Original article
Retinal Ganglion Cell Death Induced by Retinal Ischemia: Neuroprotective Effects of Two Alpha-2 Agonists

https://doi.org/10.1016/S0039-6257(01)00205-3Get rights and content

Abstract

We have investigated in adult Sprague-Dawley rats the neuroprotective effects of two α-2-selective agonists [AGN 191,103 (AGN) and brimonidine tartrate (BMD)] on retinal ganglion cell (RGC) survival after transient retinal ischemia. RGCs were labelled with Fluorogold (FG) applied to both superior colliculi. Seven days later, 90 min of retinal ischemia were induced in the left eyes by ligature of the ophthalmic vessels (LOV). In one group of animals, vehicle or AGN (0.01 mg/kg) were administered systemically 1 hr before ischemia. In another group of animals, two 5 μl drops of vehicle, AGN (0.05%) or BMD (0.1%) were administered topically in the left eye 1 hr before ischemia. The animals were processed 7 or 21 days later. RGC survival was estimated by counting FG-labelled cells in 12 standard areas of each retina. In control retinas of systemically pretreated animals, mean densities of labelled RGCs were 2372 ± 49 cells/mm2 (mean ± SEM; n = 6). In experimental retinas of systemically pretreated animals, mean RGC densities had decreased 7 days after ischemia to 53% (n = 6) or 81% (n = 6) of control in the groups treated with vehicle or AGN, respectively. Twenty-one days after ischemia, mean RGC densities had decreased to 38% (n = 6) or 79% (n = 6) of control in the groups treated with vehicle or AGN, respectively. In control retinas of topically pretreated animals, mean densities of labelled RGCs were 2208 ± 29 cells/mm2 (n = 6). In experimental retinas of topically pretreated animals, mean RGC densities had decreased 7 days after ischemia to 54% (n = 6), 95% (n = 6) or 96% (n = 6) of control in the groups treated with vehicle, AGN or BMD, respectively. These results indicate that pretreatment with a single systemic or topical dose of AGN or BMD can prevent completely the early rapid phase of RGC loss and abolish the delayed RGC loss observed after 90 min of retinal ischemia induced by ligature of the ophthalmic vessels.

Section snippets

Methods

Adult Sprague-Dawley rats were anesthetized with 7% chloral hydrate in saline administered intraperitoneally (IP; 0.42 mg/g body weight). The RGC population was retrogradely labelled from the superior colliculi (SCi) with the fluorescent tracer fluorogold (FG) following already described protocols.14, 19, 20 In brief, the midbrain was exposed, the pia overlying both SCi was removed and a small piece of gelatin sponge (Spongostan® Film, Ferrosan, Denmark) soaked in a solution of 3% FG and 10%

Results

The main findings of this study can be summarized as follows. 1) Seven days after 90 min of retinal ischemia, there is loss of approximately 47% of the RGC population. Between day 7 and day 21 there is an additional delayed loss of 15% of the RGC population. 2) Systemic or topical pretreatment with a single dose of the two α-2 agonists protects RGCs from ischemia-induced cell death. These agents have a potent neuroprotective effect and may prevent the early as well as the protracted phase of

Discussion

Neuroprotection implies prevention of injury- or disease-induced neuronal death. This is a relatively recent term that has evolved over the last years and is based on basic research that has been conducted to understand the process of neuronal death both during development and after injury. It is well established that a common mechanism of cell death during development of the central nervous system, responsible for the death of approximately 50% of embryonic neurons, is apoptosis. This type of

Acknowledgements

The authors thank Dr. Larry Wheeler for helpful discussions during the course of this work, and Dr. Marcelino Avilés for help with the photography.

Supported in part by The Spanish Fondo de Investigación Sanitaria (98/0341; 99/1090); The Fundación Séneca de la Comunidad Autónoma de Murcia (PB18FS97), and; an unrestricted grant from Allergan Inc. (USA).

The authors have no proprietary or commercial interest in any product or concept discussed in this article.

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