Fig. 3. Real-time PCR of BDNF expression in the diurnal period. Real-time PCR showed that BDNF message increased when light was turned on and reached its maximum 30 min after light was turned off, and then decreased in the dark. Retinas from 30-day-old C57/BL6 mice were used for this study. Realtime PCR was performed using a 7300 real-time PCR system (Applied Biosystems, Foster City, CA) for 50 cycles. The primer set and probe were located within BDNF exon-V (Applied Biosystems). The bracketed time points had significant differences of Po0.05. The ANOVA procedure t-test (LSD) was used. Values represented mean7SD (n as labeled on the chart).

in the retina increases in a dark-rearing paradigm (Xue et al., 2001) but the levels of the CaMKII-aB transcripts, in particular, have not been measured in the diurnal period. It would be useful to see if they correlate with the patterns of BDNF expression. The mRNA levels of both BDNF and its cognate receptor TrkB have also been shown to oscillate during 24 h light–dark cycles in rat hippocampus and the frontal cortex (Bova, 1998). There appears to be a delay in the elevation of TrkB mRNA relative to BDNF in these brain regions (Bova, 1998) consistent with the notion that BDNF may have a role in regulating the transcription of TrkB mRNA (Robinson et al., 1996). While we now know that the expression, translation, and secretion of BDNF in RGCs can be regulated and manipulated via CaMKII-depen- dent mechanisms, the regulatory mechanisms for BDNF receptors is less clear. However, some evidence indicates that TrkB receptors in the retina are downregulated following application of BDNF

533

(Chen and Weber, 2004). Thus, the application of exogenous BDNF may have limited practical value and other targets may have to be explored for therapeutic intervention.

Summary and conclusions

In summary, data indicate that the cytoplasmic CaMKII-a is likely involved in cell death pathways through activation of caspase-3 and through inhibition of BDNF release. In contrast, the nuclear isoform, CaMKII-aB seems to be involved in cell survival responses through regulating expression of pro-survival genes including BDNF. The dual action of release inhibition and upregulated expression appears to be related to homeostasis of BDNF levels in retinal cells.

In response to glutamate stimulation, the level of intracellular Ca2+ increases and CaMKII-a becomes auto-phosphorylated (T286/287) (see Diagram 1). On the one hand, this leads to the downstream activation of caspase-3, the reduction of BDNF autocrine secretion, and the activation of NFkB (Diagram 2). On the other hand, the translocation of CaMKII-aB to the nucleus is thought to be inhibited by autophosphorylation (Schulman, 2004) (see Diagram 2). As a result of the actions on these two pathways, the cells die. Thus, m-AIP, a specific inhibitor of CaMKII-a activity, may protect the cells from dying by blocking the cell death pathways at both the cytoplasmic and/or nuclear levels and by enhancing the survival pathways at the nuclear and/or cytoplasmic levels (Diagram 2). In this scenario, CaMKII plays a truly pivotal role. NMDA appears to transmit signals to the nucleus by multiple mechanisms including CaMKII-aB and NFkB. The relative roles of these two pathways in the cell death and survival still remain to be completely resolved, and the diagrammatic depiction of events (Diagram 2) is intended to provide heuristic value rather than a conclusive summary of the signal transduction pathways.

It is known from in vivo studies that cell deathrelated genes and gene-products such as TNFR1, Fasl, Nur77, GADD45, and GADD153 are also upregulated in the retina following an NMDA

genes) tic -apopto (Pro

Gene Expression (anti-apoptotic genes, ie, BDNF)

stimulus, and the upregulation of such genes is also blocked by m-AIP (Laabich et al., 2001). It is not yet known if regulation of these ‘‘bad’’ genes is mediated through the cytoplasmic or the nuclear forms of CaMKII. Glutamate agonists appear to stimulate both the death and survival pathways in RGCs, and it appears that the balance is in favor of the cell death pathways. We still do not know why, logically, this would be the case, but clearly the stimulation of the survival pathways is insufficient to meet the challenge in the presence of excess glutamate. However, the use of glutamate receptor antagonists and downstream inhibition of the CaMKII activity appears to redress the balance in favor of survival through inhibiting the transcription and/or activity of the ‘‘bad’’ genes

and by enhancing the transcription and/or activity of the ‘‘good’’ genes. The NMDA receptor is a current target for pharmacotherapies. While some details remain to be filled in, CaMKII would appear to be a good second target, downstream of the NMDA receptor, and deserving of further exploration. The prospects for improving the chances of RGC survival under duress are looking better.

