Axonal Protection by Brimonidine with Modulation of P62 Expression in TNF-induced Optic Nerve Degeneration

Overview

Journal Graefes Arch Clin Exp Ophthalmol

Specialty Ophthalmology

Date 2015 Apr 13

PMID 25863674

Citations 3

Authors

Yasushi Kitaoka

Kaori Kojima

Yasunari Munemasa

Kana Sase

Hitoshi Takagi

Affiliations

Soon will be listed here.

Abstract

Purpose: The p62, also called sequestosome 1 (SQSTM1), plays a crucial role in tumor necrosis factor (TNF)-induced optic nerve degeneration. Brimonidine has been shown to have protective effects on retinal ganglion cell bodies, although its role in their axons remains to be examined. We determined whether brimonidine modulates axonal loss induced by TNF and affects the expression of p62 in the optic nerve.

Methods: Experiments were performed on adult male Wistar rats that received an intravitreal injection of 10 ng TNF alone or simultaneous injection of TNF and 2, 20, or 200 pmol of brimonidine tartrate. The expression of p62 in the optic nerve was examined by immunoblot analysis. The effects of brimonidine on axons were evaluated by counting axon numbers 2 weeks after intravitreal injection.

Results: Intravitreal injection of brimonidine exerted substantial axonal protection against TNF-induced optic nerve degeneration. Immunoblot analysis showed that p62 was upregulated in the optic nerve after intravitreal injection of TNF, and that this increase was completely inhibited by brimonidine. Treatment with brimonidine alone also significantly decreased p62 protein levels in the optic nerve compared with the basal level.

Conclusions: These results suggest that the modulation of p62 levels in the optic nerve by brimonidine may be involved partly in its axonal protection.

Citing Articles

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References

Prokosch V, Panagis L, Volk G, Dermon C, Thanos S . Alpha2-adrenergic receptors and their core involvement in the process of axonal growth in retinal explants. Invest Ophthalmol Vis Sci. 2010; 51(12):6688-99. DOI: 10.1167/iovs.09-4835. View

Fujita Y, Sato A, Yamashita T . Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation. Cell Death Dis. 2013; 4:e763. PMC: 3763459. DOI: 10.1038/cddis.2013.298. View

Johansen T, Lamark T . Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2010; 7(3):279-96. PMC: 3060413. DOI: 10.4161/auto.7.3.14487. View

Aviles-Trigueros M, Mayor-Torroglosa S, Garcia-Aviles A, Lafuente M, Rodriguez M, de Imperial J . Transient ischemia of the retina results in massive degeneration of the retinotectal projection: long-term neuroprotection with brimonidine. Exp Neurol. 2004; 184(2):767-77. DOI: 10.1016/S0014-4886(03)00298-X. View

Kitaoka Y, Hayashi Y, Kumai T, Takeda H, Munemasa Y, Fujino H . Axonal and cell body protection by nicotinamide adenine dinucleotide in tumor necrosis factor-induced optic neuropathy. J Neuropathol Exp Neurol. 2009; 68(8):915-27. DOI: 10.1097/NEN.0b013e3181afecfa. View

Danylkova N, Alcala S, Pomeranz H, McLoon L . Neuroprotective effects of brimonidine treatment in a rodent model of ischemic optic neuropathy. Exp Eye Res. 2006; 84(2):293-301. DOI: 10.1016/j.exer.2006.10.002. View

Tanabe F, Yone K, Kawabata N, Sakakima H, Matsuda F, Ishidou Y . Accumulation of p62 in degenerated spinal cord under chronic mechanical compression: functional analysis of p62 and autophagy in hypoxic neuronal cells. Autophagy. 2011; 7(12):1462-71. PMC: 3288020. DOI: 10.4161/auto.7.12.17892. View

Sawada H, Fukuchi T, Tanaka T, Abe H . Tumor necrosis factor-alpha concentrations in the aqueous humor of patients with glaucoma. Invest Ophthalmol Vis Sci. 2009; 51(2):903-6. DOI: 10.1167/iovs.09-4247. View

Tezel G, Li L, Patil R, Wax M . TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001; 42(8):1787-94. View

10.

Gal J, Strom A, Kilty R, Zhang F, Zhu H . p62 accumulates and enhances aggregate formation in model systems of familial amyotrophic lateral sclerosis. J Biol Chem. 2007; 282(15):11068-77. DOI: 10.1074/jbc.M608787200. View

11.

Lee D, Kim K, Noh Y, Chai S, Lindsey J, Ellisman M . Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury. PLoS One. 2012; 7(10):e47098. PMC: 3467218. DOI: 10.1371/journal.pone.0047098. View

12.

Kitaoka Y, Munemasa Y, Hayashi Y, Kuribayashi J, Koseki N, Kojima K . Axonal protection by 17β-estradiol through thioredoxin-1 in tumor necrosis factor-induced optic neuropathy. Endocrinology. 2011; 152(7):2775-85. DOI: 10.1210/en.2011-0046. View

13.

Lopez-Herrera M, Mayor-Torroglosa S, de Imperial J, Villegas-Perez M, Vidal-Sanz M . Transient ischemia of the retina results in altered retrograde axoplasmic transport: neuroprotection with brimonidine. Exp Neurol. 2002; 178(2):243-58. DOI: 10.1006/exnr.2002.8043. View

14.

Lafuente M, Villegas-Perez M, Mayor S, Aguilera M, de Imperial J, Vidal-Sanz M . Neuroprotective effects of brimonidine against transient ischemia-induced retinal ganglion cell death: a dose response in vivo study. Exp Eye Res. 2002; 74(2):181-9. DOI: 10.1006/exer.2001.1122. View

15.

Kuusisto E, Salminen A, Alafuzoff I . Early accumulation of p62 in neurofibrillary tangles in Alzheimer's disease: possible role in tangle formation. Neuropathol Appl Neurobiol. 2002; 28(3):228-37. DOI: 10.1046/j.1365-2990.2002.00394.x. View

16.

Aranguiz-Urroz P, Canales J, Copaja M, Troncoso R, Vicencio J, Carrillo C . Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation. Biochim Biophys Acta. 2010; 1812(1):23-31. DOI: 10.1016/j.bbadis.2010.07.003. View

17.

Puissant A, Fenouille N, Auberger P . When autophagy meets cancer through p62/SQSTM1. Am J Cancer Res. 2012; 2(4):397-413. PMC: 3410580. View

18.

Levkovitch-Verbin H, Groner Y, Wheeler L, Schwartz M, Yoles E . RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection. Invest Ophthalmol Vis Sci. 2000; 41(13):4169-74. View

19.

Yuan L, Neufeld A . Tumor necrosis factor-alpha: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia. 2000; 32(1):42-50. View

20.

Gao H, Qiao X, Cantor L, WuDunn D . Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells. Arch Ophthalmol. 2002; 120(6):797-803. DOI: 10.1001/archopht.120.6.797. View