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Cannabidiol and ( ) 9-Tetrahydrocannabinol Are Neuroprotective Antioxidants

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Cannabidiol and ( ) 9-Tetrahydrocannabinol Are Neuroprotective Antioxidants Proc. Natl. Acad. Sci. USA Vol. 95, pp. 8268–8273, July 1998 Medical Sciences Cannabidiol and (2)D9-tetrahydrocannabinol are neuroprotective antioxidants A. J. HAMPSON*†,M.GRIMALDI‡,J.AXELROD*, AND D. WINK§ *Laboratory of Cellular and Molecular Regulation, National Institutes of Mental Health, Bethesda, MD 20892; ‡Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892; and §Radiology and Biology Branch, National Cancer Institute, Bethesda, MD 20892 Contributed by Julius Axelrod, April 27, 1998 ABSTRACT The neuroprotective actions of cannabidiol reduce the toxic reactive oxygen species (ROS) formed during and other cannabinoids were examined in rat cortical neuron ischemic metabolism. Cannabinoids like (2)D9-tetrahydrocan- cultures exposed to toxic levels of the excitatory neurotrans- nabinol (THC) and its psychoactive analogues also have been mitter glutamate. Glutamate toxicity was reduced by both reported to be neuroprotective against glutamate toxicity in cannabidiol, a nonpsychoactive constituent of marijuana, and vitro (7). Cannabinoids have been suggested to prevent gluta- the psychotropic cannabinoid (2)D9-tetrahydrocannabinol mate neurotoxicity by activating cannabinoid receptors (7, 8), (THC). Cannabinoids protected equally well against neuro- which can reduce calcium influx through voltage sensitive toxicity mediated by N-methyl-D-aspartate receptors, 2-ami- calcium channels (8, 9). A synthetic cannabinoid (HU-211) no-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid recep- also has been demonstrated to be neuroprotective even though tors, or kainate receptors. N-methyl-D-aspartate receptor- it does not activate cannabinoid receptors. This compound is induced toxicity has been shown to be calcium dependent; this an atypical cannabinoid, however, in that it, unlike other study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisox- cannabinoids, directly antagonizes NMDAr (10) and possesses azol-5-yl)propionic acidykainate receptor-type neurotoxicity some antioxidant properties (11). The present study examines is also calcium-dependent, partly mediated by voltage sensi- classical cannabinoids as neuroprotectants in vitro but focuses tive calcium channels. The neuroprotection observed with on the nonpsychoactive cannabinoid cannabidiol. Like THC, cannabidiol and THC was unaffected by cannabinoid receptor cannabidiol is a natural component of the marijuana plant, antagonist, indicating it to be cannabinoid receptor indepen- Cannabis sativa, although unlike THC, cannabidiol does not dent. Previous studies have shown that glutamate toxicity may activate cannabinoid receptors and so is devoid of psychoactive be prevented by antioxidants. Cannabidiol, THC and several effects (12). This study reports that cannabidiol and other synthetic cannabinoids all were demonstrated to be antioxi- cannabinoids such as THC are potent antioxidants that protect dants by cyclic voltametry. Cannabidiol and THC also were neurons from glutamate-induced death without cannabinoid shown to prevent hydroperoxide-induced oxidative damage as receptor activation. well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was MATERIALS AND METHODS more protective against glutamate neurotoxicity than either ascorbate or a-tocopherol, indicating it to be a potent anti- Materials. Cannabidiol, THC, and reagents other than oxidant. These data also suggest that the naturally occurring, those specifically listed below were purchased from Sigma. nonpsychotropic cannabinoid, cannabidiol, may be a poten- Cyclothiazide, glutamatergic ligands, and MK-801 were ob- tially useful therapeutic agent for the treatment of oxidative tained from Tocris Cookson (Bristol, U.K.). Dihydrorhodam- neurological disorders such as cerebral ischemia. ine was supplied by Molecular Probes. Tert-butyl hydroperox- ide, tetraethylammonium chloride, ferric citrate, and sodium Cannabinoid components of marijuana are known to exert dithionite were all purchased from Aldrich. Agatoxin and behavioral and psychotropic effects but also to possess ther- conotoxin were obtained through Biomol (Plymouth Meeting, y apeutic properties including analgesia (1), ocular hypotension PA). All culture media were GIBCO BRL products. (2), and antiemesis (3). This report examines another potential Solution Preparation. Solutions of cannabinoids, cyclothia- therapeutic role for cannabinoids as neuroprotectants and zide, and other lipophiles were prepared by evaporating a 10 describes their mechanism of action in rat cortical neuronal mM ethanolic solution (under a stream of nitrogen) in a , cultures. siliconized microcentrifuge tube. Dimethyl