Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

in macular degeneration patients with an oral dosage of 200 mg of zinc sulfate daily for 2 years with no significant adverse effects (Newsome et al., 1988).

In another study, HSP70 expression was induced in a rat glaucoma model by a systemic administration of geranylgeranylacetate (GGA), an anti-ulcer drug developed in Japan (Ishii et al., 2003; Murakami et al., 1981). It has been suggested that GGA may exert its cytoprotective action through an increase of prostaglandin E2 (Kurihara et al., 1996), maintenance of nitric oxide synthase activity (Nishida et al., 1999), or induction of HSPs (Hirakawa et al., 1996). The administration of GGA was shown to induce the expression of HSP72 in neuronal cells of the adult rat retina. The bioavailability of GGA (125 mg/kg) given by intravenous injection peaks at 6 hours after

administration and can be detected for up to 42 days (Nishizawa et al., 1983). GGA was administered intraperitoneally to rats daily and produced an increased expression of HSP72 in RGCs after 3 days, with no observable side effects. The subsequent chronic administration of GGA (twice weekly) sustained the increased expression of HSP70 and appeared to be non-toxic (Figure 19.4). The administration of GGA enhances RGC survival and reduces axonal injury in the optic nerve of a rat glaucoma model. The results of this study indicate that the neuroprotective effects of GGA may be related to the expression of HSP70 because co-administration with quercetin inhibited HSP70 and blocked the protection of RGCs induced by GGA in a rat glaucoma model (Figure 19.5) (Ishii et al., 2003).

VII. IMMUNE RESPONSE AND

NEUROPROTECTION

BOX 19.1

A growing number of studies associate the immune system with the cell degenerative process during glaucomatous neuropathy. The main function of the immune system is to defend the organism against invading pathogens. Immune responses are well regulated to ensure that when pathogens are eliminated, the immune response is shut down. However, the immune system can occasionally attack self tissues and produce autoimmunity, which is caused by an adaptive immune response against “self” antigens, and may be organ-specific or systemic. Autoimmunity in many cases needs to be diminished or at least minimized in order to preserve health. Autoimmunity can also be beneficial, if it is properly regulated (Hauben et al., 2001; Schwartz, 2001). The role of the immune system response in glaucomatous optic nerve degeneration was described both as neuroprotective and neurodestructive (Tezel and Wax, 2004; Schwartz, 2004).

Although there is no direct evidence, it has been suggested that in some patients, mostly, but not exclusively, in patients with “normal pressure”, an autoimmune mechanism may be responsible for glaucomatous optic nerve degeneration (Wax, 2000). The potential pathogenic role of the immune system in glaucomatous neurodegeneration was substantiated by several findings: an increased prevalence of monoclonal gammopathy (Wax et al., 1994), retinal immunoglobulin deposition (Wax et al., 1998a), elevated serum titers of autoantibodies to many optic nerves (Tezel et al., 1999) and retina antigens (Romano et al., 1995; Wax et al., 1998b, 2001; Tezel et al., 1998; Yang et al., 2001a), and abnormal T-cell subsets (Yang et al., 2001b). Among autoantibodies that

were reported to be increased in the glaucoma patients’ serum were autoantibodies to HSPs, including HSP60, HSP27, and alpha crystallins (Wax et al., 1998b; Tezel et al., 1998). These autoantibodies have been reported to induce neuronal apoptosis (Tezel and Wax, 2000).

The neuroprotective effect of T-cells against specific antigens has been demonstrated in different animal models of RGC degeneration. In the optic nerve crush-injury rat model, T-cell accumulation at the site of the injury and adjacent regions has been shown (Hirschberg et al., 1998; Moalem et al., 1999). It was suggested that T-cells “orchestrate the local immune response to destructive self-compounds” and might have a positive effect in reducing neuronal loss from secondary degeneration. Increasing the number of T-cells at the lesion site with T-cells specific to myelin basic proteins (MBP) was found to be morphologically and functionally neuroprotective (Fisher et al., 2001; Moalem et al., 2000a). The number of healthy fibers was twoto three-fold higher in injured optic nerves treated by passive transfer of anti-MBP T-cells than in untreated controls. However, vaccination with myelin-derived peptides showed no neuroprotective effect in rats with elevated IOP.

Vaccination with R16, a peptide derived from interphotoreceptor retinoid-binding protein (IRBP), an immunodominant antigen residing in the eye, was found to protect RGCs against IOP-induced death, but caused transiently developed experimental autoimmune uveitis (EAU) in susceptible rats. However, vaccination with a copoly- mer-1 (Cop-1) effectively protects RGCs from death induced by optic nerve injury, glutamate toxicity, or ocular hypertension in both EAU-resistant and EAU-suscepti- ble strains (Bakalash et al., 2003).

The neuroprotective effect of low dose radiation on RGC survival in a rat model of (Continued)

Bhavnani, B.R., Berco, M., Binkley, J. (2003). Equine estrogens differentially prevent neuronal cell death induced by glutamate. Soc. Gynecol. Invest. 10, 302–308.