Acknowledgments

This work is supported in part by NIH grants: P20RR16481; P30ES014443.

References

Areosa, S.A., Sherriff, F. and McShane, R. (2005) Memantine for dementia. Cochrane Database Syst. Rev., 20(3): p. CD003154.

Armaly, M.F., Krueger, D.E., Maunder, L., Becker, B., Hetherington, J., Jr., Kolker, A.E., Levene, R.Z., Maumenee, A.E., Pollack, I.P. and Shaffer, R.N. (1980) Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field defects. Arch. Ophthalmol., 98: 2163–2171.

Armstrong, R.C., Aja, T.J., Hoang, K.D., Gaur, S., Bai, X., Alnemri, E.S., Litwack, G., Karanewsky, D.S., Fritz, L.C. and Tomaselli, K.J. (1997) Activation of the CED3/ICErelated protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis. J. Neurosci., 17: 553–562.

Benfenati, F., Valtorta, F., Rubenstein, J.L., Gorelick, F.S., Greengard, P. and Czernik, A.J. (1992) Synaptic vesicleassociated Ca2+/calmodulin-dependent protein kinase II is a binding protein for synapsin I. Nature, 359: 417–420.

Bennett, J.L., Zeiler, S.R. and Jones, K.R. (1999) Patterned expression of BDNF and NT-3 in the retina and anterior segment of the developing mammalian eye. Invest. Ophthalmol. Vis. Sci., 40: 2996–3005.

Bosco, A. and Linden, R. (1999) BDNF and NT-4 differentially modulate neurite outgrowth in developing retinal ganglion cells. J. Neurosci. Res., 57: 759–769.

535

Bova, R. (1998) BDNF and TrkB mRNAs oscillate in rat brain during the light-dark cycle. Brain Res. Mol. Brain Res., 57: 321–324.

Bronstein, J.M., Farber, D.B. and Wasterlain, C.G. (1993) Regulation of type-II calmodulin kinase: functional implications. Brain Res. Revs., 18: 135–147.

Bronstein, J.M., Wasterlain, C.G., Bok, D., Lasher, R. and Farber, B.D. (1988a) Localization of retinal calmodulin kinase. Exp. Eye Res., 47: 391–402.

Bronstein, J.M., Wasterlain, C.G. and Farber, B.D. (1988b) A retinal calmodulin-dependent kinase: calcium/calmodulinstimulated and inhibited states. J. Neurochem., 50: 438–446.

Bronstein, J.M., Wasterlain, C.G., Lasher, R. and Farber, B.D. (1989) Dark-induced changes in activity and compartmentalization of retinal calmodulin kinase in the rat. Brain Res., 495: 83–88.

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

Chaum, E. (2003) Retinal neuroprotection by growth factors: a mechanistic perspective. J. Cell Biochem., 88: 57–75.

Chen, H. and Weber, A.J. (2004) Brain-derived neurotrophic factor reduces TrkB protein and mRNA in the normal retina and following optic nerve crush in adult rats. Brain Res., 1011: 99–106.

Chen, J.C., Nagayama, T., Jin, K., Stetler, R.A., Zhu, R.L., Graham, S.H. and Simon, R.P. (1998) Induction of caspase- 3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J. Neurosci., 18: 4914–4928.

Chen, L. and Huang, L.Y.M. (1992) Protein kinase C reduces magnesium block of NMDA-receptor channels as a mechanism of modulation. Nature, 356: 521–523.

