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Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration
E Yoles1, L A Wheeler, M Schwartz
1Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.
Purpose:
The neurodegenerative progression of glaucoma is considered to be related not only to primary risk factors such as the elevation of intraocular pressure, but also to mediators of secondary neuronal degeneration. In the present study, the neuroprotective activity of the alpha2-adrenoreceptor agonists brimonidine, AGN 191103, and clonidine were examined in an animal model that simulates secondary neuronal degeneration of the optic nerve in a way thought to be independent of elevation of intraocular pressure. The beta-blocker timolol, currently used clinically to decrease intraocular pressure, was also examined for neuroprotective activity at dosages corresponding to the effective antihypertensive dosage.
Methods:
A single dose of each of the tested compounds was administered intraperitoneally immediately after partial crush injury of the rat optic nerve. Secondary degeneration was measured by determining injury-induced deficits with and without the drug. This was achieved electrophysiologically by measurement of compound action potential amplitude, and morphometrically by counting the retrogradely labeled retinal ganglion cells, representing viable optic nerve axons, in wholemounted retinas.
Results:
All three alpha2-adrenoreceptor agonists, but not timolol, exhibited neuroprotective effects. Treatment immediately after injury with each of these agonists resulted in a dose-dependent attenuation of the injury-induced decrease in compound action potential amplitude. Moreover, after treatment with 100 microg/kg brimonidine administered intraperitoneally, the loss of retinal ganglion cells 2 weeks after injury was three times lower than in saline-treated animals.
Conclusions:
In addition to their known effect of lowering intraocular pressure, alpha2-adrenoreceptor agonists, unlike timolol, exert a neuroprotective effect. Use of the rat optic nerve model of partial crush injury can serve as a method of screening compounds that are potentially capable of alleviating the progression of secondary neuronal degeneration.