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 Delta9-tetrahydrocannabinol, a non-selective cannabinoid receptor agonist, or with SR141716, a selective antagonist for the cannabinoid CB(1) 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 Delta9-tetrahydrocannabinol increased malonate-induced striatal lesions compared to vehicle and, surprisingly, SR141716, far from producing effects opposite to those of Delta9-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 CB(1) receptor agonists might be necessary to produce neuroprotective effects against indirect excitotoxicity.
Lastres-Becker
Isabel
I
URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du Général Leclerc, 91401-Orsay Cedex, France.
Bizat
Nicolas
N
Boyer
Frédéric
F
Hantraye
Philippe
P
Brouillet
Emmanuel
E
Fernández-Ruiz
Javier
J
D000818:Animals; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000037:antagonists & inhibitors; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D013759:Dronabinol / Q000009:adverse effects* / Q000627:therapeutic use; D042963:Electron Transport Complex II; D004791:Enzyme Inhibitors; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008314:Malonates; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000009:adverse effects* / Q000627:therapeutic use; D011619:Psychotropic Drugs / Q000009:adverse effects* / Q000627:therapeutic use; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D004791:Enzyme Inhibitors; D008314:Malonates; D009097:Multienzyme Complexes; D010880:Piperidines; D011619:Psychotropic Drugs; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; C030290:malonic acid; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D000077285:Rimonabant