Background We have previously shown a protective effect of Δ9-tetrahydrocannabinol (THC) in Parkinson's disease (PD) cell culture models associated with increased CB1 cannabis receptor cDNA. Here we investigate whether this protective effect is mediated via the CB1 receptor.

Methods SH-SY5Y human neuroblastoma cells were differentiated to a neuronal phenotype. The presence of an endocannabinoid system (ECS) was investigated by immunocytochemistry, Western blotting and reverse transcriptase PCR. Cannabinoids and ECS modulators were co-administered with PD-relevant toxins (MPP+ (mitochondrial inhibitor), lactacystin (proteasome inhibitor), paraquat (free radical generator) to determine any protective effect.

Results The protective effect of Δ9-THC was not blocked by the CB1 antagonist AM251, nor reproduced by the CB1 agonist WIN55,212-2. Δ9-THC is known to be antioxidant. Cannabidiol, an antioxidant with little CB1 receptor affinity, exerted a protective effect against MPP+ with no effect against paraquat or lactacystin. Cannabidiol may be acting via modulation of anandamide hydrolysis. We found expression of the enzyme involved in endocannabinoid hydrolysis, fatty-acid amide hydrolase (FAAH). Co-administration of URB597, an FAAH inhibitor, was protective against MPP+, an effect which was not blocked by antagonism of the CB1 receptor.

Conclusions Our results suggest that the protective effects of cannabinoids in cell culture models of PD may be mediated by modulation of the ECS.