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G.I. Liou, S. Matragoon, A.B. El-Remessy, I.E. Khalil, G. Abou-Mohamed, N. Tsai, R.W. Caldwell, R.B. Caldwell; Neuroprotective Effect of (-)&Delta_upper;9-Tetrahydrocannabinol in NMDA-Induced Apoptosis in Rat Retina . Invest. Ophthalmol. Vis. Sci. 2003;44(13):107.
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Purpose:In glaucoma, the increased release of excitatory neurotransmitter glutamate is the major cause of retinal ganglion cell death. Constituents of marijuana, including psychotropic and non-psychotropic 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 nitric oxide, superoxide anion and peroxynitrite in vivo, and that the psychotropic cannabinoid, Δ 9-tetrahydroxycannabinol (THC) protects retinal neurons via the attenuation of this formation. Methods:Excitotoxicity of the retina was induced by intravitreal injection of a glutamate analog, N-methyl-D-aspartate (NMDA) in rats. Rats also received intravitreal injections of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-n-oxyl (TEMPOL), N-omega-nitro-D-arginine methyl ester (L-NAME), or intravenous injections of THC. Retinal levels of nitric oxide, superoxide anion and peroxynitrite were determined by measurements of nitrite, lipid peroxides and nitrotyrosine, respectively. Retinal neuron survival was determined by TDT-mediated-dUTP nick end labeling (TUNEL) assay, inner retinal thickness measurement, and quantification of the mRNAs of ganglion cell markers. Results:NMDA induced a time-related accumulation of nitric oxide, superoxide anion and peroxynitrite, and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or THC protected retinal neurons and attenuated accumulation of nitric oxide, superoxide anion and peroxynitrite. Treatment with TEMPOL protected retinal neurons and attenuated accumulation of superoxide anion and peroxynitrite, but not nitric oxide. Conclusions:The neuroprotection by TEMPOL and L-NAME through their respective superoxide scavenging and nitric oxide synthase inhibition demonstrates the involvement of superoxide anion and peroxynitrite in the NMDA-induced retinal neurotoxicity. THC protects the retinal neurons by attenuating the formation of, or scavenging these compounds.
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