The endocannabinoid system and Huntington's disease

The research in Huntington's disease (HD) has been growing exponentially during the last decade, since the discovery of the genetic basis that leads to neurodegeneration. HD is one of several progressive neurodegenerative disorders, in which the underlying mutation is a CAG expansion encoding a polyglutamine tract in a specific protein, which in the case of HD, is called huntingtin. The first clinical symptoms of HD are generally psychiatric abnormalities, most commonly depression and mood disturbances. Involuntary choreiform movements and dementia develop over the next 15-20 years, and death generally results from complications derived from immobility. There is currently no cure, or even an effective therapy to offset the decline in mental and motor capabilities suffered by those affected by HD, but recent studies have started to examine the usefulness of different classes of new compounds. Among these, plant-derived, synthetic or endogenous cannabinoids have been proposed to have therapeutic value for the treatment of HD, since they act on cannabinoid CB(1) receptors located in the basal ganglia circuitry, that is affected by the striatal atrophy typical of HD. Recent studies have characterized the changes in these receptors, as well as their endogenous ligands, in the basal ganglia in a variety of animal models of HD. The results are indicative that the endocannabinoid system becomes hypofunctional in this disease, which could be related to the hyperkinesia typical of the earliest phases of this disease. In addition, it has been proposed that the loss of these receptors might be involved in the process of pathogenesis itself. This, together with the well-known protective properties of cannabinoid-related compounds, suggest that, in addition to a symptomatic usefulness, cannabinoids might also serve to delay or to arrest the development of this disease. The present article will review all recent data dealing with the biochemical, pharmacological and therapeutic bases that support a potential role of cannabinoids in the pathogenesis and/or therapeutic treatment of this motor disorder.