Cannabinoid receptor agonist protects cultured dopaminergic neurons from the death by the proteasomal dysfunction

Cannabinoids have been proposed to possess neuroprotective properties; though their mechanism of action remains contentious, they are posited to prevent neurodegenerative disorders, including Parkinson's disease, the pathogenesis of which has not been established. Recent studies have demonstrated that induction of proteasomal dysfunction in animal models results in a phenotype similar to Parkinson's disease. Here, we investigated the neuroprotective function of a synthetic cannabinoid-receptor agonist (WIN55.212.2) in dopaminergic neuronal death induced by a proteasomal synthase inhibitor (PSI), additionally testing the hypothesis that WIN55.212.2 modulates cytoplasmic accumulation of parkin and ${\alpha}$-synuclein, a key feature of proteasomal dysfunction in Parkinson's. WIN55.212.2 protects PC12 cells from PSI-induced cytotoxicity, concomitantly inhibiting PSI-induced polyADP ribose polymerase expression and activation of caspase-3. While PSI induces cytoplasmic accumulation of ${\alpha}$-synuclein and parkin, WIN55.212.2 counters these effects. Interestingly, however, while PSI induces the activation and nuclear translocalization of nuclear factor ${\kappa}B$, WIN55.212.2 potentiates this effect. These data are suggestive that WIN55.212.2 might confer a neuroprotective benefit in PSI-induced proteasomal dysfunction, and could further protect against neuronal degeneration stemming from cytoplasmic accumulation of ${\alpha}$-synuclein and parkin. These results indicate that WIN55.212.2 may be a candidate for treatment of neurodegenerative diseases, including Parkinson's disease.