The neuroprotective mechanism of lithium after ischaemic stroke

Using the MCAO stroke mouse model, Chen et al. identify pathways that underlie the neuroprotective properties of lithium by using inhibitors of AKT/GSK3 beta/beta-catenin and AKT/FoxO3a/beta-catenin signaling. They report that the inhibitors reverse the protective effects of lithium thus conclude that both pathways are key for lithium-mediated neuroprotection. 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/GSK3 beta/beta-catenin and AKT/FoxO3a/beta-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.

Automated summary

This study reveals that lithium inhibits the production of reactive oxygen species (ROS) through two signaling pathways, resulting in neuroprotection and improved functional outcomes in ischemic stroke.