Alpha-2 adrenoceptor agonists have previously been shown to enhance neuronal survival in an optic nerve mechanical injury model and to protect photoreceptors in a light-induced degeneration model. The purpose of this study was to examine the effect of the alpha-2 adrenoceptor agonist in a pressure-induced retinal ischemia model. Brown-Norway rats were treated systemically or topically with alpha-2 adrenoceptor specific agonist brimonidine. Retinal ischemia was induced by increasing the intraocular pressure to 110 mm Hg for 50 min. The effect of brimonidine on retinal ischemic injury was functionally assessed in the rats 7 d later using electroretinography (ERG). Ischemia-induced retinal cell death was studied using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. We found that brimonidine treatment significantly protected the retina from retinal ischemic injury in a dose- and time-dependent manner. This protection can be achieved either by systemic or topical application and can be blocked by pretreatment with the alpha-2 adrenoceptor antagonist, yohimbine. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, we found that brimonidine can up-regulate the expression of basic fibroblast growth factor, bcl-2 and bcl-xl in the retina. The drug also can activate two major cell survival signaling pathways in the retina: the extracellular-signal-regulated kinases (ERKs) and phosphatidylinositol-3′ kinase/protein kinase Akt pathways. All these aforementioned factors may potentially contribute in mediating brimonidine's protective effect in this acute retinal ischemia model.

Choroidal blood flow (ChBF) in birds is regulated by a neural circuit whose components are the retina, the suprachiasmatic nucleus, the medial division of the Edinger-Westphal nucleus (EWM), the ciliary ganglion, and the choriod. We have previously shown that lesions of EWM appear to result in pathological alterations in the retina. To determine whether EWM lesions also lead to altered visual functions, we have examined the effects of EWM lesions on visual acuity in pigeons. Bilateral lesions of EWM were made electrolytically, and visual acuity for high-contrast, square-wave gratings was determined behaviorally about 1 year later and compared to that of a group of pigeons that had received sham lesions of EW about 1 year prior to acuity testing. Because lesions targeting EWM invariably resulted in damage to the adjoining lateral part of the Edinger-Westphal nucleus (EWL), which controls pupillary constriction and accommodation, two additional control groups were studied. In one such control group, bilateral lesions in the area pretectalis (AP), which innervates the pupillary control part of EWL and thereby controls pupillary constriction, were made and the effects on visual acuity determined about 1 year later. In the second such control group, the effects of acute accommodative and pupillary dysfunction on acuity were studied in pigeons made cycloplegic. The accuracy of all lesions was later confirmed histologically. The mean acuities of birds with AP lesions (9.1 ± 1.4 cycles/deg) and sham lesions (7.1 ± 1.5 cycles/deg) were not significantly different from normal, based on published normative data on pigeons. In contrast, pigeons with lesions that completely destroyed EW bilaterally showed visual acuity (2.7 ± 0.1 cycles/deg) that was well below the acuity of the sham and AP-lesion control groups. The acuity of the cycloplegic pigeons (4.8 ± 0.3 cycles/deg) and one pigeon with a nearly complete bilateral EWL but a unilateral EWM lesion (6.4 cycles/deg) indicated that only about half of the loss with a bilateral EW lesion could be attributed to accommodative dysfunction. Thus, bilateral destruction of EWM appears to have led to a loss in visual acuity. This conclusion suggests that disruption of adaptive neural regulation of ChBF may impair visual function. Destruction of EWM was, however, associated with damage to the somatic components of the oculomotor and trochlear nuclei. The possibility cannot be excluded that such damage also contributed to the acuity loss.