Ischemia results 3 months later in altered ERG, degeneration of inner layers, and deafferented tectum: neuroprotection with brimonidine.

PURPOSE: To investigate the long-term effects of transient ligature of the ophthalmic vessels (LOV) on the inner and outer retina as well as on retinotectal projection, and whether brimonidine (BMD) has protective effects. METHODS: In adult rats, the left eye was subjected to 90 minutes of LOV. One hour before ischemia, 2 drops of saline alone (vehicle group) or saline containing 0.5% brimonidine (BMD group) were instilled in the left eye. The effects of LOV on the inner and outer retina were assessed with ERG recordings of a- and b-wave amplitudes at 1, 8, and 12 weeks after LOV and with analysis of layer thickness in paraffin sections. The retinotectal projection was orthogradely labeled with cholera toxin subunit B (CTB) injected in the left eye and measured in serial coronal sections of the superior colliculus. RESULTS: There were significant reductions in the mean b-wave amplitudes of the ischemic eyes at 8 and 12 weeks after LOV in the vehicle-treated group of animals, but not in the BMD-treated group. The thickness of the inner nuclear and inner plexiform layers of the vehicle-treated group of retinas had decreased to approximately 71% of the thicknesses in the BMD-treated groups. Three months after LOV, the mean volume of the retinotectal projection in the vehicle- or BMD-treated group of animals had decreased to approximately 54% or 83%, respectively, of the mean values found in the control group of animals. CONCLUSIONS: LOV induces degeneration of the inner retinal layers and the retinotectal projection 3 months after the insult. BMD administration significantly protected against LOV-induced retinal damage and degeneration of retinal projection.

Transient ischemia of the retina results in massive degeneration of the retinotectal projection: long-term neuroprotection with brimonidine.

In adult rats, we have induced retinal ischemia and investigated anterogradely labeled surviving retinal ganglion cell (RGC) afferents to the contralateral superior colliculus (SC). The animals received topically in their left eyes two 5-microl drops of saline or saline-containing 0.5% brimonidine (BMD), 1 h before 90 min of retinal ischemia induced by ligature of the left ophthalmic vessels. Two months after ischemia, the anterogradely transported neuronal tracer cholera toxin B subunit (CTB) was injected in the ischemic eyes and animals were processed 4 days later. As controls and for comparison, the retinotectal innervation of unlesioned age-matched control rats was also examined with CTB. In control and experimental animals, serial coronal sections of the mesencephalon and brainstem were immunoreacted for CTB and the area and thickness of the two most superficial layers of the SC containing densely CTB-labeled profiles were estimated with an image analysis system. Ninety minutes of ischemia resulted 2 months later in reduced density of CTB-labeled profiles in the contralateral SC of the vehicle-treated rats, representing less than one half the area occupied by CTB-labeled profiles in control rats. This resulted in shrinkage of these layers and in the presence of areas virtually devoid of CTB immunoreactivity, suggesting orthograde degeneration of retinal terminals and/or decrease of anterograde axonal transport. Topical pretreatment with BMD resulted 2 months later in CTB immunoreactivity that occupied the superficial layers of the contralateral SC in an area of approximately 86% of that observed in the unlesioned control group of animals, indicating that BMD protects against ischemia-induced degeneration of the retinotectal projection, and preserves anterograde axonal transport.