May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
Neuroprotective Effects of Cannabidiol Involve Inhibition of Glutamine Synthetase Nitration in Diabetic Retina
Author Affiliations & Notes
  • G.I. Liou
    Medical College of Georgia, Augusta, GA
    Department of Ophthalmology,
  • M.S. Ola
    Cellular & Molecular Physics, Penn State College of Medicine, Hershey, PA
  • R.B. Caldwell
    Medical College of Georgia, Augusta, GA
    Vascular Biology Center,
  • A.B. El–Remessy
    Medical College of Georgia, Augusta, GA
    Department of Pharmacology & Toxicology,
  • Footnotes
    Commercial Relationships  G.I. Liou, None; M.S. Ola, None; R.B. Caldwell, None; A.B. El–Remessy, None.
  • Footnotes
    Support  Fight for Sight, Knights Templar, SDG from AHA
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 4828. doi:
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      G.I. Liou, M.S. Ola, R.B. Caldwell, A.B. El–Remessy; Neuroprotective Effects of Cannabidiol Involve Inhibition of Glutamine Synthetase Nitration in Diabetic Retina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4828.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : We have shown that the non–psychotropic cannabinoid cannabidiol (CBD) protects retinal neurons in diabetic rats by inhibiting reactive oxygen species (ROS) and blocking tyrosine nitration. ROS may inhibit glutamine synthetase (GS), causing glutamate accumulation leading to further neural cell death. Excess glutamate also triggers a self–defense neuroprotective response via activation of the cannabinoid receptor CB1. We propose to test the hypothesis that diabetes–induced glutamate accumulation in the retina is associated with tyrosine nitration of GS, and that CBD treatment inhibits this process. We also test the hypothesis that the glutamate–induced self–defense mechanism by CB1 in diabetes is operational in the retina.

Methods: : Retinal cell death, GS tyrosine nitration and GS activity were determined in STZ–induced diabetic rats with or without the treatment of CBD, or in diabetic mice wild–type (CB1+/+) or lacking CB1 receptor (CB1–/–). Retinal GS activity was determined by the ability of retinal homogenate to convert 14C–glutamate to 14C–glutamine.

Results: : Numbers of TUNEL–HRP–labeled cells were increased by approximately 7–fold in whole–mounted retinas from diabetic rats as compared with untreated controls or CBD–treated rats. Retinal GS was tyrosine–nitrated and activity was impaired in 8–week–old diabetic rats. CBD treatment reversed these processes. In the retinas of 4–week–old diabetic CB1–/– mice, the number of TUNEL–positive cells per section was approximately 8–fold higher than the number in the age–matched diabetic CB1+/+, normal control CB1+/+, or normal control CB1–/– mice.

Conclusions: : This result suggests that reduced GS activity in retinas of diabetic rats is due to increased tyrosine nitration, and that CBD protects retinal neurons in diabetes by preserving GS via anti–oxidation. Our finding of early retinal cell loss in diabetic CB1–/– mice is consistent with the hypothesis that CB1 receptor/endogenous cannabinoid system protects the diabetic retina from degeneration by mitigating glutamate toxicity.

Keywords: antioxidants • diabetic retinopathy • neuroprotection 

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