Chidlow, G., Wood, J.P.M. and Casson, R.J. (2007) Pharmacological neuroprotection for glaucoma. Drugs, 67: 725–759.

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

Cooper, N.G.F., Wei, X. and Liu, N. (1995) Onset of expression of the alpha subunit of Ca2+/calmodulindependent protein kinase II and a novel related protein in the developing retina. J. Mol. Neurosci., 6: 75–89.

de Erausquin, G.A., Hyrc, K., Dorsey, D.A., Mamah, D., Dokucu, M., Masco, D.H., Walton, T., Dikranian, K., Soriano, M., Verdugo, J.M.G., Goldberg, M.P. and Dugan, L.L. (2003) Nuclear translocation of nuclear transcription factor-kappa B by alpha-amino-3-hydroxy-5-methyl-4-isoxazo- lepropionic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons. Mol. Pharmacol., 63: 784–790.

Diijik, F., van Leeuwen, S. and Kamphius, W. (2004) Differential effects of ischemia/reperfusion on amacrine cell subtype-specific transcript levels in the rat retina. Brain Res., 1026: 194–204.

Dkhissi, O., Chanut, E., Versaux-Botteri, C., Minvielle, F., Trouvin, J.H. and Nguyen-Legros, J. (1996) Changes in retinal dopaminergic cells and dopamine rhythmic metabolism during the development of a glaucoma-like disorder in quails. Invest. Ophthalmol. Vis. Sci., 37: 2335–2344.

536

Dkhissi, O., Chanut, E., Versaux-Botteri, C., Trouvin, J.H., Reperant, J. and Nguyen-Legros, J. (1998) Day and night dysfunction in intraretinal melatonin and related indoleamines metabolism, correlated with the development of glaucoma-like disorder in an avian model. J. Neuroendocrinol., 10: 863–869.

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: 299–305.

Fan, W., Agarwal, N. and Cooper, N.G.F. (2006) The role of CaMKII in BDNF-mediated neuroprotection of retinal ganglion cells (RGC-5). Brain Res., 1067: 48–57.

Fan, W., Agarwal, N., Kumar, M.D. and Cooper, N.G.F. (2005) Retinal ganglion cell death and neuroprotection: involvement of the CaMKII-alpha gene. Brain Res. Mol. Brain Res., 139: 306–316.

Fan, W., Li, X. and Cooper, N.G.F. (2007) CaMKII-aB mediates a survival response in retinal ganglion cells subjected to a glutamate stimulus. Invest. Ophthalmol. Vis. Sci., 48: 3854–3863.

Flammer, J. (1994) The vascular concept of glaucomaSurv. Ophthalmol., 38(Suppl.): S3–S6. Review

Fukunaga, K. and Soderling, T.R. (1990) Activation of calcium/calmodulin-dependent kinase II in cerebellar granule cells by N-methyl-D-aspartate receptor activation. Mol. Cell. Neurosci., 1: 133–138.

Fukunaga, K., Soderling, T.R. and Miyamoto, E. (1992) Activation of Ca2+/calmodulin-dependent protein kinase II and protein kinase C by glutamate in cultured rat neurons. J. Biol. Chem., 267: 22527–22533.

Gao, H., Qiao, X., Hefti, F., Hollyfield, J.G. and Knusel, B. (1997) Elevated mRNA expression of brain-derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury. Invest. Ophthalmol. Vis. Sci., 38: 1840–1847.

Garcia, M., Forster, V., Hicks, D. and Vecino, E. (2003) In vivo expression of neurotrophins and neurotrophin receptors is conserved in adult porcine retina in vitro. Invest. Ophthalmol. Vis. Sci., 44: 4532–4541.

Gaudilliere, B., Konishi, Y., de la Iglesia, N., Yao, G.l. and Bonni, A. (2004) A CaMKII-NeuroD signaling pathway specifies dendritic morphogenesis. Neuron, 41: 229–241.