Beere, H.M., Wolf, B.B., Cain, K., Mosser, D.D., Mahboubi, A., Kuwana, T., Tailor, P., Morimoto, R.I., Cohen, G.M., Green, D.R. (2000). Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell. Biol. 2, 469–475.

Behl, C., Skutella, T., Lezoualc’h, F., Post, A., Widmann, M., Newton, C.I., Holsboer, F. (1997). Neuroprotection against oxidative stress by estrogens: structure–activity relationship. Mol. Pharmacol. 51, 535–541.

Blatt, N.B., Glick, G.D. (2001). Signaling pathways and effector mechanisms of pre-programmed cell death.

Bioorg. Med. Chem. 9, 1371–1384.

Bo, L., Dawson, T.M., Wesselingh, S., Mork, S., Choi, S., Kong, P.A., Hanley, D., Trapp, B.D. (1994). Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann. Neurol. 36, 778–786.

Bok, D., Yasumura, D., Matthes, M.T., Ruiz, A., Duncan, J.L., Chappelow, A.V., Zolutukhin, S., Hauswirth, W., LaVail, M.M. (2002). Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation. Exp. Eye Res. 74, 719–735.

Bonfanti, L., Strettoi, E., Chierzi, S., Cenni, M.C., Liu, X.H., Martinou, J.-C., Maffei, L, Rabacchi, S.A. (1996). Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2. J. Neurosci. 16, 4186–4194.

Boveris, A., Chance, B. (1973). The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem. J. 134, 707–716.

Bredt,D.S.,Snyder,S.H.(1994).Nitricoxide:aphysiologic messenger molecule. Ann. Rev. Biochem. 63, 175–195.

Brunet, A., Datta, S.R., Greenberg, M.E. (2001). Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297–305.

Cayouette, M., Gravel, C. (1997). Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum. Gene Ther. 8, 423–430.

Cayouette, M., Behn, D., Sendtner, M., Lachapelle, P., Gravel, C. (1998). Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J. Neurosci. 18, 9282–9293.

Cellerino, A., Carroll, P., Thoenen, H., Barde, Y.-A. (1997). Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Mol. Cell. Neurosci. 9, 397–408.

Chao, M.V., Hempstead, B.L. (1995). p75 and Trk: a two-receptor system. Trends Neurosci. 18, 321–326.

Cheema, S.S., Barrett, G.L., Bartlett, P.F. (1996). Reducing p75 nerve growth factor receptor levels using antisense nucleotides prevents the loss of axotomized sensory neurons in the dorsal root ganglia of newborn rats. J. Neurosci. Res. 46, 239–245.

Chen, H.-S.V., Wang, Y.F., Rayudu, P.V. (1998). Neuroprotective concentrations of the NMDA openchannel blocker memantine are effective without cytoplasmic vacuolization following post-ischemic administration and do not block maze learning or LTP. Neuroscience 86, 1121–1132.

Cheng, L., Sapieha, P., Kittlerova, P., Hauswirth, W.W., Di Polo, A. (2002). Trk B gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J. Neurosci. 22, 3977–3986.

Choi, D.W. (1988). Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634.

Choi, D.W., Koh, J.Y. (1998). Zinc and brain injury.

Ann. Rev. Neurosci. 21, 347–375.

Conover, J.C., Erickson, J.T., Katz, D.M., Bianchi, L.M., Poueymirou, W.T., McClain, J., Pan, L., Helgren, M., Ip, N.Y., Boland, P., Friedman, B., Wiegand, S., Vejsada, R., Kato, A.C., DeChiara, T.M., Yancopoulos, G.D. (1995). Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature 375, 235–238.

Cui, Q., Lu, Q., So, K.F., Yip, H.K. (1999). CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters. Invest. Ophthalmol. Vis. Sci. 40, 760–766.

Daugas, E., Susin, S.A., Zamzami, N., Ferri, K.F., Irinopoulou, T., Larochette, N., Prevost, M.C., Leber, B., Andrews, D., Penninger, J., Kroemer, G. (2000). Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 14, 729–739.

De Almeida, L.P., Zala, D., Aebischer, P., Deglon, N. (2001). Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington’s disease. Neurobiol. Dis. 8, 433–446.

Delbarre, G., Delbarre, B., Calinon, F., Ferger, A. (1991). Accumulation of amino acids and hydroxyl free radicals in brain and retina of gerbil after transient ischemia. J. Ocul. Pharmacol. 7, 147–155.

Denkert, C., Kobel, M., Pest, S., Koch, I., Berger, S., Schwabe, M., Siegert, A., Reles, A., Klosterhalfen, B., Hauptmann, S. (2002). Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. Am. J. Pathol. 160, 893–903.

Derouiche, A. (1996). Possible role of the Müller cell in uptake and metabolism of glutamate in the mammalian outer retina. Vision Res. 36, 3875–3878.

Dingledine, R., Borges, K., Bowie, D., Traynelis, S.F. (1999). The glutamate receptor ion channels.

Pharmacol. Rev. 51, 7–61.

Donello, J.E., Padillo, E.U., Webster, M.L., Wheeler, L.A., Gil, D.W. (2001). Alpha(2)-adrenoceptor agonists inhibit vitreal glutamate and aspartate accumulation and preserve retinal function after transient ischemia. J. Pharmacol. Exp. Ther. 296, 216–223.

