GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke

Abstract

The mood stabilizer lithium inhibits glycogen synthase kinase-3 (GSK-3) directly or indirectly by enhancing serine phosphorylation of both α and β isoforms. Lithium robustly protected primary brain neurons from glutamate-induced excitotoxicity; these actions were mimicked by other GSK-3 inhibitors or silencing/inhibiting GSK-3α and/or β isoforms. Lithium rapidly activated Akt to enhance GSK-3 serine phosphorylation and to block glutamate-induced Akt inactivation. Lithium also up-regulated Bcl-2 and suppressed glutamate-induced p53 and Bax. Induction of brain-derived neurotrophic factor (BDNF) was required for lithium’s neuroprotection to occur. BDNF promoter IV was activated by GSK-3 inhibition using lithium or other drugs, or through gene silencing/inactivation of either isoform. Further, lithium’s neuroprotective effects were associated with inhibition of NMDA receptor-mediated calcium influx and down-stream signaling. In rodent ischemic models, post-insult treatment with lithium decreased infarct volume, ameliorated neurological deficits, and improved functional recovery. Up-regulation of heat-shock protein 70 and Bcl-2 as well as down-regulation of p53 likely contributed to lithium’s protective effects. Delayed treatment with lithium improved functional MRI responses, which was accompanied by enhanced angiogenesis. Two GSK-3-regulated pro-angiogenic factors, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor were induced by lithium. Finally, lithium promoted migration of mesenchymal stem cells (MSCs) by up-regulation of MMP-9 through GSK-3β inhibition. Notably, transplantation of lithium-primed MSCs into ischemic rats enhanced MSC migration to the injured brain regions and improved the neurological performance. Several other GSK-3 inhibitors have also been reported to be beneficial in rodent ischemic models. Together, GSK-3 inhibition is a rational strategy to combat ischemic stroke and other excitotoxicity-related brain disorders.

GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

“…These findings were later confirmed demonstrating that overexpression of GSK-3β impaired activation of HSF-1, whereas HSF-1 activation was facilitated by lithium (Bijur et al 2000). Recently, protective lithium effects were also shown to be associated with improved HSP levels in ischaemic brain injury (Ren et al 2003;Xu et al 2006Xu et al , 2007Rowe and Chuang 2004;Ryves and Harwood 2001;Carmichael et al 2002;Chuang et al 2011).…”

“…Lithium has been reported to be a selective inhibitor of GSK-3β catalytic activity by competition for magnesium (Ryves et al 2002) and to indirectly increase inhibitory phosphorylation of GSK-3β (De Sarno et al 2002). We decided to focus on LiCl as this compound is broadly investigated as standard GSK-3β inhibitor both in clinical and experimental research (Carmichael et al 2002;Chuang et al 2011;Li et al 2011). In our study, LiCl was found to be most effective at concentrations of 10 mM, which is the dose used in the majority of in vitro studies (Lewitt et al 2001;Mantelli and Ledda 1989;Gregory et al 2005;Lucas et al 2010;Li et al 2011).…”

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

“…[46][47][48] Interestingly, GSK-3b is a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. 49 GSK-3b activity has been associated with many psychiatric and neurodegenerative diseases, and it has become increasingly apparent that GSK-3b might be a common therapeutic target for different classes of psychiatric drugs. 50 Thus, Dock3 and GSK-3b could be potential targets for both neuroprotection and regeneration therapy.…”

Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1

“…It is a multifaceted protein that is highly expressed in the mammalian brain and involved in diverse cellular and neurophysiological functions (Chuang et al 2011). One of the most notable qualities of GSK-3 is the vast number of signaling pathways that converge on it, suggesting that it may be an important biological target (Forde and Dale 2007;Miura and Miki 2009).…”