Gavrielli, Y., Sherman, Y. and Ben-Sasson, S.A. (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol., 119: 493–501.

Goldberg, M.P. and Choi, D.W. (1993) Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent protein kinase mechanism of neuronal injury. J. Neurosci., 13: 3510–3524.

Hajimohammadreza, I., Probert, A.W., Coughenour, L.L., Borosky, S.A., Marcoux, F.W., Boxer, P.A. and Wang, K.W. (1995) A specific inhibitor of calcium/calmodulin-dependent protein kinase II provides neuroprotection against NMDA and Hypoxia/Hypoglycemia induced cell death. J. Neurosci., 15: 4093–4101.

Hama, Y., Katsuki, H., Tochikawa, Y., Suminaka, C., Kume, T. and Akaike, A. (2006) Contribution of endogenous glycine

site NMDA agonists to excitotoxic retinal damage in vivo. Neurosci. Res., 56: 279–285.

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

Hare, W., WoldeMussie, E., Lai, R., Ton, H., Ruiz, G., Feldmann, B., Wijono, M., Chun, T. and Wheeler, L. (2001) Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey. Surv. Ophthalmol., 45(suppl. 3): S284–S289.

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: 1472–1483.

Hinds, H.L., Goussakov, I., Nakazawa, K., Tonegawa, S. and Bolshakov, V.Y. (2003) Essential function of alpha-calcium/ calmodulin-dependent protein kinase II in neurotransmitter release at a glutamatergic central synapse. Proc. Natl. Acad. Sci. U.S.A., 100: 4275–4280.

Hof, P.R., Lee, P.Y., Yeung, G., Wang, R.F., Podos, S.M. and Morrison, J.H. (1998) Glutamate receptor subunit GluR2 and NMDAR1 immunoreactivity in the retina of macaque monkeys with experimental glaucoma does not identify vulnerable neurons. Exp. Neur., 153: 234–241.

Honjo, M., Tainihara, H., Inatani, M., Kido, N., Sawamura, T., Yue, B.Y., Narumiya, S. and Honda, Y. (2001) Effects of Rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest. Ophthalmol. Vis. Sci., 42: 137–144.

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. Ophthlmol., 121: 183–188.

Hood, D.C., Greenstein, V., Frishman, L., Holopigian, K., Viswanathan, S., Seiple, W., Ahmed, J. and Robson, J.G. (1999) Identifying inner retinal contributions to the human multifocal ERG. Vis. Res., 39: 2285–2291.

Hood, D.C. and Zhang, X. (2000) Multifocal ERG and VEP responses and visual fields: comparing disease-related changes. Doc. Ophthalmol., 100: 115–137.

Ishida, A., Kameshita, I., Okuno, S., Kitani, T. and Fujisawa, H. (1995) A novel highly specific and potent inhibitor of calmodulin-dependent protein kinase II. Biochem. Biophys. Res. Comm., 212: 806–812.

Ishida, A., Shigeri, Y., Tatsu, Y., Uegaki, K., Kameshita, I., Okuno, S., Kitani, T., Yumoto, N. and Fujisawa, H. (1998) Critical amino acid residues of AIP, a highly specific inhibitory peptide of calmodulin-dependent protein kinase II. FEBS Lett., 427: 115–118.

Jiang, X., Zhu, D., Okagaki, P., Lipsky, R., Wu, X., Banaudha, K., Mearow, K., Strauss, K.I. and Marini, A.M. (2003)

N-methyl-D-aspartate and TrkB receptor activation in cerebellar granule cells: an in vitro model of preconditioning to stimulate intrinsic survival pathways in neurons. Ann. N. Y. Acad. Sci., 993: 134–145.

Johnson, J.E., Barde, Y.A., Schwab, M. and Thoenen, H. (1986) Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells. J. Neurosci., 6: 3031–3038.

Kaiser, H.J., Flammer, J. and Burckhardt, D. (1993) Silent myocardial ischemia in glaucoma patients. Ophthalmologica, 207: 6–7.

