Curcumin Ameliorates White Matter Injury after Ischemic Stroke by Inhibiting Microglia/Macrophage Pyroptosis through NF-κB Suppression and NLRP3 Inflammasome Inhibition.

Yuanyuan Ran,Lin Ye,Wei Su,Fuhai Gao,Xuechai Chen,Jianing Xi,Zongjian Liu,Shuiqing Yang,Zitong Ding,Guiqin Tian,Wen-Jun Tu

doi:10.1155/2021/1552127

Abstract

NLRP3 inflammasome-mediated pyroptosis is a proinflammatory programmed cell death pathway, which plays a vital role in functional outcomes after stroke. We previously described the beneficial effects of curcumin against stroke-induced neuronal damage through modulating microglial polarization. However, the impact of curcumin on microglial pyroptosis remains unknown. Here, stroke was modeled in mice by middle cerebral artery occlusion (MCAO) for 60 minutes and treated with curcumin (150 mg/kg) intraperitoneally immediately after reperfusion, followed by daily administrations for 7 days. Curcumin ameliorated white matter (WM) lesions and brain tissue loss 21 days poststroke and improved sensorimotor function 3, 10, and 21 days after stroke. Furthermore, curcumin significantly reduced the number of gasdermin D+ (GSDMD+) Iba1+ and caspase-1+Iba1+ microglia/macrophage 21 days after stroke. In vitro, lipopolysaccharide (LPS) with ATP treatment was used to induce pyroptosis in primary microglia. Western blot revealed a decrease in pyroptosis-related proteins, e.g., GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18, following in vitro or in vivo curcumin treatment. Mechanistically, both in vivo and in vitro studies confirmed that curcumin inhibited the activation of the NF-κB pathway. NLRP3 knocked down by siRNA transfection markedly increased the inhibitory effects of curcumin on microglial pyroptosis and proinflammatory responses, both in vitro and in vivo. Furthermore, stereotaxic microinjection of AAV-based NLRP3 shRNA significantly improved sensorimotor function and reduced WM lesion following curcumin treatment in MCAO mice. Our study suggested that curcumin reduced stroke-induced WM damage, improved functional outcomes, and attenuated microglial pyroptosis, at least partially, through suppression of the NF-κB/NLRP3 signaling pathway, further supporting curcumin as a potential therapeutic drug for stroke.

Highlights

Stroke remains the leading cause of death and long-term disability all over the world with ischemic stroke accounting for approximately 85% of all cases
To verify the beneficial effects of curcumin on white matter damage and functional outcome poststroke, infarction was induced in mice through middle cerebral artery occlusion (MCAO) and treated with curcumin intraperitoneal injection immediately after reperfusion
Our previous study revealed that curcumin treatment improved neurological function during the early disease stage in a distal MCAO model [21]

Summary

Introduction

Stroke remains the leading cause of death and long-term disability all over the world with ischemic stroke accounting for approximately 85% of all cases. Recanalization of the occluded blood vessels with thrombolytic/thrombectomy therapies is the preferred treatment for acute ischemic stroke. Many ischemic stroke patients are ineligible for these treatments due to the narrow therapeutic time window and the risk of intracerebral hemorrhage. White matter injury is one of the major pathophysiological processes involved in ischemic stroke [2]. White matter injury, characterized as demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor deficits and cognitive impairments [2, 3]. Compelling evidence shows that endogenous or intervention-dependent white matter repairs, including remyelination, axon preservation, and oligodendrogenesis, can reverse structural disruption, rebuild the neural circuitry, and restore function [4, 5]

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