Activation of UCP2 by anethole trithione suppresses neuroinflammation after intracerebral hemorrhage

Xiao-ling Yan1,2, Fu-you Xu3, Jing-jing Ji3, Peng Song3, Ya-qin Pei2, Mei-jun He2, Zi-chuang Wang3, Shou-jiang You1, Zi-chun Hua4, Jian Cheng1,3, Jia Jia2
1 Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215123, China
2 Jiangsu Key Laboratory of Neuropsychiatric Diseases & College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
3 Jiangsu Key Laboratory of Neuropsychiatric Diseases & Institute of Neuroscience, Soochow University, Suzhou 215123, China
4 School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, China
Correspondence to: Zi-chun Hua:, Jian Cheng:, Jia Jia:,
DOI: 10.1038/s41401-021-00698-1
Received: 28 December 2020
Accepted: 14 May 2021
Advance online: 28 June 2021


Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/ macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg−1 ·d−1, ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.
Keywords: intracerebral hemorrhage; uncoupling protein 2; mitochondrial uncoupling; AMP-activated protein kinase; neuroinflammation; microglia; anetholetrithione; FCCP

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