Cannabidiol and (−)Δ ⁹ -tetrahydrocannabinol are neuroprotective antioxidants

TLDR

Neurotoxicity from glutamate and NMDA receptor activation is calcium‑dependent and has been shown to be mitigated by antioxidant strategies. The study examined the neuroprotective effects of cannabidiol and THC in rat cortical neuron cultures exposed to glutamate‑induced excitotoxicity. Cannabidiol and THC protected rat cortical neurons from glutamate, NMDA, AMPA, and kainate receptor–mediated toxicity, acted as potent antioxidants independent of cannabinoid receptors, outperformed ascorbate and α‑tocopherol, and may serve as therapeutic agents for oxidative neurological disorders.

Abstract

The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (−)Δ 9 -tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl- d -aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl- d -aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or α-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.