Lithium: from mood stabilizer to putative cognitive enhancer

The monovalent cation lithium, whose introduction in psychiatry dates back at the end of the 1940s, remains the first-line agent in the management of patients with bipolar disorder (BD). It is effective in the treatment of moderate-to-severe acute mania, prophylactic for recurrent manic and depressive episodes, and reduces the risk of suicide. It can also boost antidepressants effects in the treatment of major depressive disorder (Albert et al., 2014). More recently, a growing body of evidence seems to suggest that the benefits of lithium extend beyond mood stabilization. In vitro, lithium has been shown to provide neuroprotection against excitotoxicity induced by glutamate and N-methyl-D-aspartate (NMDA) receptor activation, calcium, thapsigargin, β-amyloid, aging, serum/growth factor deprivation, low potassium concentration, C2-ceramide, aluminum, ouabain, and specific HIV regulatory proteins. Lithium's neuroprotective effects have further been demonstrated in a series of in vivo animal models of ischemic/hemorrhagic stroke, traumatic brain/spinal cord injury (TBI/SCI), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), Parkinson's disease (PD), retinal degeneration, multiple sclerosis (MS), alcohol-induced degeneration, Down syndrome, spinocerebellar ataxia-1, HIV-associated neurotoxicity, and irradiation (Chiu et al., 2013). In spite of this, very little is understood about its mechanism of action. Recent research findings indicate that lithium's neuroprotective effects may stem, at least in part, from its ability to inhibit the glycogen synthase kinase-3β (GSK-3β) by directly binding to its enzyme's magnesium-sensitive site and indirectly by enhancing phosphorylation of this kinase at specific serine residues. Indeed lithium's direct inhibition of GSK-3β leads to activation of several transcription factors, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), heat-shock factor-1 (HSF-1), and β-catenin, with subsequent induction of major neurotrophic, angiogenic, anti-inflammatory, and anti-apoptotic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), heat shock protein 70 (HSP70), and B-cell lymphoma/leukemia-2 protein (Bcl-2), respectively. Suppressed GSK-3β further reduces the activity of the pro-apoptotic proteins p53 and Bax and their negative regulatory action on Bcl-2. Noteworthy, BDNF and NGF have been reported to function as both downstream molecules resulting from the inhibition of GSK-3β and upstream signals able to inhibit this molecular pathway via specific survival signaling cascades such as the phosphatidylinositol-3-kinase (PI3K)/Akt and the MAP kinase (MEK)/ERK pathways. Lithium also indirectly inhibits GSK-3β via PI3K-dependent activation of protein kinase C (PKC), cAMP-dependent activation of protein kinase A (PKA), and the Wnt/β-catenin pathway (via Frizzled receptors). On the other hand, by decreasing inositol 1,4,5-trisphosphate (IP3) levels, lithium has been shown to induce autophagy, a sort of ‘quality control’ process believed to be particularly important in neurodegenerative disorders such as HD, AD, ALS, and PD characterized by the accumulation of misfolded disease-causing proteins. In these same neurodegenerative disorders as well as in stroke, TBI/SCI, retinal degeneration, MS, and HIV, lithium inhibits glutamate-induced excitotoxicity mediated by NMDA receptors, specifically attenuating the NR2B subunit constitutive tyrosine phosphorylation, and subsequent calcium influx, thus suppressing excitotoxicity-induced p38 and c-Jun N-terminal kinase (JNK), and subsequent transcription factor activator protein-1 (AP-1) activation to block neuronal apoptosis. Inhibition of oxidative stress, implicated in numerous central nervous system (CNS) disorders such as BD, stroke, TBI/SCI, HD, AD, and ALS may further underlie lithium beneficial effects towards these pathologies (Chiu et al., 2013, Figure 1).