Doonan, F., Donovan, M., Cotter, T.G. (2003). Caspaseindependent photoreceptor apoptosis in mouse models of retinal degeneration. J. Neurosci. 23, 5723–5731.

Dugan, L.L., Sensi, S.L., Canzoniero, L.M., Handran, S.D., Rothman, S.M., Lin, T.S., Goldberg, M.P., Choi, D.W. (1995). Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J. Neurosci. 15, 6377–6388.

Dykens, J.A., Simpkins, J.W., Wang, J., Gordon, K. (2003). Polycyclic phenols, estrogens and neuroprotection: a proposed mitochondrial mechanism. Exp. Gerontol. 38, 101–107.

Emerich, D.F., Lindner, M.D., Winn, S.R., Chen, E.Y., Frydel, B.R., Kordower, J.H. (1996). Implants of encapsulated human cntf-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington’s disease. J. Neurosci. 16, 5168–5181.

Emerich, D.F., Winn, S.R., Hantraye, P.M., Peschanski, M., Chen, E.Y., Chu, Y., McDermott, P., Baetge, E.E., Kordower, J.H. (1997). Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 386, 395–399.

Ernfors, P., Lee, K.-F., Jaenisch, R. (1994). Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150.

Farkas, R.H., Grosskreutz, C.L. (2001). Apoptosis, neuroprotection, and retinal ganglion cell death: an overview. Int. Ophthalmol. Clin. 41, 111–130.

Fisher, J., Levkovitch-Verbin, H., Schori, H., Yoles, E., Butovsky, O., Kaye, J.F., Ben-Nun, A., Schwartz, M. (2001). Vaccination for neuroprotection in the mouse optic nerve: implications for optic neuropathies.

J. Neurosci. 21, 136–142.

Frade, J.M., Barde, Y.A. (1999). Genetic evidence for cell death mediated by nerve growth factor and the neurotrophin receptor p75 in the developing mouse retina and spinal cord. Development 126, 683–690.

Francis, P.T., Sims, N.R., Procter, A.W., Bowen, D.M. (1993a). Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer’s disease: investigative and therapeutic perspectives. J. Neurochem. 60, 1589–1604.

Francis, P.T., Webster, M.T., Chessell, I.P., Holmes, C., Stratmann, G.C., Procter, A.W., Cross, A.J., Green, A.R., Bowen, D.M. (1993b). Neurotransmitters and second messengers in aging and Alzheimer’s disease. Ann. NY Acad. Sci. 695, 19–26.

Gabai, V.L., Meriin, A.B., Mosser, D.D., Caron, A.W., Rits, S., Shifrin, V.I., Sherman, M.Y. (1997). Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J. Biol. Chem. 272, 18033–18037.

Gabai, V.L., Yaglom, J.A., Volloch, V., Meriin, A.B., Force, T., Koutroumanis, M., Massie, B., Mosser, D.D., Sherman, M.Y. (2000). Hsp72-mediated suppression

of c-Jun N-terminal kinase is implicated in development of tolerance to caspase-independent cell death. Mol. Cell. Biol. 20, 6826–6836.

Garcia-Segura, L.M., Azcoitia, I., DonCarlos, L.L. (2001). Neuroprotection by estradiol. Prog. Neurobiol. 63, 29–60.

Garthwaite, J., Boulton, C.L. (1995). Nitric oxide signaling in the central nervous system. Ann. Rev. Physiol. 57, 683–706.

Ghosh, A., Greenberg, M.E. (1995). Distinct roles of bFGF and NT-3 in the regulation of cortical neurogenesis. Neuron. 15, 89–103.

Green, D.R. (1998). Apoptotic pathways: the roads to ruin. Cell 9, 695–698.

Green, P.S., Gridley, K.E., Simpkins, J.W. (1998). Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione. Neuroscience 84, 7–10.

Greene, L.A., Kaplan, D.R. (1995). Early events in neurotrophin signalling via Trk and p75 receptors. Curr. Opin. Neurobiol. 5, 579–587.

Hains, B.C., Waxman, S.G. (2005). Neuroprotection by sodium channel blockade with phenytoin in an experimental model of glaucoma. Invest. Ophthalmol. Vis. Sci. 46, 4164–4169.

Hanninen, V.A., Pantcheva, M.B., Freeman, E.E., Poulin, N.R., Grosskreutz, C.L. (2002). Activation of caspase 9 in a rat model of experimental glaucoma.

Curr. Eye Res. 25, 389–395.

Hare, W., WoldeMussie, E., Lai, R., Ton, H., Ruiz, G., Feldmann, B., Wijono, M., Chun, T., Wheeler, L. (2001). Efficacy and safety of memantine, an NMDAtype open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey. Surv. Ophthalmol. 45, S284–289.

Harms, C., Lautenschlager, M., Bergk, A., Katchanov, J., Freyer, D., Kapinya, K., Herwig, U., Megow, D., Dirnagl, U., Weber, J.R., Hortnagl, H. (2001). Differential mechanisms of neuroprotection by 17beta-estradiol in apoptotic versus necrotic neurodegeneration. J. Neurosci. 21, 2600–2609.

