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.