Effects of cannabinoids in the rat model of Huntington's disease generated by an intrastriatal injection of malonate

Cannabinoids could provide neuroprotection in neurodegenerative disorders. In this study, we examined whether a treatment with Delta(9)-tetrahydrocannabinol, a non-selective cannabinoid receptor agonist, or with SR141716, a selective antagonist for the cannabinoid CB1 receptor subtype, could affect the toxicity of the complex II reversible inhibitor malonate injected into the striatum, which replicates the mitochondrial complex II deficiency seen in Huntington's disease patients. As expected, malonate injection produced a significant reduction in cytochrome oxidase activity in the striatum consistent with the expected neurodegeneration caused by this toxin. The administration of Delta(9)-tetrahydrocannabinol increased malonate-induced striatal lesions compared to vehicle and, surprisingly, SR141716, far from producing effects opposite to those of Delta(9)-tetrahydrocannabinol, also enhanced malonate effects, and to an even greater extent. In summary, our results are compatible with the idea that manipulating the endocannabinoid system can modify neurodegeneration in Huntington's disease, and suggest that highly selective CB1 receptor agonists might be necessary to produce neuroprotective effects against indirect excitotoxicity.