Hartle, F.U. (1996). Molecular chaperones in cellular protein folding. Nature 381, 571–579.

Hauben, E., Agranov, E., Gothilf, A., Nevo, U., Cohen, A., Smirnov, I., Steinman, L., Schwartz, M. (2001). Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease.

J. Clin. Invest. 108, 591–599.

Heumann, R. (1994). Neurotrophin signalling. Curr. Biol. 4, 668–679.

Hirakawa, T., Rokutan, K., Nikawa, T., Kishi, K. (1996). Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 111, 345–357.

Hirschberg, D.L., Moalem, G., He, J., Mor, F., Cohen, I.R., Schwartz, M. (1998). Accumulation of passively transferred primed T-cells independently of their

antigen specificity following central nervous system trauma. J. Neuroimmunol. 89, 88–96.

Hofseth, L.J., Hussain, S.P., Harris, C.C. (2004). p53: 25 years after its discovery. Trends Pharmacol. Sci. 25, 177–181.

Hollmann, M., Heinemann, S. (1994). Cloned glutamate receptors. Ann. Rev. Neurosci. 17, 31–108.

Huang, W., Fileta, J.B., Dobberfuhl,A., Filippopolous, T., Guo, Y., Kwon, G., Grosskreutz, C.L. (2005). Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma.

Proc. Natl Acad. Sci. USA 102, 12242–12247.

Hunot, S., Boissiere, F., Faucheux, B., Brugg, B., Mouatt-Prigent, A., Agid, Y., Hirsch, E.C. (1996). Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 72, 355–363.

Isenmann, S., Cellerino, A., Gravel, C., Bahr, M. (1999). Excess target-derived brain-derived neurotrophic factor preserves the transient uncrossed retinal projection to the superior colliculus. Mol. Cell. Neurosci. 14, 52–65.

Ishii, Y., Kwong, J.M., Caprioli, J. (2003). Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model. Invest. Ophthalmol. Vis. Sci. 44, 1982–1992.

Jaattela, M., Wissing, D. (1993). Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection. J. Exp. Med. 177, 231–236.

Ji, J.Z., Elyaman, W., Yip, H.K., Lee, V.W., Yick, L.W., Hugon, J., So, K.F. (2004). CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur. J. Neurosci. 19, 265–272.

Johnson, D., Lanahan, A., Buck, C.R., Sehgal, A., Morgan, C., Mercer, E., Bothwell, M., Chao, M. (1986). Expression and structure of the human NGF receptor. Cell 47, 545–554.

Jones, K.R., Farinas, I., Backus, C., Reichardt, L.F. (1994). Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76, 989–999.

Joza, N., Susin, S.A., Daugas, E., Stanford, W.L., Cho, S.K., Li, C.Y., Sasaki, T., Elia, A.J., Cheng, H.Y., Ravagnan, L., Ferri, K.F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H., Kong, Y.Y., Mak, T.W., ZunigaPflucker, J.C., Kroemer, G., Penninger, J.M. (2001). Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410, 549–554.

Karcioglu, Z.A. (1982). Zinc in the eye. Surv. Ophthalmol. 27, 114–122.

Kiechle, F.L., Malinski, T. (1993). Nitric oxide. Biochemistry, pathophysiology, and detection. Am. J. Clin. Pathol. 100, 567–575.

Kipnis, J., Avidan, H., Markovich, Y., Mizrahi, T., Hauben, E., Prigozhina, T.B., Slavin, S., Schwartz, M. (2004). Low-dose gamma-irradiation promotes survival of injured neurons in the central nervous

system via homeostasis-driven proliferation of T cells. Eur. J. Neurosci. 19, 1191–1198.

Kluck, R.M., Bossy-Wetzel, E., Green, D.R., Newmeyer, D.D. (1997). The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275, 1132–1136.

Kobayashi, K., Kobayashi, H., Ueda, M., Honda, Y. (1998). Estrogen receptor expression in bovine and rat retinas. Invest. Ophthalmol. Vis. Sci. 39, 2105–2110.

Kumar, D.M., Perez, E., Cai, Z.Y., Aoun, P., BrunZinkernagel, A.M., Covey, D.F., Simpkins, J.W., Agarwal, N. (2005). Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate-induced cytotoxicity. Free Radic. Biol. Med. 38, 1152–1163.

Kurihara,T.,Kitamura,Y.,Adachi,Y.,Obuchi,M.,Abe,K., Akimoto, M., Hashimoto, H., Ishiguro, H., Niimi, A., Maeda, A., Shigemoto, M., Yamashita, K., Yokoyama, I. (1996). Increase in hepatic tissue blood flow by teprenone. J. Gastroenterol. Hepatol. 11, 978–984.

Le, D.A., Lipton, S.A. (2001). Potential and current use of N-methyl-D-aspartate (NMDA) receptor antagonists in diseases of aging. Drugs Aging 18, 717–724.

