TY - JOUR
T1 - Neuroprotective Effect of(-)Δ9-Tetrahydrocannabinol and Cannabidiol in N-Methyl-D-Aspartate-Induced Retinal Neurotoxicity
T2 - 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.
N1 - Funding Information:
Supported in part by an unrestricted departmental award from Research to Prevent Blindness Inc., New York, NY (to G. I. L. and R. B. C.), the American Heart Association (to R. W. C.) and the National Institutes of Health (grants EY12078 to G. I. L., EY04618 and EY11766 to R. B. C.).
PY - 2003/11
Y1 - 2003/11
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 Δ9-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-ω-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.
AB - 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 Δ9-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-ω-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.
UR - http://www.scopus.com/inward/record.url?scp=0142151067&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0142151067&partnerID=8YFLogxK
U2 - 10.1016/S0002-9440(10)63558-4
DO - 10.1016/S0002-9440(10)63558-4
M3 - Article
C2 - 14578199
AN - SCOPUS:0142151067
SN - 0002-9440
VL - 163
SP - 1997
EP - 2008
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -