temporal manner by delaying the development of peak RGC apoptosis as well as reducing the peak level of RGC apoptosis. Among them, the anti-Ab ab appeared the most effective in the prevention of RGC apoptosis compared with CR and the bSI. The single application of the Abab showed a prolonged effect up to 16 weeks following IOP elevation. In comparison, CR appeared to have a shorter window of RGC protection and bSI showed no significant effect on glaucomatous RGC apoptosis (Fig. 4).

Perhaps the most significant finding of the work with DARC has been combination therapy, targeting three different aspects of the Ab pathway. In combination, the neuroprotective effect of all three agents (triple therapy) was significantly improved at 3 weeks after IOP elevation compared with Abab alone (Fig. 5). The combination therapy produced the maximal reduction of RGC apoptosis (W80%).

Using DARC, we have highlighted that Ab is a likely mediator of pressure-induced RGC death and that targeting multiple stages in the Ab pathway may provide a potential neuroprotective strategy in glaucoma management.

Assessment of coenzyme Q10 in glaucoma-related models with DARC

Coenzyme Q10 (CoQ10) is an important insoluble component of the mitochondrial respiratory chain where it transports electrons from complexes I and II to complex III, by which ATP is produced. CoQ10 has been reported to afford neuroprotection, preventing neuronal death (Papucci et al.,

2003). CoQ10 acts as a potent antioxidant by maintaining the mitochondrial membrane potential and inhibiting ROS generation when neuronal cells are subject to oxidative stress (McCarthy et al., 2004; Somayajulu et al., 2005). CoQ10 has been shown to prevent RGC apoptosis in a pressure-induced transient ischemia model by minimizing synaptic glutamate increase and inhibiting the MPTP formation (Nucci et al., 2007). CoQ10 has been safely used in patients with neurodegenerative disorders (Levy et al., 2006; Liu, 2007).

We have investigated the effects of topical CoQ10 on reducing RGC apoptosis in vivo using our SSP rat model (Cordeiro et al., 2007). Our DARC imaging results showed that CoQ10 0.1% significantly reduced SSP-induced RGC apoptosis compared to CoQ10 0.05% and carrier. The most effective timing administration was at 1 h after SSP application. The effects of CoQ10 on preventing RGC apoptosis may be attributed to its property of inhibiting mitochondrial depolarization, cytochrome c release, and caspase-9 activation (Papucci et al., 2003).

Summary

Currently, there is no good and quick method for assessing neuroprotection in glaucoma. The only neuroprotective drug that has undergone large scale clinical trial in glaucoma, memantine, has relied on visual field status as a defined end point, which has led to an expensive 6-year period of follow-up — with still no published outcome. We

446

believe our recently developed DARC imaging technology is a major advance in this area, with the potential of providing a much needed new end point in glaucoma. This is supported by our experimental work, which has clearly shown the power of this technology in assessing neuroprotective strategies. Clinical trials of DARC are due to start in 2008, and we eagerly await the results.

Acknowledgment

The work was supported by Wellcome Trust Grant, T.F.C. Frost and Lilly Research Laboratories.

References

Archer, S., Hirano, J., Diss, J.K., Fraser, S.P. and Djamgoz, M.B. (1998) Expression and localization in the fish retina of a homologue of the Alzheimer’s related PS1 gene. Neuroreport, 9(9): 2049–2056.

Auld, D.S., Kornecook, T.J., Bastianetto, S. and Quirion, R. (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog. Neurobiol., 68(3): 209–245.

Bard, F., Cannon, C., Barbour, R., Burke, R.L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguyen, M., Soriano, F., Vasquez, N., Weiss, K., Welch, B., Seubert, P., Schenk, D. and Yednock, T. (2000) Peripherally administered antibodies against amyloid betapeptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med., 6(8): 916–919.

Bayer, A.U., Keller, O.N., Ferrari, F. and Maag, K.P. (2002) Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer’s disease and Parkinson’s disease. Am. J. Ophthalmol., 133(1): 135–137.

Belmokhtar, C.A., Hillion, J. and Segal-Bendirdjian, E. (2001) Staurosporine induces apoptosis through both caspasedependent and caspase-independent mechanisms. Oncogene, 20(26): 3354–3362.

Berisha, F., Feke, G.T., Trempe, C.L., McMeel, J.W. and Schepens, C.L. (2007) Retinal abnormalities in early Alzheimer’s disease. Invest. Ophthalmol. Vis. Sci., 48(5): 2285–2289.

