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.

Fig. 1

Neurotrophic and neuroprotective pathways targeted by lithium. BDNF receptor (Trk-B) activation activates the ERK/MAPK pathway, which inhibits GSK-3β (a critical cellular target and effector for diverse proteins) and bad. This activation increases the expression of nuclear CREB, in turn facilitating the expression of neurotrophic/neuroprotective proteins such as bcl-2 and BDNF itself. Mitochondrial bcl-2 also inhibits pro-apoptotic activation of bad, as well as consequent mitochondrial increases of calcium influx and cytochrome c release. Dysregulated intracellular calcium levels, which may increase the risk of cellular apoptosis, have been associated with the pathophysiology of bipolar disorder. Lithium downregulates ER calcium release via an IP₃ Rdependent mechanism, and also increases bcl-2 expression, which improves mitochondrial stability and prevents the activation of apoptotic cascades. IMPase, also directly inhibited by lithium, recycles IP₃. In addition, cellular signaling through Wnt glycoproteins and frizzled receptors inhibits GSK-3β. Lithium's inhibition of GSK-3β prevents β-catenin phosphorylation and stimulates its translocation to the nucleus, thus targeting the transcription of specific genes activating neurotrophic effects and synaptogenesis. Different neurotransmitters target receptors coupled to G proteins. Among these, D₁, D₅, and β-adrenergic receptors are coupled to G α stimulatory proteins that activate AC; H₃, D₂, D₃, and D₄ receptors are coupled to Gα inhibitory proteins that inhibit AC; serotonergic, α₁-adrenergic, M₁, M₃, and M₅ receptors are coupled to G_q/11, which activates PLC. PLC, in turn, hydrolyses PIP₂ to IP₃ and DAG. DAG activates PKC, which plays a significant role in regulating pre- and postsynaptic aspects of neurotransmission and diverse cellular processes. Lithium also indirectly inhibits PKC. The text provides a complete description of these interactions. Arrows represent ‘activation’, perpendicular lines represent ‘inhibition’, and dotted lines represent ‘indirect effects’. bad = bcl-2-associated death promoter; bag-1 = bcl-2-associated athanogene; GPCR = G-protein-coupled receptors; IP₃R = IP₃ receptor; MARCKS = myristoylated alanine-rich C kinase substrate; Raf, MEK, ERK, RSK = components of the ERK pathway; Trk-B = tropomyosin receptor kinase.