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Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.
Am J Pathol 2003; 163(5):1997-2008AJ

Abstract

In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14578199

Citation

El-Remessy, Azza B., et al. "Neuroprotective Effect of (-)Delta9-tetrahydrocannabinol and Cannabidiol in N-methyl-D-aspartate-induced Retinal Neurotoxicity: Involvement of Peroxynitrite." The American Journal of Pathology, vol. 163, no. 5, 2003, pp. 1997-2008.
El-Remessy AB, Khalil IE, Matragoon S, et al. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol. 2003;163(5):1997-2008.
El-Remessy, A. B., Khalil, I. E., Matragoon, S., Abou-Mohamed, G., Tsai, N. J., Roon, P., ... Liou, G. I. (2003). Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. The American Journal of Pathology, 163(5), pp. 1997-2008.
El-Remessy AB, et al. Neuroprotective Effect of (-)Delta9-tetrahydrocannabinol and Cannabidiol in N-methyl-D-aspartate-induced Retinal Neurotoxicity: Involvement of Peroxynitrite. Am J Pathol. 2003;163(5):1997-2008. PubMed PMID: 14578199.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. AU - El-Remessy,Azza B, AU - Khalil,Ibrahim E, AU - Matragoon,Suraporn, AU - Abou-Mohamed,Gamal, AU - Tsai,Nai-Jer, AU - Roon,Penny, AU - Caldwell,Ruth B, AU - Caldwell,Robert W, AU - Green,Keith, AU - Liou,Gregory I, PY - 2003/10/28/pubmed PY - 2003/12/6/medline PY - 2003/10/28/entrez SP - 1997 EP - 2008 JF - The American journal of pathology JO - Am. J. Pathol. VL - 163 IS - 5 N2 - In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma. SN - 0002-9440 UR - https://www.unboundmedicine.com/medline/citation/14578199/abstract/Neuroprotective_effect_of____Delta9_tetrahydrocannabinol_and_cannabidiol_in_N_methyl_D_aspartate_induced_retinal_neurotoxicity:_involvement_of_peroxynitrite DB - PRIME DP - Unbound Medicine ER -