Preclinical and clinical investigations of mood stabilizers for Huntington's disease: what have we learned?

Abstract

Huntington's disease (HD) is a lethal, autosomal dominant neurodegenerative disorder caused by CAG repeat expansions at exon 1 of the huntingtin (Htt) gene, which encodes for a mutant huntingtin protein (mHtt). Prominent symptoms of HD include motor dysfunction, characterized by chorea; psychiatric disturbances such as mood and personality changes; and cognitive decline that may lead to dementia. Pathologically multiple complex processes and pathways are involved in the development of HD, including selective loss of neurons in the striatum and cortex, dysregulation of cellular autophagy, mitochondrial dysfunction, decreased neurotrophic and growth factor levels, and aberrant regulation of gene expression and epigenetic patterns. No cure for HD presently exists, nor are there drugs that can halt the progression of this devastating disease. Therefore, the need to discover neuroprotective modalities to combat HD is critical. In basic and preclinical studies using cellular and animal HD models, the mood stabilizers lithium and valproic acid (VPA) have shown multiple beneficial effects, including behavioral and motor improvement, enhanced neuroprotection, and lifespan extension. Recent studies in transgenic HD mice support the notion that combined lithium/VPA treatment is more effective than treatment with either drug alone. In humans, several clinical studies of HD patients found that lithium treatment improved mood, and that VPA treatment both stabilized mood and moderately reduced chorea. In contrast, other studies observed that the hallmark features of HD were unaffected by treatment with either lithium or VPA. The current review discusses preclinical and clinical investigations of the beneficial effects of lithium and VPA on HD pathophysiology.

Keywords: Glycogen Synthase Kinase-3 Inhibitor; Histone Deacetylase Inhibitor; Huntington's disease; Lithium; Therapeutic Potential.; Valproic Acid.

Figure 1

The major pathophysiological pathways in Huntington's disease (HD). Mutant huntingtin (mHtt) protein disrupts many normal physiological processes and leads to unbalanced homeostasis of apoptotic molecules, deficits in autophagy, axonal transport impairment, transcriptional dysregulation, reduced cellular neurotrophic support, mitochondrial abnormalities, and glutamate excitotoxicity. mHtt disturbs the balance between pro-apoptotic (such as Bax and p53) and cell survival (such as Bcl-2 and Bcl-xl) molecules. Transcriptional regulation is disrupted in HD; as described in the text, mHtt allows REST translocation to the nucleus resulting in repression of genes including BDNF. As a result of decreased BDNF axonal transport and repression of gene transcription by REST, neurotrophic support of cells is diminished in HD. Impaired axonal transport of autophagosomes also increases autophagy deficits observed in HD. Mitochondrial abnormalities in HD include decreased ATP production and PGC-1a expression, as well as increased cytochrome c release which leads to cell apoptosis. Glutamate excitotoxicity, caused by hyperactivation of excitatory amino acid receptors that increase cell ion permeability and lead to intracellular calcium overload and ultimately cell death, is strongly implicated in HD. The pointed arrows indicate that mHtt increases the described physiological pathway; arrows with blocked ends indicate prevention of a physiological event.

Figure 2

The preclinical and clinical effects of lithium and valproic acid (VPA) treatment in Huntington's disease (HD). Preclinical and clinical studies have shown that HD pathophysiology involves the dysfunction of multiple complex physiological processes and signaling pathways. More recent preclinical investigations have demonstrated that lithium and VPA exert numerous beneficial effects including enhanced neuroprotection, motor function recovery, mHtt protein clearance, and gene expression regulation. The lithium- or VPA-mediated reduction of mitochondrial abnormality, which is closely related to decreased PGC-1a expression, or inflammation, caused by NF-kB activation, have yet to be determined in HD models. Clinically, HD patients treated with lithium or VPA exhibit improved psychiatric outcomes including reduced irritability, anxiety, depression, and suicidal ideation. It has yet to be validated whether lithium or VPA can reduce chorea in HD patients. Pointed arrows indicate increases or decreases in the respective effects due to lithium- or VPA-induced actions on each physiological process. Arrows with blocked ends indicate lithium- or VPA- mediated prevention of a pathophysiological event. Question marks (?) indicate known effects of lithium or VPA, which have yet to be verified in HD models and patients.