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Alteration of retinal intrinsic survival signal and effect of α2–adrenergic receptor agonist in the retina of the chronic ocular hypertension rat

Published online by Cambridge University Press:  19 July 2007

HWA SUN KIM ,
YONG IK CHANG ,
JIE HYUN KIM  and
CHAN KEE PARK
HWA SUN KIM
Affiliation:
Department of Ophthalmology, College of Medicine, The Catholic University of Korea, Seoul, Korea
YONG IK CHANG
Affiliation:
Department of Ophthalmology, College of Medicine, The Catholic University of Korea, Seoul, Korea
JIE HYUN KIM
Affiliation:
Department of Ophthalmology, College of Medicine, The Catholic University of Korea, Seoul, Korea
CHAN KEE PARK
Affiliation:
Department of Ophthalmology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Abstract

The purpose of this study is to examine the retinal expression of intrinsic cell survival molecules and to elucidate the effect of an α2-adrenergic receptor agonist in the chronic ocular hypertensive rat model. Chronic ocular hypertension was induced in both eyes of each rat by episcleral vein cauterization. Two five-microliter drops of the selective α2-adrenoceptor agonist brimonidine 0.2% (Alphagan; Allergan Inc., Irvine, CA, USA) were topically administered twice daily for up to eight weeks in one eye. The fellow eye received balanced salt solution as a control. Protein and mRNA expression were evaluated at 1, 4, and 8 weeks after injury. Retinal expression of BDNF, Akt, and GFAP was assessed using immunohistochemistry. Retinal levels of mRNA for BDNF, bcl-2, and bcl-xL were determined using semi-quantitative RT-PCR. Retinal ganglion cell (RGC) density was evaluated after retrograde labeling with 4-Di-10-ASP (DiA). A significant decrease in RGC density was observed in ocular hypertensive eyes. Cauterized eyes showed an increase in GFAP expression from one week after injury, and the expression of bcl-2, bcl-xL, and BDNF mRNA was also increased. Treatment of ocular hypertensive eyes with brimonidine resulted in a reduction in RGC loss, a decrease in the level of GFAP immunoreactivity, and an increment in BDNF mRNA and p-Akt expression. Brimonidine appears to protect RGCs from neurodegeneration through mechanisms involving α2-adrenergic receptor mediated survival signal activation and up-regulation of endogenous neurotrophic factor expression in the chronic ocular hypertensive rat retina.

Keywords

Alpha 2 adrenergic receptor agonistApoptosisBDNFGlaucomaNeuroprotection
Type
Research Article
Information
Visual Neuroscience , Volume 24 , Issue 2 , March 2007 , pp. 127 - 139
Copyright
2007 Cambridge University Press

