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Y. Bai, Z. Shi, K. Burgess, Y. Zhuo, H. Saragovi; In Experimental Glaucoma Using Agonists or Antagonists of TrkA, TrkB, or TrkC Reveal Neuro-Glial Mechanisms of Action and Novel Approaches to Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5462.
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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 TrkB or TrkC with selective functional ligands acting as agonists or as antagonists.
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. Biochemical and genetic studies addressed the mechanism of action of each pharmacological agent.
Elevated IOP was maintained ~1.6-fold above normal throughout the experiment. In hypertensive eyes after 42 days there was 30% RGCs death. Treatment with PBS vehicle or with neurotrophins did not prevent or accelerate RGC death. Neuroprotection was obtained with selective agonists of TrkA or TrkB; whereas accelerated RGC death was obtained with TrkA selective antagonists. Suprisingly, antagonists of TrkC afford neuroprotection, whereas agonists of TrkC accelerate RGC death. The mechanism of action of this unexpected finding was uncovered using biochemical and genetic tools.
In the rat glaucoma model, pharmacological modulation of neurotrophin receptors with agonists and antagonists reveal strategies for protecting RGCs. These data validate these receptors as pharmacological targets for neuroprotection in glaucoma therapeutics. A novel mechanism of action is uncovered for TrkC receptors in the progressive death of RGCs.
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