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L. Guo, T.E. Salt, A. Maass, V. Luong, S.E. Moss, F.W. Fitzke, M.F. Cordeiro; Investigation of in vivo Effects of Glutamate Modulating Stratages in Glaucoma–Related Models of Retinal Ganglion Cell Apoptosis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3921.
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© ARVO (1962-2015); The Authors (2016-present)
To assess neuroprotective effects of different glutamate modulation strategies, with the NMDA receptor antagonists (MK801 and Ifenprodil), and a metabotropic glutamate receptor agonist (LY354740), using glaucoma–related in vivo rat models.
Retinal ganglion cell (RGC) apoptosis was induced in Dark Agouti (DA) rats (n=94) by staurosporine (SSP) treatment. Single agents of MK801, ifenprodil and LY354740 or combined applications of MK801 and LY354740 were administrated intravitreally at different doses. Eyes were imaged in vivo using our recently established technique, and results confirmed histologically. The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model (n=16) with application at 0, 1 and 2 weeks after OHT surgery, and effects assessed as described before.
All strategies of glutamate modulation reduced SSP–induced–RGC apoptosis compared to control, in a dose–dependent manner by MK801 (R2=0.8863), ifenprodil (R2=0.4587) and LY354740 (R2=0.9094), with EC50s of 0.074, 0.0138 and 19 nmol respectively. The most effective combination dose of MK801/LY354740 was 0.06/20nmol (p<0.05), and the optimal timing of this was at 0 weeks after OHT surgery (p<0.05).
Our novel SSP–model was validated as a useful tool for screening neuroprotective strategies in vivo. Group II mGluR modulation may be a useful treatment strategy for preventing RGC death. Combination therapy optimised to limit neurotoxic effects of MK801 may be an effective neuroprotective approach in retinal degenerative disease. Furthermore, strategies minimising secondary RGC degeneration effects may be most useful in glaucoma.
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