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References

REFERENCES

Adams, J.M. & Cory, S. (1998). The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322–1326.CrossRefGoogle Scholar
Akman, A., Cetinkaya, A., Akova, Y.A. & Ertan, A. (2005). Comparison of additional intraocular pressure-lowering effects of latanoprost vs brimonidine in primary open-angle glaucoma patients with intraocular pressure uncontrolled by timolol-dorzolamide combination. Eye 19, 145–151.Google Scholar
Baptiste, D.C., Hartwick, A.T., Jollimore, C.A., Baldridge, W.H., Chauhan, B.C., Tremblay, F. & Kelly, M.E. (2002). Comparison of the neuroprotective effects of adrenoceptor drugs in retinal cell culture and intact retina. Investigative and Ophthalmology & Visual Science 43, 2666–2676.Google Scholar
Bennett, J.L., Zeiler, S.R. & Jones, K.R. (1999). Patterned expression of BDNF and NT-3 in the retina and anterior segment of the developing mammalian eye. Investigative Ophthalmology Visual Science 40, 2996–3005.Google Scholar
Cory, S. & Adams, J.M. (2002). The Bcl2 family: Regulators of the cellular life-or-death switch. Nature Reviews. Cancer 2, 647–656.CrossRefGoogle Scholar
Dolcet, X., Egea, J., Soler, R.M., Martin-Zanca, D. & Comella, J.X. (1999). Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival. Journal of Neurochemistry 73, 521–531.Google Scholar
Dolcet, X., Soler, R.M., Gould, T.W., Egea, J., Oppenheim, R.W. & Comella, J.X. (2001). Cytokines promote motoneuron survival through the Janus kinase-dependent activation of the phosphatidylinositol 3-kinase pathway. Molecular and Cell Neuroscience 18, 619–631.CrossRefGoogle Scholar
Encinas, M., Iglesias, M., Llecha, N. & Comella, J.X. (1999). Extracellular-regulated kinases and phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor-mediated survival and neuritogenesis of the neuroblastoma cell line SH-SY5Y. Journal of Neurochemistry 73, 1409–1421.Google Scholar
Evan, G. & Littlewood, T. (1998). A matter of life and cell death. Science 281, 1317–1322.CrossRefGoogle Scholar
Facchinetti, F., Dawson, V.L. & Dawson, T.M. (1998). Free radicals as mediators of neuronal injury. Cellular and Molecular Neurobiology 18, 667–682.CrossRefGoogle Scholar
Faden, A.I. (1987). Pharmacotherapy in spinal cord injury: a critical review of recent developments. Clinical Neuropharmacology 10, 193–204.CrossRefGoogle Scholar
Gao, H., Qiao, X., Cantor, L.B. & WuDunn, D. (2002). Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells. Archives of Ophthalmology 120, 797–803.CrossRefGoogle Scholar
Hetman, M., Kanning, K., Cavanaugh, J.E. & Xia, Z. (1999). Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. The Journal of Biological Chemistry 274, 22569–22580.CrossRefGoogle Scholar
Ishii, Y., Kwong, J.M. & Caprioli, J. (2003). Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model. Investigative Ophthalmology & Visual Science 44, 1982–1992.CrossRefGoogle Scholar
Kent, A.R., Nussdorf, J.D., David, R., Tyson, F., Small, D. & Fellows, D. (2001). Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology 108, 784–787.CrossRefGoogle Scholar
Kermer, P., Klocker, N., Labes, M. & Bahr, M. (1998). Inhibition of CPP32-like proteases rescues axotomized retinal ganglion cells from secondary cell death in vivo. Journal of Neuroscience 18, 4656–4662.Google Scholar
Kermer, P., Klocker, N., Labes, M. & Bahr, M. (2000). Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo. Journal of Neuroscience 20, 2–8.Google Scholar
Kermer, P., Klocker, N., Labes, M., Thomsen, S., Srinivasan, A. & Bahr, M. (1999). Activation of caspase-3 in axotomized rat retinal ganglion cells in vivo. FEBS Letters 453, 361–364.CrossRefGoogle Scholar
Kim, H.S. & Park, C.K. (2005). Retinal ganglion cell death is delayed by activation of retinal intrinsic cell survival program. Brain Research 1057, 17–28.CrossRefGoogle Scholar
Klocker, N., Kermer, P., Weishaupt, J.H., Labes, M., Ankerhold, R. & Bahr, M. (2000). Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3'-kinase/protein kinase B signaling. Journal of Neuroscience 20, 6962–6967.Google Scholar
