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.
Highlights
Glutamate excitotoxicity-induced oxidative stress has been linked to mitochondrial dysfunction in retinal ischemia and optic neuropathies including glaucoma [1,2,3,4,5,6], suggesting a distinct mitochondrial dysfunction-mediated cell death pathway is activated in retinal injury
The pressure was enough to induce retinal ischemia and the phenotype was similar to pathologic acute angle closure glaucoma because when intraocular pressure (IOP) reached 60 mmHg, the retina flow rate decreased by 68% for retinal artery in rat [30]
Consistent with our results that BMD promoted retinal ganglion cells (RGCs) survival against ischemic injury, we found that BMD significantly decreased Bax but increased Bcl-xL and phosphorylated Bad (pBad) protein expression in ischemic retina
Summary
Glutamate excitotoxicity-induced oxidative stress has been linked to mitochondrial dysfunction in retinal ischemia and optic neuropathies including glaucoma [1,2,3,4,5,6], suggesting a distinct mitochondrial dysfunction-mediated cell death pathway is activated in retinal injury. Brimonidine (BMD), a selective alpha 2-adrenergic agonist that lowers intraocular pressure (IOP), protects retinal ganglion cells (RGCs) against glutamate excitotoxicity in culture system in vitro [9,10] as well as in rodent models of experimental ischemia and glaucoma [11,12,13,14,15]. BMD is neuroprotective against oxidative stress that induces reactive oxygen species (ROS) formation including superoxide radicals (O22) in culture system in vitro [14] as well as in rodent models of ocular hypertension [13,18,19].
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