Activation of AdipoR1 with rCTRP9 Preserves BBB Integrity through the APPL1/AMPK/Nrf2 Signaling Pathway in ICH Mice.

Xiu Gong,Wei Zhao,Zaiyu Guo,Fanping Kong,Lianhua Zhao,Sa Wang,Kamil Duris

doi:10.1155/2021/2801263

Abstract

Background The disruption of the blood brain barrier (BBB) is the key factor leading to neurological impairment after intracerebral hemorrhage (ICH) injury. Adiponectin receptor 1 (AdipoR1) has an important effect contributing to the integrity of BBB. As a homologue of adiponectin, recombinant C1q/TNF-related protein 9 (rCTRP9) has neuroprotective effect in cerebrovascular diseases. The aim of this study was to investigate the protective effect of AdipoR1 activation with rCTRP9 on BBB integrity after ICH injury and the potential mechanisms. Methods 177 male mice were subjected in this study. ICH was induced by injecting collagenase into the right basal ganglia. rCTRP9 was treated intranasally at 1 hour after ICH. Selective siRNA was administered prior to ICH. Western blot, immunofluorescence staining, neurobehavioral tests, and BBB permeability were evaluated. Results ICH increased the expression of endogenous AdipoR1 and CTRP9. Administration of rCTRP9 ameliorated neurological deficits and reduced the BBB permeability at 24 hours in ICH mice. Furthermore, rCTRP9 promoted the expression of AdipoR1, APPL1, p-AMPK, Nrf2, and tight junctional proteins. The intervention of specific siRNA of AdipoR1, APPL1, and p-AMPK reversed the protective effects of rCTRP9. Conclusions Activation of AdipoR1 with rCTRP9 improved neurological functions and preserved BBB integrity through the APPL1/AMPK/Nrf2 signaling pathway in ICH mice. Therefore, CTRP9 could serve as a promising therapeutic method to alleviate BBB injury following ICH in patients.

Highlights

Intracerebral hemorrhage (ICH) is the most lethal subtype of all strokes with high mortality and morbidity [1], which often results in neurological damage in survivors
We demonstrated that activation of Adiponectin receptor 1 (AdipoR1) with recombinant C1q/TNF-related protein 9 (rCTRP9) could protect the integrity of blood brain barrier (BBB) following intracerebral hemorrhage (ICH) in mice which is partly mediated by the APPL1/AMPK/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway
Our findings showed that the expression of endogenous AdipoR1 and CTRP9 was increased and reached the peak at 24 hours after ICH injury

Summary

Introduction

Intracerebral hemorrhage (ICH) is the most lethal subtype of all strokes with high mortality and morbidity [1], which often results in neurological damage in survivors. The treatment strategy of reducing the damage of BBB will help to attenuate early brain injury and improve neurological impairments for ICH patients. It has reported that adiponectin exerts brain protective effect mediated by endothelial nitric oxide synthases (eNOS) signaling pathway [8]. They found that adiponectin-KO mice showed larger cerebral infarction size and more severe neurological impairments after cerebral ischemia-reperfusion. The aim of this study was to investigate the protective effect of AdipoR1 activation with rCTRP9 on BBB integrity after ICH injury and the potential mechanisms. Activation of AdipoR1 with rCTRP9 improved neurological functions and preserved BBB integrity through the APPL1/AMPK/Nrf signaling pathway in ICH mice. CTRP9 could serve as a promising therapeutic method to alleviate BBB injury following ICH in patients

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