Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects

Abstract

The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…24 Neurogenesis is responsible for the differentiation and survival of new neurons necessary to maintain the neural circuitry in the adult brain. 25 Much interest is now focused on the idea that BD may be caused by a decline in the action of neurotrophins, such as BDNF, which regulate this process of neurogenesis. 25 Patients with depression have low serum levels of BDNF.…”

“…25 Much interest is now focused on the idea that BD may be caused by a decline in the action of neurotrophins, such as BDNF, which regulate this process of neurogenesis. 25 Patients with depression have low serum levels of BDNF. Some of the most effective mood stabilizing drugs, such as lithium (Li + ) and valproate, act by modulating downstream intracellular signaling pathways that regulate both neurogenesis and membrane excitability (Fig.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…A Phase II clinical trial studying the effect of lithium treatment in patients with AD is currently underway (ClinicalTrials.gov identifier: NCT00088387), and in a small cohort of patients lithium reduced the progression from mild cognitive impairment to full AD 55 . In addition to increasing BDNF levels, lithium also inhibits the hyperphosphorylation of Tau mediated by GSK3β and has additional beneficial effects in the activation of pro-survival CREB signalling and the activation of autophagy [56][57][58][59] ( Figure 2, and see below). Due to these multiple effects, lithium is a suboptimal tool compound to investigate specific pathways, but remains a potential therapeutic.…”

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

“…In the present study, we investigated the possibility that sub-effective doses of ketamine when combined with lithium, a nonselective GSK-3 inhibitor, could mimic the synaptogenic and antidepressant effects observed with the tenfold higher effective dose of ketamine (Li et al, 2010). However, given the diverse actions of lithium (Quiroz et al, 2010), we also investigated whether a preferential GSK-3b inhibitor could mimic potentiating effects of lithium on subthreshold doses of ketamine.…”