Brimonidine prevents neurodegeneration in a mouse model of normal tension glaucoma.

K Semba,Y Mitamura,T Harada,A Kimura,K Namekata,C Harada

doi:10.1038/cddis.2014.306

K Semba, Y Mitamura + Show 4 more

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https://doi.org/10.1038/cddis.2014.306

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Abstract

Glaucoma is one of the leading causes of irreversible blindness that is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino-acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). Brimonidine (BMD) is an α2-adrenergic receptor agonist and it is commonly used in a form of eye drops to lower IOP in glaucoma patients. Recent studies have suggested that BMD has direct protective effects on RGCs involving IOP-independent mechanisms, but it is still controversial. In the present study, we examined the effects of BMD in EAAC1-deficient (KO) mice, an animal model of normal tension glaucoma. BMD caused a small decrease in IOP, but sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with BMD was highly effective for RGC protection in EAAC1 KO mice. BMD suppressed the phosphorylation of the N-methyl-D-aspartate receptor 2B (NR2B) subunit in RGCs in EAAC1 KO mice. Furthermore, in cultured Müller glia, BMD stimulated the production of several neurotrophic factors that enhance RGC survival. These results suggest that, in addition to lowering IOP, BMD prevents glaucomatous retinal degeneration by stimulating multiple pathways including glia–neuron interactions.

Highlights

Knockout (KO) mice show progressive retinal ganglion cells (RGCs) loss and optic nerve degeneration without elevated intraocular pressure (IOP), and glutamate neurotoxicity and oxidative stress is involved in its mechanism.[3,8,9,10] In adult excitatory amino-acid carrier 1 (EAAC1) and glutamate/aspartate transporter (GLAST) KO mice, lipid hydroperoxides were increased and glutathione concentrations were decreased in retinas, suggesting the involvement of oxidative stress in RGC loss
We showed that BMD prevents progressive RGC loss, thinning of the inner retinal layer (IRL) and visual impairment in EAAC1 KO mice
As the mean IOP was similar in both groups at the 4-year follow-up, these results suggested that BMD has IOP-independent neuroprotective effects on RGCs

Summary

Introduction

Knockout (KO) mice show progressive RGC loss and optic nerve degeneration without elevated IOP, and glutamate neurotoxicity and oxidative stress is involved in its mechanism.[3,8,9,10] In adult EAAC1 and GLAST KO mice, lipid hydroperoxides were increased and glutathione concentrations were decreased in retinas, suggesting the involvement of oxidative stress in RGC loss. Recent studies have shown that BMD protects RGCs from glutamate neurotoxicity, oxidative stress and hypoxia in vitro.[15,16] In addition, BMD provides neuroprotective effects in various animal models of optic neuropathy including experimental glaucoma, ischemia, oxidative stress and optic nerve injury.[17,18,19] BMD may exert its neuroprotective effects via the upregulation of neurotrophic factors, such as brainderived neurotrophic factor (BDNF)[20] and basic fibroblast growth factor (bFGF),[21,22] in RGCs. the neuroprotective

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