Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells

Objectives: Brimonidine tartrate ophth, an alpha(2)-adrenergic agonist, is widely used as an antiglaucoma agent for lowering intraocular pressure. Recent studies suggest that brimonidine may be neuroprotective for retinal ganglion cells (RGCs) following optic nerve crush injury. Brain-derived neurotrophic factor (BDNF), a potent neuroprotective factor present in the RGCs, promotes RGC survival in culture and following optic nerve injury. We tested the hypothesis that a possible mechanism of brimonidine neuroprotection is through up-regulation of endogenous BDNF expression in the RGCs. Methods: A single dosage of brimonidine tartrate ophth solution (0.85-34muM) was injected intravitreally into Sprague-Dawley rat eyes. The fellow eyes of each animal were injected with balanced salt solution (BSS) and used as control eyes. To determine BDNF messenger RNA expression, animal eyes were enucleated and processed for in situ hybridization, or retinas were isolated and processed for Northern blot analysis using rat BDNF radiolabeled riboprobes. Results: In the control eyes injected with saline, BDNF was present in a minority of the RGCs. Two days after brimonidine injection, the number of BDNF-positive RGCs was increased from 55% to 166%, depending on brimonidine concentrations, when compared with those in the controls. In addition, the BDNF signal intensities in individual RGCs were elevated 50% in brimonidine-injected eyes compared with control eyes. Northern blot revealed a 28% increase of BDNF expression in the brimonidine group compared with the controls (P < .003). No significant difference was observed in BDNF receptor, trk B, expression between brimonidine, or BSS control groups. Conclusions: A single dose of a low concentration of intravitreal brimonidine is sufficient to significantly increase endogenous BDNF expression in RGCs. These results suggest that brimonidine neuroprotection may be mediated through up-regulation of BDNF in the RGCs. The BDNF should be further investigated regarding its role in the neuroprotective effects reported with brimonidine. Clinical Relevance: Brimonidine may be (potentially) used clinically as a neuroprotective agent in optic neuropathy, including glaucoma, and ischemic and traumatic optic neuropathy.