Le Niculescu, H., Bonfoco, E., Kasuya, Y., Claret, F.X., Green, D.R., Karin, M. (1999). Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death. Mol. Cell. Biol. 19, 751–763.

Leaver, S.G., Cui, Q., Plant, G.W., Arulpragasam, A., Hisheh, S., Verhaagen, J., Harvey, A.R. (2006). AAVmediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells. Gene Ther. 13, 1328–1341.

Lehwalder, D., Jeffrey, P.L., Unsicker, K. (1989). Survival of purified embryonic chick retinal ganglion cells in the presence of neurotrophic factors.

J. Neurosci. Res. 24, 329–337.

Leske, M.C. (1983). The epidemiology of open-angle glaucoma: a review. Am. J. Epidemiol. 118, 166–191.

Liang, F.Q., Aleman, T.S., Dejneka, N.S., Dudus, L., Fisher, K.J., Maguire, A.M., Jacobson, S.G., Bennett, J. (2001). Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa. Mol. Ther. 4, 461–472.

Liang, F.Q., Dejneka, N.S., Cohen, D.R., Krasnoperova, N.V., Lem, J., Maguire, A.M., Dudus, L., Fisher, K.J., Bennett, J. (2001). AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor survival in the rhodopsin knockout mouse. Mol. Ther. 3, 241–248.

Lieberman, A.P., Pitha, P.M., Shin, H.S., Shin, M.L. (1989). Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc. Natl Acad. Sci. USA 86, 6348–6352.

Liepinsh, E., Ilag, L.L., Otting, G., Ibanez, C.F. (1997). NMR structure of the death domain of p75 neurotrophin receptor. EMBO J. 16, 4999–5005.

Lindsay, R.M. (1994). Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor.

Neurobiol. Aging 15, 249–251.

Lipton, S.A. (1993). Prospects for clinically-toler- ated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci. 16, 527–532.

Lipton, S.A., Rosenberg, R.A. (1994). Mechanisms of disease: excitatory amino acids as a final common pathway in neurologic disorders. N. Engl. J. Med. 330, 613–622.

Liu, X., Ernfors, P., Wu, H., Jaenisch, R. (1995). Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature 375, 238–241.

Loopuijt, L.D., Schmidt, W.J. (1998). The role of NMDA receptors in the slow neuronal degeneration of Parkinson’s disease. Amino Acids 14, 17–23.

Majdan, M., Lachange, C., Gloster, A., Aloyz, R., Zeindler, C., Bamji, S., Bhakar, A., Belliveau, D.J., Fawcett, J.W., Miller, F.D., Barker, P.A. (1997). Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis. J. Neurosci. 17, 6988–6998.

Mansour-Robaey, S., Clarke, D.B., Wang, Y.C., Bray, G.M., Aguayo, A.J. (1994). Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc. Natl Acad. Sci. USA 91, 1632–1636.

Martin, K.R., Quigley, H.A., Zack, D.J., LevkovitchVerbin, 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. Invest. Ophthalmol. Vis. Sci. 44, 4357–4365.

Massey, S.C. (1990). Cell types using glutamate as a neurotransmitter in the vertebrate retina, in: Progress in Retinal Research (N.N. Osborne, G.J. Chader, eds), pp. 399–425. Pergamon Press: Oxford.

Matsumori, Y., Hong, S.M., Aoyama, K., Fan, Y., Kayama, T., Sheldon, R.A., Vexler, Z.S., Ferriero, D.M., Weinstein, P.R., Liu, J. (2005). Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ ischemic brain injury. J. Cereb. Blood Flow Metab. 25, 899–910.

McKinnon, S.J., Lehman, D.M., Kerrigan-Baumrind, L.A., Merges, C.A., Pease, M.E., Kerrigan, D.F., Ransom, N.L., Tahzib, N.G., Reitsamer, H.A., Levkovitch-Verbin, H., Quigley, H.A., Zack, D.J. (2002a). Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest. Ophthalmol. Vis. Sci. 43, 1077–1087.

McKinnon, S.J., Lehman, D.M., Tahzib, N.G., Ransom, N.L., Reitsamer, H.A., Liston, P., LaCasse, E., Li, Q., Korneluk, R.G., Hauswirth, W.W. (2002b). Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model. Mol. Ther. 5, 780–787.

Mey, J., Thanos, S. (1993). Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res. 602, 304–317.

Moalem, G., Monsonego, A., Shani, Y., Cohen, I.R., Schwartz, M. (1999). Differential T-cell response in central and peripheral nerve injury: connection with immune privilege. FASEB J. 13, 1207–1217.

Moalem, G., Yoles, E., Leibowitz-Amit, R., MullerGilor, S., Mor, F., Cohen, I.R., Schwartz, M. (2000a). Autoimmune T-cells retard the loss of function in injured rat optic nerves. J. Neuroimmunol. 106, 189–197.

Moalem, G., Gdalyahu, A., Shani, Y., Otten, U., Lazarovici, P., Cohen, I.R., Schwartz, M. (2000b). Production of neurotrophins by activated T-cells: implications for neuroprotective autoimmunity.

J. Autoimmun. 15, 331–345.

Moncada, S. (1992). Nitric oxide gas: mediator, modulator, and pathophysiologic entity. J. Lab. Clin. Med. 120, 187–191.