Blankenberg, F.G., Katsikis, P.D., Tait, J.F., Davis, R.E., Naumovski, L., Ohtsuki, K., Kopiwoda, S., Abrams, M.J., Darkes, M., Robbins, R.C., Maecker, H.T. and Strauss, H.W. (1998) In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc. Natl. Acad. Sci. U.S.A., 95(11): 6349–6354.

Blanks, J.C., Schmidt, S.Y., Torigoe, Y., Porrello, K.V., Hinton, D.R. and Blanks, R.H. (1996a) Retinal pathology in Alzheimer’s disease. II. Regional neuron loss and glial changes in GCL. Neurobiol. Aging, 17(3): 385–395.

Blanks, J.C., Torigoe, Y., Hinton, D.R. and Blanks, R.H. (1996b) Retinal pathology in Alzheimer’s disease. I. Ganglion cell loss in foveal/parafoveal retina. Neurobiol. Aging, 17(3): 377–384.

Boersma, H.H., Liem, I.H., Kemerink, G.J., Thimister, P.W., Hofstra, L., Stolk, L.M., van Heerde, W.L., Pakbiers, M.T., Janssen, D., Beysens, A.J., Reutelingsperger, C.P. and Heidendal, G.A. (2003) Comparison between human pharmacokinetics and imaging properties of two conjugation methods for 99mTc-annexin A5. Br. J. Radiol., 76(908): 553–560.

Bond, A., O’Neill, M.J., Hicks, C.A., Monn, J.A. and Lodge, D. (1998) Neuroprotective effects of a systemically active group II metabotropic glutamate receptor agonist LY354740 in a gerbil model of global ischaemia. Neuroreport, 9(6): 1191–1193.

Brandstatter, J.H., Hartveit, E., Sassoe-Pognetto, M. and Wassle, H. (1994) Expression of NMDA and high-affinity kainate receptor subunit mRNAs in the adult rat retina. Eur. J. Neurosci., 6(7): 1100–1112.

Brooks, D.E., Garcia, G.A., Dreyer, E.B., Zurakowski, D. and Franco-Bourland, R.E. (1997) Vitreous body glutamate concentration in dogs with glaucoma. Am. J. Vet. Res., 58(8): 864–867.

Carter-Dawson, L., Crawford, M.L., Harwerth, R.S., Smith, E.L., 3rd, Feldman, R., Shen, F.F., Mitchell, C.K. and Whitetree, A. (2002) Vitreal glutamate concentration in monkeys with experimental glaucoma. Invest. Ophthalmol. Vis. Sci., 43(8): 2633–2637.

Chaudhary, P., Ahmed, F. and Sharma, S.C. (1998) MK801 — a neuroprotectant in rat hypertensive eyes. Brain Res., 792(1): 154–158.

Citron, M. (2002) Beta-secretase as a target for the treatment of Alzheimer’s disease. J. Neurosci. Res., 70(3): 373–379.

Collaborative Normal-Tension Glaucoma Study Group. (1998) Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am. J. Ophthalmol., 126(4): 487–497.

Cordeiro, M.F., Guo, L., Cheung, W., Wood, N. and Salt, T.E. (2007) Topical CoQ10 Is Neuroprotective in Experimental Glaucoma. ARVO, Fort Lauderdale, USA.

Cordeiro, M.F., Guo, L., Luong, V., Harding, G., Wang, W., Jones, H.E., Moss, S.E., Sillito, A.M. and Fitzke, F.W. (2004) Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc. Natl. Acad. Sci. U.S.A., 101(36): 13352–13356.

Danesh-Meyer, H.V., Carroll, S.C., Ku, J.Y., Hsiang, J., Gaskin, B., Gamble, G.G. and Savino, P.J. (2006) Correlation of retinal nerve fiber layer measured by scanning laser polarimeter to visual field in ischemic optic neuropathy. Arch. Ophthalmol., 124(12): 1720–1726.

Dkhissi, O., Chanut, E., Wasowicz, M., Savoldelli, M., Nguyen-Legros, J., Minvielle, F. and Versaux-Botteri, C. (1999) Retinal TUNEL-positive cells and high glutamate levels in vitreous humor of mutant quail with a glaucoma-like disorder. Invest. Ophthalmol. Vis. Sci., 40(5): 990–995.

