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

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 (؊)⌬ 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 receptorinduced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid͞kainate 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 ␣-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.Cannabinoid components of marijuana are known to exert behavioral and psychotropic effects but also to possess therapeutic properties including analgesia (1), ocular hypotension (2), and antiemesis (3). This report examines another potential therapeutic role for cannabinoids as neuroprotectants and describes their mechanism of action in rat cortical neuronal cultures.During an ischemic episode, large quantities of the excitatory neurotransmitter glutamate are released. This event causes neuronal death by over-stimulating N-methyl-Daspartate receptors (NMDAr) and 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid (AMPA) and kainatetype receptors and results in metabolic stress and accumulation of toxic levels of intracellular calcium (4). In vitro and in vivo studies (4,5,6) have demonstrated that such neurotoxicity can be reduced by antioxidants or antagonists to NMDAr and AMPA͞kainate receptors. Antioxidants such as ␣-tocopherol (5, 6) are effective neuroprotectants because of their ability to reduce the toxic reactive oxygen species (ROS) formed during ischemic metabolism. Cannabinoids like (Ϫ)⌬ 9

CB1 cannabinoid receptors are involved in neuroprotection via NF-κB inhibition

“…In addition to their antiinflammatory activities, cannabinoids act also as antioxidants. Cannabidiol is a potent antioxidative agent (Hampson et al, 1998) Figure 2 for the WT mice was found for the CB 1 (À/À) control CHI mice (lanes 2,4,9). Treatment with 2-AG (lanes 3,5,8,10) had no effect on NF-kB nuclear translocation.…”

“…Cultured rat hippocampal neurons and cerebral cortical neurons are protected from excitotoxicity or ischemia by cannabinoid receptor agonists (Shen and Thayer, 1998;Sinor et al, 2000). In addition, N-methyl-D-aspartate-induced (NMDA) Ca 2 þ flux is reduced by anandamide, while SR141716A, a cannabinoid receptor (CB 1 ) antagonist, counteracted this activity (Hampson et al, 1998). In vivo models support these observations.…”

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

“…These e ects of CBD may be due to its anti-oxidant properties (Hampson et al, 1998), to its direct interaction with cytochrome p450-enzymes (Bornheim & Correia, 1989) and other enzymes of the`arachidonate cascade' (Burstein et al, 1985), or to an action at a speci®c receptor. Recent studies have investigated whether CBD interacts with proteins of thè endocannabinoid signalling system' other than the CB 1 /CB 2 receptors.…”

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes

“…The synthetic cannabinoid, WIN55,212-2, was found to inhibit HIV-1 expression in a concentration-and time-dependent manner (Peterson et al, 2004). Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical system (Fenton reaction) with neuronal cultures (Hampson et al, 1998). Cannabidiol was more protective against glutamate-induced neurotoxicity than either ascorbate or α-tocopherol, demonstrating that it is a potent antioxidant (Hampson et al, 1998).…”