Mood Stabilizers Offer Hope For Huntington’s Treatment

Two mood stabilizers with a long history of safe use in humans—lithium and valproate—may hold important therapeutic potential for patients with the devastating and ultimately fatal neurode-generative disorder Huntington’s disease.

This message, based on results from two transgenic mouse models of Huntington’s, was reported in the November Neuropsychopharmacology and at the annual meeting of the American College of Neuropsychopharmacology in Hawaii in December.

The senior investigator was De-Maw Chuang, Ph.D., chief of the Section on Molecular Neurobiology at the National Institute of Mental Health.

Although lithium has been a standard treatment for bipolar disorder for more than half a century, and although valproate is also effective in treating bipolar disorder, the precise mechanisms of how these drugs work are still poorly understood. Yet emerging evidence suggests that both drugs promote cell proliferation and neurogenesis in the central nervous system. Thus both drugs might be capa ble of preventing neuronal cell death in Huntington’s, Chuang and his colleagues reasoned.

Another reason why they believed that this might be the case is that the two drugs promote cell proliferation and neurogenesis by inhibiting certain enzymes—glycogen synthase kinase 3 and histone deacetylases—and levels of these enzymes decrease in the brains of mouse models of Huntington’s around the time that behavioral deficits resulting from the disease become apparent.

Chuang and his group thus decided to see whether giving a combination of lithium and valproate in the diet to two widely used transgenic mouse models of Huntington’s disease could counter disease symptoms in the mice. Using multiple well-validated behavioral tests, they found that the combined drug treatment alleviated movement deficits, suppressed anxiety- and depressive-like behaviors, improved motor-skill learning and coordination, and prolonged average survival—from 32 weeks to 42 weeks.

The scientists also gave the two drugs separately to other Huntington’s mice and found similarly positive results, but not to the extent as when the two drugs were given together.