Ko, M.L., Hu, D.N., Ritch, R., Sharma, S.C. & Chen, C.F. (2001). Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neuroscience Letters 305, 139–142.CrossRefGoogle Scholar
Levkovitch-Verbin, H., Quigley, H.A., Martin, K.R., Valenta, D., Baumrind, L.A. & Pease, M.E. (2002). Translimbal laser photocoagulation to the trabecular meshwork as a model of glaucoma in rats. Investigative Ophthalmology & Visual Science 43, 402–410.Google Scholar
Levkovitch-Verbin, H., Quigley, H.A., Martin, K.R., Zack, D.J., Pease, M.E. & Valenta, D.F. (2003). A model to study differences between primary and secondary degeneration of retinal ganglion cells in rats by partial optic nerve transection. Investigative Ophthalmolology & Visual Science 44, 3388–3393.CrossRefGoogle Scholar
Lynch, D.R. & Dawson, T.M. (1994). Secondary mechanisms in neuronal trauma. Current Opinions in Neurology 7, 510–516.CrossRefGoogle Scholar
Maier, C., Steinberg, G.K., Sun, G.H., Zhi, G.T. & Maze, M. (1993). Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology 79, 306–312.CrossRefGoogle Scholar
Martin, K.R., Levkovitch-Verbin, H., Valenta, D., Baumrind, L., Pease, M.E. & Quigley, H.A. (2002). Retinal glutamate transporter changes in experimental glaucoma and after optic nerve transection in the rat. Investigative & Ophthalmology Visual Science 43, 2236–2243.Google Scholar
Martin, K.R., Quigley, H.A., Zack, D.J., Levkovitch-Verbin, H., Kielczewski, J., Valenta, D., Baumrind, L., Pease, M.E., Klein, R.L. & Hauswirth, W.W. (2003). Gene therapy with brain-derived neurotrophic factor as a protection: Retinal ganglion cells in a rat glaucoma model. Investigative Ophthalmology & Visual Science 44, 4357–4365.CrossRefGoogle Scholar
Matsuzaki, H., Namikawa, K., Kiyama, H., Mori, N. & Sato, K. (2004). Brain-derived neurotrophic factor rescues neuronal death induced by methamphetamine. Biological Psychiatry 55, 52–60.CrossRefGoogle Scholar
McKinnon, S.J. (1997). Glaucoma, apoptosis, and neuroprotection. Current Opinions in Ophthalmology 8, 28–37.CrossRefGoogle Scholar
Miller, D.B., Blackman, C.F. & O'Callaghan, J.P. (1987). An increase in glial fibrillary acidic protein follows brain hyperthermia in rats. Brain Research 415, 371–374.CrossRefGoogle Scholar
Moore, C.G., Epley, D., Milne, S.T. & Morrison, J.C. (1995). Long-term non-invasive measurement of intraocular pressure in the rat eye. Current Eye Research 14, 711–717.CrossRefGoogle Scholar
Moore, C.G., Milne, S.T. & Morrison, J.C. (1993). Noninvasive measurement of rat intraocular pressure with the Tono-Pen. Investigative Ophthalmology & Visual Science 34, 363–369.Google Scholar
Morrison, J.C., Moore, C.G., Deppmeier, L.M., Gold, B.G., Meshul, C.K. & Johnson, E.C. (1997). A rat model of chronic pressure-induced optic nerve damage. Experimental Eye Research 64, 85–96.CrossRefGoogle Scholar
Nakamura, T., Komiya, M., Gotoh, N., Koizumi, S., Shibuya, M. & Mori, N. (2002). Discrimination between phosphotyrosine-mediated signaling properties of conventional and neuronal Shc adapter molecules. Oncogene 21, 22–31.CrossRefGoogle Scholar
Nakamura, T., Muraoka, S., Sanokawa, R. & Mori, N. (1998). N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling. Journal of Biological Chemistry 273, 6960–6967.CrossRefGoogle Scholar
Nakamura, T., Sanokawa, R., Sasaki, Y., Ayusawa, D., Oishi, M. & Mori, N. (1996). N-Shc: A neural-specific adapter molecule that mediates signaling from neurotrophin/Trk to Ras/MAPK pathway. Oncogene 13, 1111–1121.Google Scholar
Nakazawa, T., Tamai, M. & Mori, N. (2002b). Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death through MAPK and PI3K signaling pathways. Investigative Ophthalmology & Visual Science 43, 3319–3326.Google Scholar
Naskar, R., Wissing, M. & Thanos, S. (2002). Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma. Investigative Ophthalmology & Visual Science 43, 2962–2968.Google Scholar