Dreyer, E.B., Zurakowski, D., Schumer, R.A., Podos, S.M. and Lipton, S.A. (1996) Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch. Ophthalmol., 114(3): 299–305.

Dumont, E.A., Hofstra, L., van Heerde, W.L., van den Eijnde, S., Doevendans, P.A., DeMuinck, E., Daemen, M.A., Smits, J.F., Frederik, P., Wellens, H.J., Daemen, M.J. and Reutelingsperger, C.P. (2000) Cardiomyocyte death induced by myocardial ischemia and reperfusion: measurement with recombinant human annexin-V in a mouse model. Circulation, 102(13): 1564–1568.

Dumont, E.A., Reutelingsperger, C.P., Smits, J.F., Daemen, M.J., Doevendans, P.A., Wellens, H.J. and Hofstra, L. (2001) Real-time imaging of apoptotic cell-membrane changes at the

447

single-cell level in the beating murine heart. Nat. Med., 7(12): 1352–1355.

el-Asrar, A.M., Morse, P.H., Maimone, D., Torczynski, E. and Reder, A.T. (1992) MK-801 protects retinal neurons from hypoxia and the toxicity of glutamate and aspartate. Invest. Ophthalmol. Vis. Sci., 33(12): 3463–3468.

Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L. and Henson, P.M. (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol., 148(7): 2207–2216.

Fitzke, F. (2000) Imaging the optic nerve and ganglion cell layer. Eye, 14: 450–453.

Fletcher, E.L., Hack, I., Brandstatter, J.H. and Wassle, H. (2000) Synaptic localization of NMDA receptor subunits in the rat retina. J. Comp. Neurol., 420(1): 98–112.

Goldblum, D., Kipfer-Kauer, A., Sarra, G.M., Wolf, S. and Frueh, B.E. (2007) Distribution of amyloid precursor protein and amyloid-{beta} immunoreactivity in DBA/2J glaucomatous mouse retinas. Invest. Ophthalmol. Vis. Sci., 48(11): 5085–5090.

Greenfield, D.S., Girkin, C. and Kwon, Y.H. (2005) Memantine and progressive glaucoma. J. Glaucoma, 14(1): 84–86.

Guo, L., Moss, S.E., Alexander, R.A., Ali, R.R., Fitzke, F.W. and Cordeiro, M.F. (2005a) Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix. Invest. Ophthalmol. Vis. Sci., 46(1): 175–182.

Guo, L., Tsatourian, V., Luong, V., Podoleanu, A.G., Jackson, D.A., Fitzke, F.W. and Cordeiro, M.F. (2005b) En face optical coherence tomography: a new method to analyse structural changes of the optic nerve head in rat glaucoma. Br. J. Ophthalmol., 89(9): 1210–1216.

Guo, L., Salt, T.E., Maass, A., Luong, V., Moss, S.E., Fitzke, F.W. and Cordeiro, M.F. (2006) Assessment of neuroprotective effects of glutamate modulation on glaucoma-related retinal ganglion cell apoptosis in vivo. Invest. Ophthalmol. Vis. Sci., 47(2): 626–633.

Guo, L., Salt, T.E., Luong, V., Wood, N., Cheung, W., Maass, A., Ferrari, G., Russo-Marie, F., Sillito, A.M., Cheetham, M.E., Moss, S.E., Fitzke, F.W. and Cordeiro, M.F. (2007) Targeting amyloid-beta in glaucoma treatment. Proc. Natl. Acad. Sci. U.S.A., 104(33): 13444–13449.

Hamassaki-Britto, D.E., Hermans-Borgmeyer, I., Heinemann, S. and Hughes, T.E. (1993) Expression of glutamate receptor genes in the mammalian retina: the localization of GluR1 through GluR7 mRNAs. J. Neurosci., 13(5): 1888–1898.

Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 297(5580): 353–356.

Hare, W.A., WoldeMussie, E., Lai, R.K., Ton, H., Ruiz, G., Chun, T. and Wheeler, L. (2004a) Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: Functional measures. Invest. Ophthalmol. Vis. Sci., 45(8): 2625–2639.

Hare, W.A., WoldeMussie, E., Weinreb, R.N., Ton, H., Ruiz, G., Wijono, M., Feldmann, B., Zangwill, L. and Wheeler, L.

448

(2004b) Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: Structural measures. Invest. Ophthalmol. Vis. Sci., 45(8): 2640–2651.