Moncada, S., Higgs, A. (1993). The L-arginine-nitric oxide pathway. N. Engl. J. Med. 329, 2002–2012.

Mosser, D.D., Caron, A.W., Bourget, L., Denis-Larose, C., Massie, B. (1997). Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol. Cell. Biol. 17, 5317–5327.

Murakami, M., Oketani, K., Fujisaki, H., Wakabayashi, T., Ohgo, T. (1981). Antiulcer effect of geranylgeranylacetone, a new acyclic polyisoprenoid on experimentally induced gastric and duodenal ulcers in rats. Arzneimittelforschung 31, 799–804.

Nakanishi, S. (1992). Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597–603.

Nakazawa, T., Takahashi, H., Shimura, M. (2006). Estrogen has a neuroprotective effect on axotomized RGCs through ERK signal transduction pathway. Brain Res. 1093, 141–149.

Neufeld, A.H., Das, S., Vora, S., Gachie, E., Kawai, S., Manning, P.T., Connor J.R. (2002). A prodrug of a selective inhibitor of inducible nitric oxide synthase is neuroprotective in the rat model of glaucoma.

J. Glaucoma 11, 221–225.

Neufeld, A.H., Liu, B. (2003). Glaucomatous optic neuropathy: when glia misbehave. Neuroscientist 9, 485–495.

Newsome, D.A., Swartz, M., Leone, N.C., Elston, R.C., Miller, E. (1988). Oral zinc in macular degeneration.

Arch. Ophthalmol. 106, 192–198.

Nickells, R.W. (1999). Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv. Ophthalmol. 43, S151–161.

Nishida, K., Ohta, Y., Ishiguro, I. (1999). Preventive effect of teprenone on stress-induced gastric mucosal lesions and its relation to gastric mucosal constitutive nitric oxide synthase activity. Pharmacol. Res. 39, 325–332.

Nishizawa, Y., Tanaka, H., Kinoshita, K. (1983). Absorption, distribution, metabolism and egestion of tetraprenylacetone in rats and guinea pigs. Prog. Med. 3, 1029–1035.

Osborne, N.N., Chidlow, G., Nash, M.S., Wood, J.P. (1999a). The potential of neuroprotection in glaucoma treatment. Curr. Opin. Ophthalmol. 10, 82–92.

Osborne, N.N., Wood, J.P., Chidlow, G., Bae, J.H., Melena, J., Nash, M.S. (1999b). Ganglion cell death in glaucoma: what do we really know? Br. J. Ophthalmol. 83, 980–986.

Otori, Y., Wei, J.Y., Barnstable, C.J. (1998). Neurotoxic effects of low doses of glutamate on purified rat retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 39, 972–981.

Park, H.S., Lee, J.S., Huh, S.H., Seo, J.S., Choi, E.J. (2001a). Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J. 20, 446–456.

Park, K.H., Cozier, F., Ong, O.C., Caprioli, J. (2001b). Induction of heat shock protein 72 protects retinal ganglion cells in a rat glaucoma model. Invest. Ophthalmol. Vis. Sci. 42, 1522–1530.

Pin, J.P., Duvoisin, R. (1995). The metabotropic glutamate receptors: structure and functions.

Neuropharmacology 34, 1–26.

Pinkoski, M.J., Green, D.R. (1999). Fas ligand, death gene. Cell Death Differ. 6, 1174–1181.

Plaitakis, A., Caroscio, J.T. (1987). Abnormal glutamate metabolism in amyotrophic lateral sclerosis.

Ann. Neurol. 22, 575–579.

Polla, B.S., Kantengwa, S., Francois, D., Salvioli, S., Franceschi, C., Marsac, C., Cossarizza, A. (1996). Mitochondria are selective target for the protective effects of heat shock against oxidative injury. Proc. Natl Acad. Sci. USA 93, 6458–6463.

Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W., Vogelstein, B. (1997). A model for p53-induced apoptosis. Nature 389, 300–305.

Quigley, H.A., Anderson, D.R. (1977). Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head.

Invest. Ophthalmol. Vis. Sci. 16, 640–644.

Quigley, H.A., Addicks, E.M., Green, W.R., Maumenee, A.E. (1981). Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch. Ophthalmol. 99, 635–649.

Quigley, H.A. (1999). Neuronal death in glaucoma.

Prog. Retin. Eye Res. 18, 39–57.

Quigley, H.A., McKinnon, S.J., Zack, D.J., Pease, M.E., Kerrigan-Baumrind, L.A., Kerrigan, D.F., Mitchell, R.S. (2000). Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest. Ophthalmol. Vis. Sci. 41, 3460–3466.

Rabizadeh, S., Bredesen, D.E. (1994). Is p75NGFR involved in developmental neural cell death? Dev. Neurosci. 16, 207–211.

Raoul, C., Pettmann, B., Henderson, C.E. (2000). Active killing of neurons during development and

following stress: a role for p75NTR and Fas? Curr. Opin. Neurobiol. 10, 111–117.

