Title

Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia-Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model

Document Type

Article

Publication Date

10-19-2021

Publication Title

Journal of the American Heart Association

E-ISSN

2047-9980

Abstract

Background Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia-induced blood-brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia-induced HE in a male mouse model of ICH. Methods and Results CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2',4'-trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3-methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin-1/transforming growth factor-β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB-related proteins, ZO-1 and Claudin-5. Conclusions AHR may serve as a potential therapeutic target to attenuate hyperglycemia-induced hematoma expansion and to preserve the BBB in patients with ICH.

Volume

10

Issue

20

First Page

e022701

DOI

10.1161/JAHA.121.022701

PubMed ID

34622690

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