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.