Brimonidine Blocks Glutamate Excitotoxicity-Induced Oxidative Stress and Preserves Mitochondrial Transcription Factor A in Ischemic Retinal Injury

Abstract

Glutamate excitotoxicity-induced oxidative stress have been linked to mitochondrial dysfunction in retinal ischemia and optic neuropathies including glaucoma. Brimonindine (BMD), an alpha 2-adrenergic receptor agonist, contributes to the neuroprotection of retinal ganglion cells (RGCs) against glutamate excitotoxicity or oxidative stress. However, the molecular mechanisms of BMD-associated mitochondrial preservation in RGC protection against glutamate excitotoxicity-induced oxidative stress following retinal ischemic injury remain largely unknown. Here, we tested whether activation of alpha 2 adrenergic receptor by systemic BMD treatment blocks glutamate excitotoxicity-induced oxidative stress, and preserves the expression of mitochondrial transcription factor A (Tfam) and oxidative phosphorylation (OXPHOS) complex in ischemic retina. Sprague-Dawley rats received BMD (1 mg/kg/day) or vehicle (0.9% saline) systemically and then transient ischemia was induced by acute intraocular pressure elevation. Systemic BMD treatment significantly increased RGC survival at 4 weeks after ischemia. At 24 hours, BMD significantly decreased Bax expression but increased Bcl-xL and phosphorylated Bad protein expression in ischemic retina. Importantly. BMD significantly blocked the upregulations of N-methyl-D-aspartate receptors 1 and 2A protein expression, as well as of SOD2 protein expression in ischemic retina at 24 hours. During the early neurodegeneration following ischemic injury (12–72 hours), Tfam and OXPHOS complex protein expression were significantly increased in vehicle-treated retina. At 24 hours after ischemia, Tfam immunoreactivity was increased in the outer plexiform layer, inner nuclear layer, inner plexiform layer and ganglion cell layer. Further, Tfam protein was expressed predominantly in RGCs. Finally, BMD preserved Tfam immunoreactivity in RGCs as well as Tfam/OXPHOS complex protein expression in the retinal extracts against ischemic injury. Our findings suggest that systemic BMD treatment protects RGCs by blockade of glutamate excitotoxicity-induced oxidative stress and subsequent preservation of Tfam/OXPHOS complex expression in ischemic retina.

New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system

“…Particularly, the αÀ2 adrenergic agonist preserved the expression of mitochondrial transcription factor A and oxidative phosphorylation complex in ischemic retina (Lee et al, 2012).…”

The Relationship Between the Renin-Angiotensin–Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death

“…[1][2][3] Various diseases of the eye, which include glaucoma 4,5 and retinal ischemia, 6,7 have been shown to be associated with the glutamate receptor-mediated excitotoxicity. Glutamate excitotoxicity triggered by overactivation of the N-methyl-Daspartate (NMDA) receptors may be a potential risk factor for retinal ganglion cell (RGC) death.…”

Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis

“…For example, BMD has previously been shown to suppress N-methyl-d-aspartate (NMDA) receptor function in RGCs [4], and interestingly, NMDA antagonists promote RGC protection in EAE rats [27]. In addition, one of the causes of RGC death associated with EAE model is increased oxidative stress levels [11], and BMD increases survival rate of RGCs following oxidative stress damage [17,18]. These observations suggest that BMD-mediated inhibition of NMDA receptor activity and oxidative stress may also be involved in RGC protection in the EAE retina.…”