The neuroprotective mechanism of lithium after ischaemic stroke

Beina Chen,Chengyi Dong,Manman Zhang,Wenliang Gong,Baoman Li,Maosheng Xia,Gehua Wen,Ming Ji,Xiafang Wu,Enyu Xu,Binjie Chen,Huiya Yuan,Alexei Verkhratsky,Dianjun Zhang,Yuefei Zhou,Xiaoni Zhan,Xinyu Li

doi:10.1038/s42003-022-03051-2

Abstract

Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. Lithium (Li+), the archetypal mood stabiliser, is neuroprotective in animal models of stroke, albeit underlying mechanisms remain unknown. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3β/β-catenin and AKT/FoxO3a/β-catenin which converge in suppressing the production of reactive oxygen species (ROS). Using immunocytochemstry, MRI imaging, and cell sorting with subsequent mRNA and protein quantification, we demonstrate that Li+ decreases the infarct volume, improves motor function, and alleviates associated cognitive and depressive impairments. In conclusion, this study reveals molecular mechanisms of Li+ neuroprotection during brain ischaemia, thus providing the theoretical background to extend clinical applications of Li+ for treatment of ischemic stroke.

Highlights

Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression
When compared to a control, protein expression of NLRP3, caspase-1 and gasdermin D (GSDMD) increased in neurones (p < 0.001), whereas expressions of caspase-1 and GSDMD increased in astrocytes and microglia (p < 0.001; Fig. 2a–f) in the ipsilateral cortex of middle cerebral artery occlusion (MCAO) mice
Nuclear FoxO3a competes with binding sites of β-catenin with TCF4, and the decrease of nuclear FoxO3a induced by Li+, further enhances formation of βcatenin/TCF4 complexes

Summary

Introduction

Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3β/β-catenin and AKT/FoxO3a/β-catenin which converge in suppressing the production of reactive oxygen species (ROS). Narrow safety range limits the neuroprotective usage of Li+ for ischaemic stroke[20], as well as for associated dementia or depression symptoms[21,22,23]. Accumulation of ROS and oxidative stress contribute to brain injury after ischaemic stroke, with suppression of ROS overproduction being considered as a therapeutic strategy[29]

Methods

Results

Conclusion