Hartveit, E., Brandstatter, J.H., Enz, R. and Wassle, H. (1995) Expression of the mRNA of seven metabotropic glutamate receptors (mGluR1 to 7) in the rat retina. An in situ hybridization study on tissue sections and isolated cells. Eur. J. Neurosci., 7(7): 1472–1483.

Hartwick, A.T., Zhang, X., Chauhan, B.C. and Baldridge, W.H. (2005) Functional assessment of glutamate clearance mechanisms in a chronic rat glaucoma model using retinal ganglion cell calcium imaging. J. Neurochem., 94(3): 794–807.

Hirakura, Y., Lin, M.C. and Kagan, B.L. (1999) Alzheimer amyloid abeta1-42 channels: effects of solvent, pH, and Congo Red. J. Neurosci. Res., 57(4): 458–466.

Hofstra, L., Dumont, E.A., Thimister, P.W., Heidendal, G.A., DeBruine, A.P., Elenbaas, T.W., Boersma, H.H., van Heerde, W.L. and Reutelingsperger, C.P. (2001) In vivo detection of apoptosis in an intracardiac tumor. JAMA, 285(14): 1841–1842.

Honkanen, R.A., Baruah, S., Zimmerman, M.B., Khanna, C.L., Weaver, Y.K., Narkiewicz, J., Waziri, R., Gehrs, K.M., Weingeist, T.A., Boldt, H.C., Folk, J.C., Russell, S.R. and Kwon, Y.H. (2003) Vitreous amino acid concentrations in patients with glaucoma undergoing vitrectomy. Arch. Ophthalmol., 121(2): 183–188.

Iseri, P.K., Altinas, O., Tokay, T. and Yuksel, N. (2006) Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J. Neuroophthalmol., 26(1): 18–24.

Johnson, L.V., Leitner, W.P., Rivest, A.J., Staples, M.K., Radeke, M.J. and Anderson, D.H. (2002) The Alzheimer’s A beta-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc. Natl. Acad. Sci. U.S.A., 99(18): 11830–11835.

Kaushik, S., Pandav, S.S. and Ram, J. (2003) Neuroprotection in glaucoma. J. Postgrad. Med., 49(1): 90–95.

Kenis, H., van Genderen, H., Bennaghmouch, A., Rinia, H.A., Frederik, P., Narula, J., Hofstra, L. and Reutelingsperger, C.P. (2004) Cell surface-expressed phosphatidylserine and annexin A5 open a novel portal of cell entry. J. Biol. Chem., 279(50): 52623–52629.

Kerrigan, L., Zack, D., Quigley, H., Smith, S.D. and Pease, M. (1997) TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch. Ophthalmol., 115: 1031–1035.

Kerrigan-Baumrind, L., Quigley, H., Pease, M., Kerrigan, D. and Mitchell, R. (2000) Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest. Ophthalmol. Vis. Sci., 41: 741–748.

Kietselaer, B.L., Reutelingsperger, C.P., Heidendal, G.A., Daemen, M.J., Mess, W.H., Hofstra, L. and Narula, J. (2004) Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N. Engl. J. Med., 350(14): 1472–1473.

Kim, T.W., Kim, D.M., Park, K.H. and Kim, H. (2002) Neuroprotective effect of memantine in a rabbit model of optic nerve ischemia. Korean J. Ophthalmol., 16(1): 1–7.

Kingston, A.E., O’Neill, M.J., Lam, A., Bales, K.R., Monn, J.A. and Schoepp, D.D. (1999) Neuroprotection by metabotropic glutamate receptor glutamate receptor agonists: LY354740, LY379268 and LY389795. Eur. J. Pharmacol., 377(2–3): 155–165.

Koh, J.Y., Wie, M.B., Gwag, B.J., Sensi, S.L., Canzoniero, L.M., Demaro, J., Csernansky, C. and Choi, D.W. (1995) Staurosporine-induced neuronal apoptosis. Exp. Neurol., 135(2): 153–159.

Koopman, G., Reutelingsperger, C.P., Kuijten, G.A., Keehnen, R.M., Pals, S.T. and van Oers, M.H. (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood, 84(5): 1415–1420.

Lagreze, W.A., Knorle, R., Bach, M. and Feuerstein, T.J. (1998) Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia. Invest. Ophthalmol. Vis. Sci., 39(6): 1063–1066.