sulfoxide ( 0.05% During an ischemic episode, large quantities of the excita- of final volume) was added to ethanol to prevent the lipophile tory neurotransmitter glutamate are released. This event from completely drying onto the tube wall. After evaporation, causes neuronal death by over-stimulating N-methyl-D- 1 ml of culture media was added, and the drug was dispersed aspartate receptors (NMDAr) and 2-amino-3-(4-butyl-3- by using a high power sonic probe. Special attention was used hydroxyisoxazol-5-yl)propionic acid (AMPA) and kainate- to ensure the solution did not overheat or generate foam. After type receptors and results in metabolic stress and accumulation dispersal, all solutions were made to their final volume in of toxic levels of intracellular calcium (4). In vitro and in vivo siliconized glass tubes by mixing with an appropriate quantity studies (4, 5, 6) have demonstrated that such neurotoxicity can of culture media. be reduced by antioxidants or antagonists to NMDAr and Neuronal Cultures. Primary cortical neuron cultures were AMPAykainate receptors. Antioxidants such as a-tocopherol prepared according to the method of Ventra et al (13). In brief, (5, 6) are effective neuroprotectants because of their ability to fetuses were extracted by C-section from a 17-day pregnant The publication costs of this article were defrayed in part by page charge Abbreviations: AMPA, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5- yl)propionic acid; BHT, butylhydroxytoluene; NMDAr, N-methyl-D- payment. This article must therefore be hereby marked ‘‘advertisement’’ in aspartate receptors; ROS, reactive oxygen species; THC, (2)D9- accordance with 18 U.S.C. §1734 solely to indicate this fact. tetrahydrocannabinol. 0027-8424y98y958268-6$0.00y0 †To whom reprint requests should be addressed. e-mail: aidan@ PNAS is available online at http:yywww.pnas.org. codon.nih.gov. 8268 Downloaded by guest on September 27, 2021 Medical Sciences: Hampson et al. Proc. Natl. Acad. Sci. USA 95 (1998) 8269 Wistar rat, and the fetal brains were placed into phosphate icity, with 20 hr of exposure resulting in a lactate dehydroge- buffered saline. The cortices then were dissected out, cut into nase release of only 5% above background, compared with small pieces, and incubated with papain for 9 min at 37°. After 100–200% of the background observed in neuron-enriched this time, the tissue was dissociated by passage through a cultures (data not shown). It was concluded, therefore, that fire-polished Pasteur pipette, and the resultant cell suspension astrocyte contamination does not contribute substantially to was separated by centrifugation over a gradient consisting of the effects of glutamate in our neuronal cultures. 10 mgyml BSA and 10 mgyml ovomucoid (a trypsin inhibitor) ROS Toxicity Assay. To examine the effects of cannabinoids in Earle’s balanced salt solution. The pellet then was resus- on ROS toxicity, 7- to 13-day-old cultured neurons were pended in high glucose, phenol red-free DMEM containing incubated with 300 mM tert-butyl hydroperoxide (an oxidant) 10% fetal bovine serum, 2 mM glutamine, 100 units of in conditioned DMEM. Tert-butyl hydroperoxide was used penicillin, and 100 mgyml streptomycin (DMEM). Cells were because its miscibility with both water and lipids allows counted, were tested for vitality by using the trypan blue oxidation to occur in both cytosolic and membrane-delimited exclusion test, and were seeded onto poly-D-lysine coated 24 cellular compartments. m multiwell plates. After 96 hr, 10 M fluorodeoxyuridine and 10 Toxicity Assay. Cell toxicity was assessed 18–20 hrs after m M uridine were added to block glial cell growth. This protocol insult by measuring lactate dehydrogenase release into the results in a highly neuron-enriched culture (13). (phenol red-free) culture media. Experiments were conducted Preparation of (Type I) Astrocytes and Conditioned Media. with triple or quadruple values at each point, and all plates Astrocyte-conditioned DMEM (phenol red-free) was used contained positive (glutamate alone) and baseline controls. y throughout the AMPA kainate toxicity procedure and after The assay was validated by comparison with a tetrazolium- glutamate exposure in the NMDAr-mediated toxicity proto- based viability assay (XTT) (20). Results were similar with col. Media were conditioned by 24 hr of treatment over a either system, although lactate dehydrogenase release was confluent layer of type I astrocytes prepared from 2-day-old used in this study because it provided a greater signal to noise Wistar rat pups (14). In brief, cortices were dissected, were cut ratio than the XTT assay. into small pieces, were digested enzymatically with 0.25% Cyclic Voltametry. Cyclic voltametry was performed with an trypsin, and then were dissociated mechanically by passage EG & G Princeton
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