Rego, A.C., Santos, M.S., Oliveira, C.R. (1996). Oxidative stress, hypoxia, and ischemia-like conditions increase the release of endogenous amino acids by distinct mechanisms in cultured retinal cells. J. Neurochem. 66, 2506–2516.

Rokutan, K., Hirakawa, T., Teshima, S., Nakano, Y., Miyoshi, M., Kawai, T., Konda, E., Morinaga, H., Nikawa, T., Kishi, K. (1998). Implications of heat shock/stress proteins for medicine and disease.

J. Med. Invest. 44, 137–147.

Romano, C., Barrett, D.A., Li, Z., Pestronk, A., Wax, M.B. (1995). Antirhodopsin antibodies in sera from patients with normal-pressure glaucoma. Invest. Ophthalmol. Vis. Sci. 36, 1968–1975.

Sagot, Y., Tan, S.A., Baetge, E., Schmalbruch, H., Kato, A.C., Aebischer. P. (1995). Polymer encapsulated cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse. Eur. J. Neurosci. 7, 1313–1322.

Salvesen, G.S., Renatus, M. (2002). Apoptosome: the seven-spoked death machine. Dev. Cell. 2, 256.

Sastry, P.S., Rao, K. (2000). Apoptosis in the nervous system. J. Neurochem. 74, 1–20.

Sattler, R., Tymianski, M. (2000). Molecular mechanisms of calcium-dependent excitotoxicity. J. Mol. Med. 78, 3–13.

Schwartz, M. (2001). Physiological approaches to neuroprotection. Boosting of protective autoimmunity.

Surv. Ophthalmol. 45, S256–260.

Schwartz, M. (2004). Vaccination for glaucoma: dream or reality? Brain Res. Bull. 62, 481–484.

Segal, R.A., Greenberg, M.E. (1996). Intracellular signaling pathways activated by neurotrophic factors.

Ann. Rev. Neurosci. 19, 463–489.

Sharp, F.R., Massa, S.M., Swanson, R.A. (1999). Heatshock protein protection. Trends Neurosci. 22, 97–99.

Shen, S., Wiemelt, A.P., McMorris, F.A., Barres, B.A. (1999). Retinal ganglion cells lose trophic responsiveness after axotomy. Neuron 23, 285–295.

Smith, S. (2001). The world according to PARP. Trends Biochem. Sci. 26, 174–179.

Stamler, J.S. (1994). Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78, 931–936.

Strasser, A., O’Connor, L., Dixit, V.M. (2000). Apoptosis signaling. Ann. Rev. Biochem. 69, 217–245.

Sucher, N.J., Lipton, S.A., Dreyer, E.B. (1997). Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res. 37, 3483–3493.

Takano, M., Horie, H., Iijima, Y., Dezawa, M., Sawada, H., Ishikawa, Y. (2002). Brain-derived neurotrophic factor enhances neurite regeneration from retinal ganglion cells in aged human retina in vitro. Exp. Eye Res. 74, 319–323.

Tao, W., Wen, R., Goddard, M.B., Sherman, S.D., O’Rourke, P.J., Stabila, P.F., Bell, W.J., Dean, B.J.,

Kauper, K.A., Budz, V.A., Tsiaras, W.G., Acland, G.M., Pearce-Kelling, S., Laties, A.M., Aguirre, G.D. (2002). Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci.

43, 3292–3298.

Tezel, G., Seigel, G.M., Wax, M.B. (1998). Autoantibodies to small heat shock proteins in glaucoma. Invest. Ophthalmol. Vis. Sci. 39, 2277–2287.

Tezel, G., Edward, D.P., Wax, M.B. (1999). Serum autoantibodies to optic nerve head glycosaminoglycans in patients with glaucoma. Arch. Ophthalmol. 117, 917–924.

Tezel, G., Wax, M.B. (2000). The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells. J. Neurosci. 20, 3552–3562.

Tezel, G., Li, L.Y., Patil, R.V., Wax, M.B. (2001). Tumor necrosis factor-alpha and its receptor-1 in the retina of normal and glaucomatous eyes. Invest. Ophthalmol. Visual Sci. 42, 1787–1794.

Tezel, G., Yang, X. (2004). Caspase-independent component of retinal ganglion cell death, in vitro. Invest. Ophthalmol. Vis. Sci. 45, 4049–4059.

Tezel, G., Yang, X., Yang, J., Wax, M.B. (2004). Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice. Brain Res. 996, 202–212.

Tezel, G., Wax, M.B. (2004). The immune system and glaucoma. Curr. Opin. Ophthalmol. 15, 80–84.

Thorburn, A. (2004). Death receptor-induced cell killing. Cell Sig. 16, 139–144.

Tolkovsky. A. (1997). Neurotrophic factors in action – new dogs and new tricks. Trends Neurosci. 20, 1–3.

Tymianski, M., Tator, C.H. (1996). Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery 38, 1176–1195.

Wang, H.G., Pathan, N., Ethell, I.M., Krajewski, S., Yamaguchi, Y., Shibasaki, F., McKeon, F., Bobo, T., Franke, T.F., Reed, J.C. (1999). Ca2 -induced apoptosis through calcineurin dephosphorylation of BAD. Science 284, 339–343.

