Associate Editor: M. Mouradian
Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders

https://doi.org/10.1016/j.pharmthera.2010.07.006Get rights and content

Abstract

Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-d-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.

Introduction

Lithium, a monovalent cation, has been the standard pharmacological treatment for bipolar disorder (BD) for more than 60 years. It remains recommended by many treatment guidelines as the first-line treatment against acute mania, and prophylactically for recurrent manic and depressive episodes. Clinically, lithium has been used adjunctively with other mood stabilizers, antidepressants, and antipsychotic medications to facilitate, enhance, or prolong both treatment response and remission (Goodwin, 2003, Lin et al., 2006). Lithium also has strong anti-suicidal properties (Tondo & Baldessarini, 2009).

The clearance of lithium is exclusively dependent on renal excretion as a free ion and is considered to be decreased with aging (Grandjean & Aubry, 2009). Although lithium has a narrow therapeutic margin and well-known adverse effects, it is safe to use in the therapeutic dose range. Several minor side effects may occur at serum levels of lithium ranging from 0.6 to 1.2 mEq/L that have been demonstrated to be efficacious in the treatment of BD (Moscovich, 1993, Speirs and Hirsch, 1978). Symptoms associated with serum levels above 1.5 mEq/L are generally mild, including tremor, nausea, diarrhea, vertigo, and confusion (American Psychiatric Association, 2002). Nonetheless, lithium levels at 1.2 mM or higher in the plasma rarely cause persistent neurological deficits (Chen et al., 2004b). Lithium does not appear to be carcinogenic or mutagenic, but may lead to renal and liver damage at prolonged exposures to serum levels of 2 mM or more (American Psychiatric Association, 2002, Gould et al., 2003, Mazlo et al., 1983). Patients may experience more severe neurological complications such as seizures, coma, cardiac dysrhythmia, and permanent neurological impairment with plasma levels of lithium greater than 2.5 mEq/L (American Psychiatric Association, 2002). Therefore, regular monitoring of serum concentrations is essential, particularly in elderly patients with lower clearance or preexisting neurological illness, to ensure optimal clinical efficacy and minimal adverse effects.

Given its long history of clinical use (Jope, 1999a), multiple actions associated with lithium's mood stabilizing effects have been recognized; nevertheless, the precise underlying biochemical mechanisms of this drug remain poorly defined. In addition, clinical use of lithium for the treatment of BD has declined in recent years due to its narrow therapeutic range and to the availability of alternative medications. However, the last decade has also seen significant attention focused on lithium's neurotrophic and neuroprotective effects. Loosely defined, neurotrophic effects encompass therapeutic strategies intended to augment proliferation, differentiation, growth, and regeneration. In contrast, neuroprotective effects are defined as those that halt or slow the progression of neuronal atrophy or cell death following the onset of insult or disease. Indeed, due to lithium's remarkable neuroprotective and neurotrophic properties, considerable research has been conducted on its efficacy as a novel therapeutic in various disease models.

Lithium is the lightest of all metals, with a density only half that of water. It induces multiple biochemical and molecular effects on neurotransmitter receptor-mediated signaling, signal transduction cascades, hormonal and circadian regulation, ion transport, and gene expression. These effects have been widely associated with the activation of neurotrophic pathways, and neuroprotection has been the most expected and replicated biological effect associated with lithium use in both human and preclinical studies. Growing evidence suggests that lithium has neuroprotective effects against a variety of insults, including glutamate-induced excitotoxicity, ischemia-induced neuronal damage, and other neurodegenerative conditions. Lithium's beneficial effects normally require long-term treatment to become evident, and are not immediately reversed after discontinuation of the drug. Therefore, it has been suggested that the therapeutic actions of lithium may involve signaling pathway and gene expression alterations in the central nervous system (CNS). In fact, recent research has recognized prominent molecular and cellular targets associated with lithium's neuroprotective effects. These include its ability to inhibit intracellular signaling kinases and phosphatases, to protect against apoptosis induced by a variety of insults in cultured neurons and neurally related cell lines, to affect transcriptional activity and gene expression, and to promote cell proliferation and likely neurogenesis in the CNS.

This article reviews the most recent findings regarding these potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. Lithium is already FDA-approved for the treatment of BD; our conclusions support the notion that its clinical relevance can be expanded to include the treatment of several neurological and neurodegenerative-related diseases.

Section snippets

Lithium as a multi-functional neuroprotectant

Initial hypotheses that lithium has neuroprotective and neurotrophic effects were based on observations that chronic lithium treatment at therapeutic concentrations increases m3-muscarinic acetylcholine receptor-mediated second messenger production and c-Fos and m3-receptor expression in cultured rat cerebellar granule cells (CGCs) (Gao et al., 1993). In addition, lithium also increases the activity of two prominent transcription factors—activator protein-1 (AP-1) and cyclic AMP-response

Bipolar disorder (BD)

BD is a common and chronic mental illness characterized by mood cycling between states of mania and depression (Manji & Lenox, 1998), and is one of the major causes of disability worldwide (Manji et al., 2003, Zarate et al., 2006). Because lithium has been the mainstay of treatment for this disorder, its neuroprotective effects may provide novel insights into the potential causes of this disease. For instance, it is interesting to note that, with very few exceptions, neuroprotection is a common

Conclusion and future directions

In recent years, accumulating evidence has focused on the neuroprotective and neurotrophic properties of lithium, rekindling interest in this drug for the treatment of a wide variety of disorders. Studies from various laboratories support the notion that lithium has robust neuroprotective effects in a vast number of cellular and animal models of brain disorders. Indeed, neuroprotection is the most consistent biological outcome associated with lithium treatment in both preclinical and clinical

Conflict of interest

The authors have no conflicts of interest, financial or otherwise, to disclose.

Acknowledgments

This work was supported by the Intramural Research Program of the NIMH, NIH. The authors thank Dr. Joshua Hunsberger, Peter Leeds, and Ioline Henter of the Mood and Anxiety Disorder Program, NIMH, NIH, for critical review and editorial assistance of this manuscript.

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