?9-tetrahydrocannabinol (?9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease

C. B. Carroll, M.-L. Zeissler, C. O. Hanemann and J. P. Zajicek (2012) Neuropathology and Applied Neurobiology38, 535547 ?9-tetrahydrocannabinol (?9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease Aims:?9-tetrahydrocannabinol (?9-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of ?9-THC. Methods: Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. Results: We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of ?9-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants a-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as ?9-THC. However, the peroxisome proliferator-activated receptor-gamma (PPAR?) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of ?9-THC, while the PPAR? agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, ?9-THC increased PPAR? expression in MPP+-treated SH-SY5Y cells, another indicator of PPAR? activation. Conclusions: We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of ?9-THC that may be mediated through PPAR? activation.