Combinatory treatment with mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington's disease

Abstract

Emerging evidence supports that mood stabilizers lithium and valproate (VPA), via inhibition of glycogen synthase kinase 3 (GSK‐3) and histone deacetylases (HDACs), respectively, have broad neuroprotective and neurotrophic properties. We have shown that co‐treatment with these two drugs produces synergistic neuroprotective effects in cultured neurons against glutamate excitotoxicity, one of the purported mechanisms underlying the pathogenesis of Huntington's disease (HD). This inherited neurodegenerative disease is characterized by movement impairment, cognitive and psychiatric disturbances, as well as premature death. Here we demonstrated that treatment of two mouse models of HD, N171‐82Q and YAC128, with a diet containing both lithium (3 g/kg) and VPA (25 g/kg) exhibited greater effects on suppressing motor deficits and psychiatric abnormalities than monotherapy with each drug alone. This combinatory treatment caused consistent inhibition of GSK‐3β and HDACs, and sustained elevation in brain‐derived neurotrophic factor and heat shock protein 70 in their brains. Most importantly, this co‐treatment markedly prolonged lifespan in N171‐82Q mice. Given that there is no proven treatment for this disease presently, our results suggest a therapeutic potential of combined use of lithium and VPA in HD patients. This work was supported by the Intramural Research Program of the NIMH, NIH.