Glutamate is an excitatory neurotransmitter widely distributed in the brain. However, over-accumulation of glutamate results in neurotoxicity, which contributes to neuronal degeneration in neurodegenerative diseases, e.g. Parkinson disease. Glutamate toxicity is mediated by excitotoxicity and oxidative stress. Tetrahydrocannabinol (THC) from Cannabis sativa has been discussed as a neuroprotective agent in several in vitro and in vivo models of brain injury. However, the mechanisms by which THC exhibits neuroprotective properties are not completely understood. In this study, we studied neuroprotective effects of THC in primary murine mesencephalic cultures and in CB1 receptor containing N18TG2 cells. Glutamate (30 µM in primary cell cultures and 30 mM in cell lines) was administered for 48h with or without concomitant THC treatment (0.1 to 10 µM). THC protected dopaminergic neurons and other cell types of primary dissociated cultures as well as N18TG2 cells from glutamate-induced neurotoxicity. Moreover, THC significantly counteracted glutamate-induced mitochondrial membrane depolarization and apoptosis in both models. SR141716A, a CB1 receptor antagonist, concentration-dependently blocked the protective effect of THC in primary mesencephalic cultures but had no effect in N18TG2 cells. A slightly recovery of glutathione levels in N18TG2 cells co-treated with THC was also observed. In conclusion, THC exerts antiapoptotic and antioxidant properties and further restores mitochondrial membrane potential via a mechanism not exclusively dependent on CB1 receptor. It provides considerable neuroprotection in both models therewith strengthening the hypothesis that THC may be a candidate to slowing down the degenerative processes in PD and other neurodegenerative diseases.
