Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis

Proliferator-activated receptor gamma (PPAR gamma) activation can result in transcription of proteins involved in oxidative stress defence and mitochondrial biogenesis which could rescue mitochondrial dysfunction in Parkinson's disease (PD). The PPAR. agonist pioglitazone is protective in models of PD; however side effects have limited its clinical use. The cannabinoid Delta(9)-tetrahydrocannabinol (Delta(9)-THC) may have PPAR gamma dependent anti-oxidant properties. Here we investigate the effects of Delta(9)-THC and pioglitazone on mitochondrial biogenesis and oxidative stress. Differentiated SH-SY5Y neuroblastoma cells were exposed to the PD relevant mitochondrial complex 1 inhibitor 1-methyl4-phenylpyridinium iodide (MPP+). We found that only Delta(9)-THC was able to restore mitochondrial content in MPP+ treated SH-SY5Y cells in a PPAR. dependent manner by increasing expression of the PPAR. co-activator 1 alpha (PGC-1 alpha), the mitochondrial transcription factor (TFAM) as well as mitochondrial DNA content. Co-application of Delta(9)-THC with pioglitazone further increased the neuroprotection against MPP+ toxicity as compared to pioglitazone treatment alone. Furthermore, using lentiviral knock down of the PPAR gamma receptor we showed that, unlike pioglitazone, Delta(9)-THC resulted in a PPAR. dependent reduction of MPP+ induced oxidative stress. We therefore suggest that, in contrast to pioglitazone, Delta(9)-THC mediates neuroprotection via PPAR gamma-dependent restoration of mitochondrial content which may be beneficial for PD treatment.