Unbound MEDLINE

Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.

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.

Links

  • PMC Free PDF
  • PMC Free Full Text
  • Publisher Full Text
  • Authors

    El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI

    Source

    The American journal of pathology 163:5 2003 Nov pg 1997-2008

    MeSH

    Animals
    Apoptosis
    Cannabidiol
    Cyclic N-Oxides
    Dose-Response Relationship, Drug
    Dronabinol
    In Situ Nick-End Labeling
    Male
    N-Methylaspartate
    NG-Nitroarginine Methyl Ester
    Neurons
    Neuroprotective Agents
    Oxidative Stress
    Peroxynitrous Acid
    Rats
    Rats, Sprague-Dawley
    Receptor, Cannabinoid, CB1
    Retina
    Reverse Transcriptase Polymerase Chain Reaction
    Spin Labels
    Time Factors

    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