Lee, P.P., Walt, J.G., Doyle, J.J., Kotak, S.V., Evans, S.J., Budenz, D.L., Chen, P.P., Coleman, A.L., Feldman, R.M., Jampel, H.D., Katz, L.J., Mills, R.P., Myers, J.S., Noecker, R.J., Piltz-Seymour, J.R., Ritch, R.R., Schacknow, P.N., Serle, J.B. and Trick, G.L. (2006) A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch. Ophthalmol., 124(1): 12–19.

Levkovitch-Verbin, H., Quigley, H.A., Kerrigan-Baumrind, L.A., D’Anna, S.A., Kerrigan, D. and Pease, M.E. (2001) Optic nerve transection in monkeys may result in secondary degeneration of retinal ganglion cells. Invest. Ophthalmol. Vis. Sci., 42(5): 975–982.

Levkovitch-Verbin, H., Martin, K.R., Quigley, H.A., Baumrind, L.A., Pease, M.E. and Valenta, D. (2002) Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection. J. Glaucoma, 11(5): 396–405.

Levkovitch-Verbin, H., Quigley, H.A., Martin, K.R., Zack, D.J., Pease, M.E. and 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. Invest. Ophthalmol. Vis. Sci., 44(8): 3388–3393.

Levy, G., Kaufmann, P., Buchsbaum, R., Montes, J., Barsdorf, A., Arbing, R., Battista, V., Zhou, X., Mitsumoto, H., Levin, B. and Thompson, J.L. (2006) A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS. Neurology, 66(5): 660–663.

Li, H.L., Roch, J.M., Sundsmo, M., Otero, D., Sisodia, S., Thomas, R. and Saitoh, T. (1997) Defective neurite extension is caused by a mutation in amyloid beta/A4 (A beta) protein precursor found in familial Alzheimer’s disease. J. Neurobiol., 32(5): 469–480.

Lipton, S.A. (1993) Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci., 16(12): 527–532.

Lipton, S.A. (2001) Retinal ganglion cells, glaucoma and neuroprotection. Prog. Brain Res., 131: 712–718.

Lipton, S.A. (2004a) Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. Neurorx, 1(1): 101–110.

Lipton, S.A. (2004b) Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J. Alzheimers Dis., 6(6 Suppl): S61–S74.

Liu, J. (2007) The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem. Res.

Lleo, A., Greenberg, S.M. and Growdon, J.H. (2006) Current pharmacotherapy for Alzheimer’s disease. Annu. Rev. Med., 57: 513–533.

Loffler, K.U., Edward, D.P. and Tso, M.O. (1995) Immunoreactivity against tau, amyloid precursor protein, and betaamyloid in the human retina. Invest. Ophthalmol. Vis. Sci., 36(1): 24–31.

Lorenzo, A. and Yankner, B.A. (1994) Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. U.S.A., 91(25): 12243–12247.

Lucas, D.R. and Newhouse, J.P. (1957) The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch. Ophthalmol., 58(2): 193–201.

Maass, A., von Leithner, P.L., Luong, V., Guo, L., Salt, T.E., Fitzke, F.W. and Cordeiro, M.F. (2007) Assessment of rat and mouse RGC apoptosis imaging in vivo with different scanning laser ophthalmoscopes. Curr. Eye Res., 32(10): 851–861.

Martin, K.R., Levkovitch-Verbin, H., Valenta, D., Baumrind, L., Pease, M.E. and Quigley, H.A. (2002) Retinal glutamate transporter changes in experimental glaucoma and after optic nerve transection in the rat. Invest. Ophthalmol. Vis. Sci., 43(7): 2236–2243.

McCarthy, S., Somayajulu, M., Sikorska, M., BorowyBorowski, H. and Pandey, S. (2004) Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble coenzyme Q10. Toxicol. Appl. Pharmacol., 201(1): 21–31.

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. and Zack, D.J. (2002) Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest. Ophthalmol. Vis. Sci., 43(4): 1077–1087.

Monn, J.A., Valli, M.J., Massey, S.M., Wright, R.A., Salhoff, C.R., Johnson, B.G., Howe, T., Alt, C.A., Rhodes, G.A., Robey, R.L., Griffey, K.R., Tizzano, J.P., Kallman, M.J., Helton, D.R. and Schoepp, D.D. (1997) Design, synthesis, and pharmacological characterization of (+)-2-aminobicy- clo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. J. Med. Chem., 40(4): 528–537.