Kawai, S.I., Vora, S., Das, S., Gachie, E., Becker, B. and Neufeld, A.H. (2001) Modeling of risk factors for the degeneration of retinal ganglion cells after ischemia/reperfusion in rats: effects of age, caloric restriction, diabetes, pigmentation, and glaucoma. FASEB J., 15: 1285–1287.

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

Kido, N., Tanihara, H., Honjo, M., Inatani, M., Tatsuno, T., Nakayama, C. and Honda, Y. (2000) Neuroprotective effects of brain-derived neurotrophic factor in eyes with NMDAinduced neuronal death. Brain Res., 884: 59–67.

Kielczewski, J.L., Pease, M.E. and Quigley, H.A. (2005) The effect of experimental glaucoma and optic nerve transection on amacrine cells in the rat retina. Invest. Ophthalmol. Vis. Sci., 46: 3188–3196.

King, A.E., Dickson, T.C., Blizzard, C.A., Foster, S.S., Chung, R.S., West, A.K., Chuah, M.I. and Vickers, J.C. (2007) Excitotoxicity mediated by non-NMDA receptors causes distal axonopathy in long-term cultured spinal motor neurons. Eur. J. Neurosci., 26: 2151–2159.

Kitamura, Y., Miyazaki, A., Yamanaka, Y. and Nomura, Y. (1993) Stimulatory effects of protein kinase C and calmodulin kinase II on N-methyl-D-aspartate receptor/channels in the postsynaptic density of rat brain. J. Neurochem., 61: 100–109.

Ko, H.W., Park, K.Y., Kim, H., Han, P.L., Kim, Y.U., Gwag, B.J. and Choi, E.J. (1998) Ca2+-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B by NMDA in cortical cell cultures. J. Neurochem., 71: 1390–1395.

Ko, M.L., Hu, D.N., Ritch, R. and Sharma, S.C. (2000) The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma. Invest. Ophthalmol. Vis. Sci., 41: 2967–2971.

Kolarow, R., Brigadski, T. and Lessmann, V. (2007) Postsynaptic secretion of BDNF and NT-3 from hippocampal neurons depends on calcium calmodulin kinase II signaling and proceeds via delayed fusion pore opening. J. Neurosci., 27: 10350–10364.

Krishnamoorthy, R.R., Agarwal, P., Prasanna, G., Vopat, K., Lambert, W., Sheedlo, H.J., Pang, I.H., Shade, D., Wordinger, R.J., Yorio, T., Clark, A.F. and Agarwal, N. (2001) Characterization of a transformed rat retinal ganglion cell line. Brain Res. Mol. Brain Res., 86: 1–12.

537

Laabich, A. and Cooper, N.G.F. (1999) Regulation of calcium/ calmodulin-dependent protein kinase II in the adult rat retina is mediated by ionotropic glutamate receptors. Exp. Eye Res., 68: 703–713.

Laabich, A. and Cooper, N.G.F. (2000) Neuroprotective effect of AIP on N-methyl-D-aspartate-induced cell death in retinal neurons. Brain Res. Mol. Brain Res., 85: 32–40.

Laabich, A., Li, G.Y. and Cooper, N.G.F. (2000) Calcium/ calmodulin-dependent protein kinase II containing a nuclear localizing signal is altered in retinal neurons exposed to N-methyl-D-aspartate. Brain Res. Mol. Brain Res., 76: 253–265.

Laabich, A., Li, G. and Cooper, N.G.F. (2001) Characterization of apoptosis-genes associated with NMDA mediated cell death in the adult rat retina. Mol. Brain Res., 91: 34–42.

Lambert, W.S., Clark, A.F. and Wordinger, R.J. (2004) Neurotrophin and Trk expression by cells of the human lamina cribrosa following oxygen-glucose deprivation. BMC Neurosci., 5: 51–65.

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

Lessmann, V., Gottmann, K. and Malcangio, M. (2003) Neurotrophin secretion: current facts and future prospects. Prog. Neurobiol., 69: 341–374.