Watanabe, M., Sawai, H., Fukuda, Y. (1997). Survival of axotomized retinal ganglion cells in adult mammals. Clin. Neurosci. 4, 233–239.

Wax, M.B., Barrett, D.A., Pestronk, A. (1994). Increased incidence of paraproteinemia and autoantibodies in patients with normal-pressure glaucoma. Am. J. Ophthalmol. 117, 561–568.

Wax, M.B., Tezel, G., Edward, P.D. (1998a). Clinical and ocular histopathological findings in a patient with normal-pressure glaucoma. Arch. Ophthalmol. 116, 993–1001.

Wax, M.B., Tezel, G., Saito, I., Gupta, R.S., Harley, J.B., Li, Z., Romano, C. (1998b). Anti-Ro/SS-A positivity and heat shock protein antibodies in patients with normal-pressure glaucoma. Am. J. Ophthalmol. 125, 145–157.

Wax, M.B. (2000). Is there a role for the immune system in glaucomatous optic neuropathy? Curr. Opin. Ophthalmol. 11, 145–150.

Wax, M.B., Tezel, G., Kawase, K., Kitazawa, Y. (2001). Serum autoantibodies to heat shock proteins in glaucoma patients from Japan and the United States. Ophthalmology 108, 296–302.

Wen, R., Cheng, T., Li, Y., Cao, W., Steinberg, R.H. (1996). Alpha-2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage. J. Neurosci. 16, 5986–5992.

Wheeler, L.A., Gil, D.W., WoldeMussie, E. (2001). Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Surv. Ophthalmol. 45, 290–294.

Williams, J.T., North, R.A. (1985). Catecholamine inhibition of calcium action potentials in rat locus coeruleus neurones. Neuroscience 14, 103–109.

Wood, J.P., Schmidt, K.G., Melena, J., Chidlow, G., Allmeier, H., Osborne, N.N. (2003). The beta-adren- oceptor antagonists metipranlol and timolol are retinal neuroprotectants: comparison with betaxolol.

Exp. Eye Res. 76, 505–516.

Wood, K.A., Youle, R.J. (1995). The role of free radicals and p53 in neuron apoptosis in vivo. J. Neurosci. 15, 5851–5857.

Yan, X., Tezel, G., Wax, M.B., Edward, D.P. (2000). Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch. Ophthalmol. 118, 666–673.

Yang, J., Liu, X., Bhalla, K., Kim, C.N., Ibrado, A.M., Cai, J., Peng, T.I., Jones, D.P., Wang, X. (1997). Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132.

Yang, J., Tezel, G., Patil, R.V., Romano, C., Wax, M.B. (2001a). Serum autoantibody against glutathione S-transferase in patients with glaucoma. Invest. Ophthalmol. Vis. Sci. 42, 1273–1276.

Yang, J., Patil, R.V.,Yu, H., Gordon, M., Wax, M.B. (2001b). T-cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am. J. Ophthalmol. 131, 421–426.

Yoles, E., Schwartz, M. (1998). Potential neuroprotective therapy for glaucomatous optic neuropathy.

Surv. Ophthalmol. 42, 367–372.

Yoles, E., Wheeler, L., Schwartz, M. (1999). Alpha2adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration. Invest. Ophthalmol. Vis. Sci. 40, 65–73.

Zaulyanov, L.L., Green, P.S., Simpkins, J.W. (1999). Glutamate receptor requirement for neuronal death from anoxia-reoxygenation: an in vitro model for assessment of the neuroprotective effects of estrogens. Cell. Mol. Neurobiol. 19, 705–717.

Zhang, J., Wu, S.M., Gross, R.L. (2003). Effects of betaadrenergic blockers on glutamate-induced calcium signals in adult mouse retinal ganglion cells. Brain Res. 959, 111–119.

Zimmermann, K.C., Bonzon, C., Green, D.R. (2001). The machinery of programmed cell death.

Pharmacol. Ther. 92, 57–70.

Degenerative retinopathies affect millions of people around the world. These mainly fall into the families of retinitis pigmentosa (RP) and macular degenerations, the latter including age-related macular degeneration (AMD). These diseases are genetic in nature although environmental factors affect AMD. Only a few treatments are currently available for these conditions. However, proof of principle for several new treatments has been established and some clinical trials have already begun. This chapter outlines current and future therapies for the retinal degenerative diseases including transplantation, electronic prosthetic devices, pharmaceutical therapy, nutritional therapy and gene therapy.

Degenerative retinopathies (i.e. retinal degenerations, retinal dystrophies) are a large family of diseases that mainly affect the retina and often lead to severe visual loss or blindness. In the retina, it is most often the photoreceptor cells that are affected although the retinal pigment epithelial (RPE) cells are often involved and may even be primarily affected (i.e. primary gene mutation). Although diverse in phenotype, the degenerations can roughly be divided into diseases that primarily affect either rod photoreceptor or cone photoreceptor neurons. The first grouping consists mainly of the retinitis pigmentosa (RP)-like diseases in which there are early dim or night vision problems and preferential loss of peripheral vision leading