Therapeutic window of globular adiponectin against cerebral ischemia in diabetic mice: the role of dynamic alteration of adiponectin/adiponectin receptor expression.

Wenying Song,Fan Guo,Lixin Liu,Lize Xiong,Rui Yang,Haixing Zhong,Qiang Wang

doi:10.1038/srep17310

Abstract

Recent studies have demonstrated that adiponectin (APN) attenuates cerebral ischemic/reperfusion via globular adiponectin (gAD). However, the therapeutic role of gAD in cerebral ischemic injury in type 1 diabetes mellitus (T1DM) remains unclear. Our results showed that gAD improved neurological scores and reduced the infarct volumes in the 8-week T1DM (T1DM-8W) mice, but not in the 2-week T1DM (T1DM-2W) mice. Moreover, the ischemic penumbra APN levels increased and peaked in T1DM-2W mice, and reduced to normal in T1DM-8W mice, while the APN receptor 1 (AdipoR1) expression change was the opposite. Administration of rosiglitazone in T1DM-2W mice up-regulated the expression of AdipoR1 and restored the neuroprotection of gAD, while intracerebroventricular injection of AdipoR1 small interfering RNA (siRNA) in T1DM-8W mice reversed it. Furthermore, the expression of p-PERK, p-IRE1 and GRP78 were increased whereas the expressions of CHOP and cleaved caspase-12 as well as the number of apoptotic neurons were decreased after gAD treatment in T1DM-8W mice. These beneficial effects of gAD were reversed by pretreatment with AdipoR1 siRNA. These results demonstrated a dynamic dysfunction of APN/AdipoR1 accompanying T1DM progression. Interventions bolstering AdipoR1 expression during early stages and gAD supplementation during advanced stages may potentially reduce the cerebral ischemic injury in diabetic patients.

Highlights

Adiponectin (APN) is regarded as an adipocyte-specific adipocytokine
Previous studies suggested the protective action of APN via an endothelial nitric oxide synthase-dependent mechanism, while Chen et al confirmed the anti-inflammatory action of APN against cerebral ischemia/reperfusion (I/R) injury[6]
Diabetes mellitus (DM) group showed a significant decrease in infarct size 24 h after I/R compared with the I/R group (P = 0.009)

Summary

Introduction

Adiponectin (APN) is regarded as an adipocyte-specific adipocytokine. Primary sequence analysis has revealed that full-length APN has four main domains, with the globular segment (gAD) at the carboxy terminus being much more potent than the full protein[4]. A previous study has confirmed that APN enhances tolerance against brain ischemia, with APN-KO mice suffering greater infarct volumes than wild-type mice[5]. Previous studies suggested the protective action of APN via an endothelial nitric oxide synthase-dependent mechanism, while Chen et al confirmed the anti-inflammatory action of APN against cerebral ischemia/reperfusion (I/R) injury[6]. The contribution of other mechanisms to the neuroprotective action of APN requires further investigation. Recent data has suggested that the protective effect of gAD against myocardial I/R was modulated through suppressing of ER stress[11]. The current study aimed to investigate the neuroprotective effect of gAD on diabetic cerebral I/R model and further explore the underlying mechanisms. We assumed that with a proper therapeutic window, gAD could induce an anti-apoptotic effect against cerebral I/R injury through ER stress-related signaling pathway

Methods

Results

Conclusion