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Y. Khalifa, M. Al–Shabrawey, S. Mian, M. Ola, R.B. Caldwell, G.I. Liou; Endocannabinoid System Modulation of Glutamate Toxicity in Oxygen–Induced Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3221.
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© ARVO (1962-2015); The Authors (2016-present)
We propose to test the hypothesis that relative retinal ischemia results in inhibition of glutamine synthetase (GS) in Muller glial cells. We also propose the endocannabinoid system modulates glutamate–induced toxicity in ischemic proliferative retinopathy through GS.
Relative retinal ischemia was induced in cannabinoid receptor 1 (CB1) knockout (CB1 –/–) and wild–type (CB1 +/+) mice via hyperoxia from postnatal day 6 (p6) through p11 followed by normoxia at p11. A third group of CB +/+ were exposed to hyperoxic conditions from p6 through p11 and treated with cannabidiol (CBD). All mice were sacrificed at p11, p13, or p16, and retinal expression of metabotropic glutamate receptor 1 (mGluR1) and GFAP was determined via immunohistochemistry; retinal cell death via TUNEL assay; and retinal GS activity via the ability of retinal cytosol to convert 14C–glutamate to 14C–glutamine.
Mice exposed to relative hyperoxia showed decreased GS activity, elevated Muller cell expression of mGluR1 (figure) and GFAP, and inner retina cell death. CBD treatment lowered the Muller expression of mGluR1 and GFAP. Reduced GS activity and increased cell death were observed in the retinas of CB1–/– mice as compared with the CB1+/+ mice.
The endocannabinoid system plays an intrinsic role in protecting the neural cells of the retina against the neurodegenerative effects of ischemic retinopathy by mitigating the ensuing glutamate toxicity via GS activity.
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