGC-1α and ATF4. APNp significantly suppressed the elevated phosphorylation and nuclear translocation of Smad3 after ICH in diabetic mice, while the protective effects of APNp on mitochondrial and ATF4-CHOP apoptosis pathways were counteracted when Smad3 was activated by exogenous transforming growth factor (TGF)-β1 treatment. CONCLUSIONS:Our study provided the first evidence that APNp promoted neural survival following ICH injury in the diabetic setting and revealed a novel mechanism by which APNp suppressed mitochondrial and ATF4-CHOP apoptosis pathways in a Smad3 dependent manner.