Murakami, Y., Takamatsu, H., Taki, J., Tatsumi, M., Noda, A., Ichise, R., Tait, J.F. and Nishimura, S. (2004) 18F-

449

Labelled annexin V: a PET tracer for apoptosis imaging. Eur. J. Nucl. Med. Mol. Imaging, 31(4): 469–474.

Narula, J., Acio, E.R., Narula, N., Samuels, L.E., Fyfe, B., Wood, D., Fitzpatrick, J.M., Raghunath, P.N., Tomaszewski, J.E., Kelly, C., Steinmetz, N., Green, A., Tait, J.F., Leppo, J., Blankenberg, F.G., Jain, D. and Strauss, H.W. (2001) Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat. Med., 7(12): 1347–1352.

Nicoletti, F., Bruno, V., Copani, A., Casabona, G. and Knopfel, T. (1996) Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders? Trends Neurosci., 19(7): 267–271.

Nucci, C., Tartaglione, R., Cerulli, A., Mancino, R., Spano, A., Cavaliere, F., Rombola, L., Bagetta, G., Corasaniti, M.T. and Morrone, L.A. (2007) Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat. Int. Rev. Neurobiol., 82: 397–406.

Oliver, J.E., Hattenhauer, M.G., Herman, D., Hodge, D.O., Kennedy, R., Fang-Yen, M. and Johnson, D.H. (2002) Blindness and glaucoma: a comparison of patients progressing to blindness from glaucoma with patients maintaining vision. Am. J. Ophthalmol., 133(6): 764–772.

Osborne, N.N. (1999) Memantine reduces alterations to the mammalian retina, in situ, induced by ischemia. Vis. Neurosci., 16(1): 45–52.

Papucci, L., Schiavone, N., Witort, E., Donnini, M., Lapucci, A., Tempestini, A., Formigli, L., Zecchi-Orlandini, S., Orlandini, G., Carella, G., Brancato, R. and Capaccioli, S. (2003) Coenzyme q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical scavenging property. J. Biol. Chem., 278(30): 28220–28228.

Parisi, V., Restuccia, R., Fattapposta, F., Mina, C., Bucci, M.G. and Pierelli, F. (2001) Morphological and functional retinal impairment in Alzheimer’s disease patients. Clin. Neurophysiol., 112(10): 1860–1867.

Pastorino, L. and Lu, K.P. (2006) Pathogenic mechanisms in Alzheimer’s disease. Eur. J. Pharmacol., 545(1): 29–38.

Pepys, M.B. (2006) Amyloidosis. Annu. Rev. Med., 57: 223–241.

Post, A.M., Katsikis, P.D., Tait, J.F., Geaghan, S.M., Strauss, H.W. and Blankenberg, F.G. (2002) Imaging cell death with radiolabeled annexin V in an experimental model of rheumatoid arthritis. J. Nucl. Med., 43(10): 1359–1365.

Quigley, H.A., Nickells, R.W., Kerrigan, L.A., Pease, M.E., Thibault, D.J. and Zack, D.J. (1995) Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest. Ophthalmol. Vis. Sci., 36(5): 774–786.

Robbins, J., Reynolds, A.M., Treseder, S. and Davies, R. (2003) Enhancement of low-voltage-activated calcium currents by group II metabotropic glutamate receptors in rat retinal ganglion cells. Mol. Cell. Neurosci., 23(3): 341–350.

Salt, T.E. and Cordeiro, M.F. (2006) Glutamate excitotoxicity in glaucoma: throwing the baby out with the bathwater? Eye, 20(6): 730–731, author reply 731–732.

Schuettauf, F., Quinto, K., Naskar, R. and Zurakowski, D. (2002) Effects of anti-glaucoma medications on ganglion cell

450

survival: the DBA/2J mouse model. Vision Res., 42(20): 2333–2337.

Shen, W. and Slaughter, M.M. (1998) Metabotropic and ionotropic glutamate receptors regulate calcium channel currents in salamander retinal ganglion cells. J. Physiol., 510(Pt 3): 815–828.

Somayajulu, M., McCarthy, S., Hung, M., Sikorska, M., Borowy-Borowski, H. and Pandey, S. (2005) Role of mitochondria in neuronal cell death induced by oxidative stress; neuroprotection by coenzyme Q10. Neurobiol. Dis., 18(3): 618–627.

Sullivan, R.K., Woldemussie, E., Macnab, L., Ruiz, G. and Pow, D.V. (2006) Evoked expression of the glutamate transporter GLT-1c in retinal ganglion cells in human glaucoma and in a rat model. Invest. Ophthalmol. Vis. Sci., 47(9): 3853–3859.