Neufeld, A.H. (1999). Nitric oxide: a potential mediator of retinal ganglion cell damage in glaucoma. Survey of Ophthalmology 43 (Suppl. 1), S129–135.CrossRefGoogle Scholar
Oltvai, Z.N., Milliman, C.L. & Korsmeyer, S.J. (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–619.CrossRefGoogle Scholar
Pease, M.E., McKinnon, S.J., Quigley, H.A., Kerrigan-Baumrind, L.A. & Zack, D.J. (2000). Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Investigative Ophthalmology & Visual Science 41, 764–774.Google Scholar
Rudzinski, M., Wong, T.P. & Saragovi, H.U. (2004). Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension. Journal of Neurobiology 58, 341–354.CrossRefGoogle Scholar
Shareef, S.R., Garcia-Valenzuela, E., Salierno, A., Walsh, J. & Sharma, S.C. (1995). Chronic ocular hypertension following episcleral venous occlusion in rats. Experimental Eye Research 61, 379–382.CrossRefGoogle Scholar
Tatton, W., Chen, D., Chalmers-Redman, R., Wheeler, L., Nixon, R. & Tatton, N. (2003). Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer's disease: Anti-apoptosis by alpha-2-adrenergic receptor activation. Survey in Ophthalmology 48 (Suppl. 1), S25–37.CrossRefGoogle Scholar
Tatton, W.G., Chalmers-Redman, R.M., Sud, A., Podos, S.M. & Mittag, T.W. (2001). Maintaining mitochondrial membrane impermeability. an opportunity for new therapy in glaucoma? Survey in Ophthalmology 45 (Suppl. 3), S277–283; discussion S295–276.CrossRefGoogle Scholar
Ueda, J., Sawaguchi, S., Hanyu, T., Yaoeda, K., Fukuchi, T., Abe, H. & Ozawa, H. (1998). Experimental glaucoma model in the rat induced by laser trabecular photocoagulation after an intracameral injection of India ink. Japan Journal of Ophthalmology 42, 337–344.CrossRefGoogle Scholar
Vijayan, V.K., Lee, Y.L. & Eng, L.F. (1990). Increase in glial fibrillary acidic protein following neural trauma. Molecular Chemical Neuropathology 13, 107–118.CrossRefGoogle Scholar
Vincent, A.M., Mobley, B.C., Hiller, A. & Feldman, E.L. (2004). IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiological Disorders 16, 407–416.Google Scholar
Vorwerk, C.K., Naskar, R., Schuettauf, F., Quinto, K., Zurakowski, D., Gochenauer, G., Robinson, M.B., Mackler, S.A. & Dreyer, E.B. (2000). Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death. Investigative Ophthalmology & Visual Science 41, 3615–3621.Google Scholar
Wagey, R., Lurot, S., Perrelet, D., Pelech, S.L., Sagot, Y. & Krieger, C. (2001). Phosphatidylinositol 3-kinase activity in murine motoneuron disease: The progressive motor neuropathy mouse. Neuroscience 103, 257–266.CrossRefGoogle Scholar
Wheeler, L.A., Gil, D.W. & WoldeMussie, E. (2001). Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Survey of Ophthalmology 45 (Suppl. 3), S290–294; discussion S295–296.CrossRefGoogle Scholar
Wheeler, L.A., Lai, R. & Woldemussie, E. (1999). From the lab to the clinic: activation of an alpha-2 agonist pathway is neuroprotective in models of retinal and optic nerve injury. European Journal of Ophthalmology 9 (Suppl. 1), S17–21.Google Scholar
Wheeler, L.A. & Woldemussie, E. (2001). Alpha-2 adrenergic receptor agonists are neuroprotective in experimental models of glaucoma. European Journal of Ophthalmology 11 (Suppl. 2), S30–35.CrossRefGoogle Scholar
Whitson, J.T., Henry, C., Hughes, B., Lee, D.A., Terry, S. & Fechtner, R.D. (2004). Comparison of the safety and efficacy of dorzolamide 2% and brimonidine 0.2% in patients with glaucoma or ocular hypertension. Journal of Glaucoma 13, 168–173.Google Scholar
Wirt, H., Draeger, J., Rumberger, E., Deutsch, C. & Dauper, J. (1989). Comparative studies of the calibration of new electronic automatic tonometers. Fortschritte der Ophthalmologie 86, 403–406.Google Scholar
WoldeMussie, E., Ruiz, G., Wijono, M. & Wheeler, L.A. (2001). Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Investigative Ophthalmology & Visual Science 42, 2849–2855.Google Scholar
Zamzami, N., Brenner, C., Marzo, I., Susin, S.A. & Kroemer, G. (1998). Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 16, 2265–2282.CrossRefGoogle Scholar