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Y. Bai, Z. Shi, K. Burgess, K. E. Neet, S. Woo, H. Mehta, Y. Zhuo, H. U. Saragovi; Glaucoma Experimental Therapeutics: Neuroprotection Using Receptor-Selective Neurotrophin Analogues and Peptidomimetics. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3089.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the pharmacological concept of neuroprotection in a rat model of glaucoma, by targeting specific neurotrophin receptors TrkA or p75 with selective functional ligands. We tested the effectiveness of (a) wild type Nerve Growth Factor (NGF) versus receptor-selective NGF mutants, and (b) drug-like small molecule NGF mimetics which target selectively TrkA or p75.
Episcleral vein cauterization was performed unilaterally. Intraocular pressure (IOP) was measured in both eyes immediately after surgery (day 1) and every week after that. The hypertensive eyes were injected intraocularly with test agents or controls. Treatment was done acutely 1x at days 14 and day 21 of hypertension, when some damage to retinal ganglion cells (RGC) has already occurred. The primary endpoint was the survival of RGCs. The number of fluorogold retrogradely-labeled RGCs in each eye were measured in flat mounted retinas at day 42 of ocular hypertension (e.g. 21 days after drug treatment). In each rat the experimental eye was compared versus the contralateral control eye, and all experimental groups were compared to each other.
Elevated IOP was maintained ~1.6-fold above normal throughout the experiment. In hypertensive eyes after 42 days there was 25% RGCs death. Treatment with PBS vehicle or with wild type NGF that binds to TrkA and p75 receptors, did not prevent or accelerate RGC death.Significant neuroprotection was obtained with an NGF mutant selective for TrkA (only 7% RGC death); whereas an NGF mutant selective for p75 exacerbated RGC death (35% death). Significant neuroprotection was obtained with peptidomimetics 3Ak and D3 which are selective agonists of TrkA (only 9% and 14% RGC death respectively). Significant neuroprotection was also obtained with peptidomimetic C-24 which is a selective antagonist of p75 (only 5% RGC death).
In the rat glaucoma model, pharmacological modulation of receptors TrkA (with agonists) and p75 (with antagonists) can protect RGCs. Consistent with this view, agonists of p75 accelerate RGC death. These data validate these receptors as pharmacological targets for neuroprotection in glaucoma therapeutics. Current studies address compound efficacy from topical administration, in combination with pressure-lowering drugs.
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