Tamura, H., Kawakami, H., Kanamoto, T., Kato, T., Yokoyama, T., Sasaki, K., Izumi, Y., Matsumoto, M. and Mishima, H.K. (2006) High frequency of open-angle glaucoma in Japanese patients with Alzheimer’s disease. J. Neurol. Sci., 246(1–2): 79–83.

Tehrani, A., Wheeler-Schilling, T.H. and Guenther, E. (2000) Coexpression patterns of mGLuR mRNAs in rat retinal ganglion cells: a single-cell RT-PCR study. Invest. Ophthalmol. Vis. Sci., 41(1): 314–319.

Thuret, G., Chiquet, C., Herrag, S., Dumollard, J.M., Boudard, D., Bednarz, J., Campos, L. and Gain, P. (2003) Mechanisms of staurosporine induced apoptosis in a human corneal endothelial cell line. Br. J. Ophthalmol., 87(3): 346–352.

van de Wiele, C., Lahorte, C., Vermeersch, H., Loose, D., Mervillie, K., Steinmetz, N.D., Vanderheyden, J.L., Cuvelier, C.A., Slegers, G. and Dierck, R.A. (2003) Quantitative tumor apoptosis imaging using technetium-99m-HYNIC annexin V single photon emission computed tomography. J. Clin. Oncol., 21(18): 3483–3487.

Vasilevko, V. and Cribbs, D.H. (2006) Novel approaches for immunotherapeutic intervention in Alzheimer’s disease. Neurochem. Int., 49(2): 113–126.

Vickers, J.C., Lazzarini, R.A., Riederer, B.M. and Morrison, J.H. (1995) Intraperikaryal neurofilamentous accumulations in a subset of retinal ganglion cells in aged mice that

express a human neurofilament gene. Exp. Neurol., 136(2): 266–269.

von Ruckmann, A., Fitzke, F.W. and Bird, A.C. (1995) Distribution of fundus autofluorescence with a scanning laser ophthalmoscope. Br. J. Ophthalmol., 79(5): 407–412.

Vriens, P.W., Blankenberg, F.G., Stoot, J.H., Ohtsuki, K., Berry, G.J., Tait, J.F., Strauss, H.W. and Robbins, R.C. (1998) The use of technetium Tc 99m annexin V for in vivo imaging of apoptosis during cardiac allograft rejection. J. Thorac. Cardiovasc. Surg., 116(5): 844–853.

Wade, A.R. and Fitzke, F.W. (1998) A fast, robust pattern recognition system for low light level image registration and its application to retinal imaging. Opt. Express, 3(5): 190–197.

Wamsley, S., Gabelt, B.T., Dahl, D.B., Case, G.L., Sherwood, R.W., May, C.A., Hernandez, M.R. and Kaufman, P.L. (2005) Vitreous glutamate concentration and axon loss in monkeys with experimental glaucoma. Arch. Ophthalmol., 123(1): 64–70.

Williams, A.J., Dave, J.R., Lu, X.M., Ling, G. and Tortella, F.C. (2002) Selective NR2B NMDA receptor antagonists are protective against staurosporine-induced apoptosis. Eur. J. Pharmacol., 452(1): 135–136.

WoldeMussie, E., Yoles, E., Schwartz, M., Ruiz, G. and Wheeler, L.A. (2002) Neuroprotective effect of memantine in different retinal injury models in rats. J. Glaucoma, 11(6): 474–480.

Woldemussie, E., Wijono, M. and Ruiz, G. (2004) Muller cell response to laser-induced increase in intraocular pressure in rats. Glia, 47(2): 109–119.

Yamamoto, R., Yoneda, S. and Hara, H. (2004) Neuroprotective effects of beta-secretase inhibitors against rat retinal ganglion cell death. Neurosci. Lett., 370(1): 61–64.

Yoneda, S., Hara, H., Hirata, A., Fukushima, M., Inomata, Y. and Tanihara, H. (2005) Vitreous fluid levels of beta- amyloid((1-42)) and tau in patients with retinal diseases. Jpn. J. Ophthalmol., 49(2): 106–108.

Yucel, Y.H., Gupta, N., Zhang, Q., Mizisin, A.P., Kalichman, M.W. and Weinreb, R.N. (2006) Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma. Arch. Ophthalmol., 124(2): 217–225.