Anti-parkinsonian efficacy of cannabinoids: motor effects of CB1R antagonism and neuroprotective effects of cannabinoid analogues acting through PPARS

Emilio Fernandez-Espejo1, Fernando Rodriguez de Fonseca2, Beatriz Galan-Rodriguez1, Isabel Caraballo1. 1University of Seville, Sevilla, Spain, 2Fundacíon IMABIS, Malaga, Spain.

Cannabinoid CB1 ligands such as the selective antagonist rimonabant could be of value for improving motor deficits in Parkinson’s disease (PD), and cannabinoid analogues such as oleylethanolamide (OEA) are interesting candidates for cytoprotection that mimic the actions of PPAR-alpha agonists (1). First, it has been observed in an animal model of PD based on unilateral 6-OHDA-induced lesion of substantia nigra that systemic administration of rimonabant exerts antiparkinsonian effects in rats with very severe model of PD (>95% nigra cell loss), but not in rats with less severe model (85-95% cell loss). Local injections into denervated striatum and corresponding globus pallidus reduced motor asymmetry in parkinsonian rats (striatum, 1μg/μl, p<0.05; 1.5μg/μl rimonabant, p<0.01; pallidus, 0.5, 1 and 1.5μg/μl rimonabant, p<0.01). Infusions into lesioned substantia nigra enhanced motor asymmetries (1, 1.5μg/μl rimonabant, p<0.01), but this effect was absent in the very severe model of PD in rats. At the striatal level, CB1 antagonists act enhancing dopamine D1 receptor function and reducing D2 receptor function, and it was observed that striatal dopaminergic denervation does not affect cannabinoid CB1 receptor coupling to G proteins. These results suggest that: i) systemic administration of CB1 antagonists in a severe model of PD in rats is ineffective because striatopallidal-mediated motor effects are antagonised by nigra-mediated activity, and ii) CB1 antagonists exert antiparkinsonian effects in a very severe model of PD because nigra-mediated inhibition somehow disappears.

Second, OEA-induced neuroprotection has been tested in vitro and in vivo models of 6-OHDA-induced degeneration of substantia nigra dopamine neurons. Regarding in vitro studies, dopamine neurons were maintained in culture, and 0.5 and 1 μM OEA were observed to exert significant neuroprotection effect against 60 μM 6-OHDA (p<0.05 vs. 6-OHDA-treated cells). For in vivo study, rats were locally injected with OEA into the right striatum and vehicle into the left striatum 60 min before bilateral 6-OHDA. In the short term, heme oxygenase-1 (oxidation marker) and GFAP (glial activation marker) were found to be significantly less intense in the 5 μM OEA-treated striatum (p<0.01). Long-term reduction in striatal TH and synaptophysin was less intense whether the right striatum was treated with OEA 5μM (p<0.05), and nigral TH+ neuron death was significantly reduced after treatment with 1 and 5 μM OEA (p<0.05). Taken together these studies reveal that: i) CB1 receptor antagonists, that lack psychoactive effects, improves motor deficits in a very severe model of PD in rats, and it might be of therapeutic value in the control of advanced stage of Parkinson’s disease in humans, and ii) the cannabinoid analog OEA shows antioxidative and neuroprotective properties in vitro and in vivo models of substantia nigra dopamine neuron degeneration, within a narrow therapeutic window.

Supported to EFE by Laboratorios Dr. Esteve, Spanish FIS (PI040155), Plan Andaluz de Investigacion (CVI127), RED de trastornos adictivos (Instituto Carlos III, RD06/0001), and Delegacion del Gobierno para el Plan Nacional sobre Drogas (3SI/05/14).

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