Neuroprotective Effect of(-)Δ 9 -Tetrahydrocannabinol and Cannabidiol in N-Methyl-D-Aspartate-Induced Retinal Neurotoxicity

Involvement of Peroxynitrite

Azza B. El-Remessy, Ibrahim E. Khalil, Suraporn Matragoon, Gamal Abou-Mohamed, Nai Jer Tsai, Penny Roon, Ruth B Caldwell, Robert William Caldwell, Keith Green, Gregory I Liou

Research output: Contribution to journalArticle

157 Citations (Scopus)

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 Δ 9 -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.

Original languageEnglish (US)
Pages (from-to)1997-2008
Number of pages12
JournalAmerican Journal of Pathology
Volume163
Issue number5
DOIs
StatePublished - Jan 1 2003

Fingerprint

Cannabidiol
Retinal Neurons
Peroxynitrous Acid
Dronabinol
Neuroprotective Agents
N-Methylaspartate
Glutamic Acid
NG-Nitroarginine Methyl Ester
Glaucoma
Apoptosis
Cannabinoid Receptor CB1
Intravitreal Injections
Cannabinoids
Retinal Ganglion Cells
Nitrites
Nitric Oxide Synthase
Ganglia
Nitrates
Lipid Peroxidation
Superoxide Dismutase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Neuroprotective Effect of(-)Δ 9 -Tetrahydrocannabinol and Cannabidiol in N-Methyl-D-Aspartate-Induced Retinal Neurotoxicity : Involvement of Peroxynitrite. / El-Remessy, Azza B.; Khalil, Ibrahim E.; Matragoon, Suraporn; Abou-Mohamed, Gamal; Tsai, Nai Jer; Roon, Penny; Caldwell, Ruth B; Caldwell, Robert William; Green, Keith; Liou, Gregory I.

In: American Journal of Pathology, Vol. 163, No. 5, 01.01.2003, p. 1997-2008.

Research output: Contribution to journalArticle

El-Remessy, Azza B. ; Khalil, Ibrahim E. ; Matragoon, Suraporn ; Abou-Mohamed, Gamal ; Tsai, Nai Jer ; Roon, Penny ; Caldwell, Ruth B ; Caldwell, Robert William ; Green, Keith ; Liou, Gregory I. / Neuroprotective Effect of(-)Δ 9 -Tetrahydrocannabinol and Cannabidiol in N-Methyl-D-Aspartate-Induced Retinal Neurotoxicity : Involvement of Peroxynitrite. In: American Journal of Pathology. 2003 ; Vol. 163, No. 5. pp. 1997-2008.
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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 Δ 9 -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.",
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AU - Abou-Mohamed, Gamal

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AU - Roon, Penny

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