Possible Role of Cannabinoid Receptors in Modulating Parkinsonian‐Like Behaviour

Cannabinoid‐receptors are one of the most abundant G‐protein coupled receptors in the brain which raises interest regarding their role in the brain physiology and pathology. To this end, this study aimed to investigate the possible role of cannabinoid‐receptors signalling modulation in Parkinsonian Disease (PD) using a model of reserpine‐induced PD‐like symptoms. Adult male Sprague‐Dawley rats were divided into 5 groups, the 1 st served as a control that received the vehicle. Animals in the 4 other groups were subcutaneously injected with reserpine (3mg/kg). Rats in the PD group were left untreated, whereas those in the other 3 group were given WIN55,212 (0.1mg/kg I.P.; group 3), rimonabant (0.1mg/kg I.P.; group 4) or a combination of both (group 5) 24 h after reserpine. Microscopical examination of the substantia nigra revealed necrosis and pyknosis in PD rats that was prevented by rimonabant and to a lesser extent by its combination with WIN55,212. Similarly, substantia nigral tyrosine hydroxylase immunostaining, as well as striatal dopamine content was reduced in PD rat, but preserved with rimonabant. Notably, rimonabant was able to hinder in part reserpine‐dependent increments in p T180/Y182 mitogen‐activated protein kinase p38, p S473‐AKT and p S536‐nuclear factor‐κB p65, as well as its down‐stream effector TNF‐α. Besides, rimonabant was able to restore the oxidant/antioxidant pool designated by increased glutathione versus decreased MDA. Notably, WIN55,212 per se intensified some of the reserpine effects and when used in combination with rimonabant, it partially antagonized the effect of the latter on almost all the aforementioned assessments. In all groups, the ATP/ADP/AMP and SIRT1 were decreased without changing mitochondrial transcription factor A (TFAM) and peroxisome proliferator‐activated receptor gamma coactivator (PGC)1α. Nonetheless, Nrf1 and mtDNA were increased with reserpine but decreased by rimonabant or combined treatment. Therefore, the study nominates a pivotal role for cannabinoid receptor activation in combating neuroinflammation instigated by PD with reduced mitochondrial biogenesis.