Neuroprotective effects of alpha(2)-selective adrenergic agonists against ischemia-induced retinal ganglion cell death.
2区 · 医学
作者: M P Lafuente ; M P Villegas-Pérez ; P Sobrado-Calvo ; A García-Avilés ; J Miralles de Imperial ; M Vidal-Sanz
To investigate in adult rats the effects of two alpha(2)-selective adrenergic agonists (alpha(2)-SAs; AGN 191103 and AGN 190342) on retinal ganglion cell (RGC) survival after transient retinal ischemia.
RGCs were labeled with a Fluorogold (FG) tracer applied to both superior colliculi. Seven days later, the left ophthalmic vessels were ligated for 60 or 90 minutes. In one group, a single dose of saline or one alpha(2)-SA was administered intraperitoneally (IP) or topically 1 hour before ischemia. In another group, a single dose of AGN 190342 was administered IP, 1, 2, 4, 24, or 72 hours after ischemia. Rats were processed 7, 14, or 21 days later. Densities of surviving RGCs were estimated by counting FG-labeled cells in 12 standard retinal areas.
Seven days after 60 or 90 minutes of retinal ischemia, death had occurred in 36% or 47%, respectively, of the RGC population, and by 21 days the loss of RGCs amounted to 42% or 62%, respectively. Systemic pretreatment with an alpha(2)-SA resulted in enhanced survival of ischemic-injured RGCs. Topical pretreatment with an alpha(2)-SA prevented up to 100% of the ischemia-induced RGC loss. Pretreatment with an alpha(2)-SA abolished the secondary slow RGC loss that occurred between days 7 and 21 after ischemia. When administered shortly after ischemia (up to 2 hours) AGN 190342 rescued substantial proportions of RGCs destined to die and diminished slow RGC death.
Pretreatment and early posttreatment with an alpha(2)-SA induces marked long-lasting neuroprotective in vivo protection against ischemia-induced cell death in RGCs.
Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration.
2区 · 医学
作者: E Yoles ; L A Wheeler ; M Schwartz
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.
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.
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.
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.