Li, G., Laabich, A., Liu, L.O., Xue, J. and Cooper, N.G. (2001) Molecular cloning and sequence analyses of calcium/ calmodulin-dependent protein kinase II from fetal and adult human brain. Sequence analyses of human brain calcium/ calmodulin-dependent protein kinase II. Mol. Biol. Rep., 28: 35–41.

Lilienbaum, A. and Israel, A. (2003) From calcium to NF- {kappa}B signaling pathways in neurons. Mol. Cell. Biol., 23: 2680–2698.

Lonngren, U., Napankangas, U., Lafuente, M., Mayor, S., Lindqvist, N., Vidal-Sanz, M. and Hallbook, F. (2006) The growth factor response in ischemic rat retina and superior colliculus after brimonidine pre-treatment. Brain Res. Bull., 71: 208–218.

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: 193–201.

Marcoux, F.W., Probert, A.W. and Weber, M.L. (1990) Hypoxic neuronal injury in tissue culture is associated with delayed calcium accumulation. Stroke, 21(Suppl. III): 71–74.

Marini, A.M., Jiang, X., Wu, X., Tian, F., Zhu, D., Okagaki, P. and Lipsky, R.H. (2004) Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: From genes to phenotype. Restor. Neurol. Neurosci., 22: 121–130.

Martin, K.R., Quigley, H.A., Zack, D.J., Levkovitch-Verbin, H., Kielczewski, J., Valenta, D., Baumrind, L., Pease, M.E., Klein, R.L. and 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.

538

Matthews, R.P., Guthrie, C.R., Wailes, L.M., Zhao, X., Means, A.R. and McKnight, G.S. (1994) Calcium/calmodulindependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol. Cell Biol., 14: 6107–6116.

Mattson, M.P., Culmsee, C., Yu, Z. and Camandola, S. (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J. Neurochem., 74: 443–456.

Mattson, M.P., Keller, J.N. and Begley, J.G. (1998) Evidence of synaptic apoptosis. Exp. Neurol., 153: 35–48.

May, C.A. and Mittag, T. (2004) Neuronal nitric oxide synthase (nNOS) positive retinal amacrine cells are altered in the DBA/2NNia mouse, a murine model for angle-closure glaucoma. J. Glaucoma., 13: 496–499.

McGlade-McCulloh, E., Yamamoto, H., Tan, S.E., Brickey, D.A. and Soderling, T.R. (1993) Phosphorylation and regulation of glutamate receptors by calcium/calmodulindependent protein kinase II. Nature, 362: 640–642.

Meffert, M.K., Chang, J.M., Wiltgen, B.J., Fanselow, M.S. and Baltimore, D. (2003) NF-kappa B functions in synaptic signaling and behavior 73. Nat. Neurosci., 6: 1072–1078.

Meisner, F., Scheller, C., Kneitz, S., Sopper, S., Neuen-Jacob, E., Riederer, P., Meulen, V.T. and Koutsilieri, E. (2008) Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine. Neuropsychopharmacology, 33: 2228–2236.

Mey, J. and 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.

Misra, R.P., Bonni, A., Miranti, C.K., Rivera, V.M., Sheng, M. and Greenberg, M.E. (1994) L-type voltage-sensitive calcium channel activation stimulates gene expression by a serum response factor-dependent pathway. J. Biol. Chem., 269: 25483–25493.

Mo, X., Yokoyama, A., Oshitari, T., Negishi, H., Dezawa, M., Mizota, A. and Adachi-Usami, E. (2002) Rescue of axotomized retinal ganglion cells by BDNF gene electroporation in adult rats. Invest. Ophthalmol. Vis. Sci., 43: 2401–2405.

Moon, J.I., Kim, I.B., Gwon, J.S., Park, M.H., Kang, T.H., Lim, E.J., Choi, K.R. and Chun, M.H. (2005) Changes in retinal neuronal populations in the DBA/2J mouse. Cell Tissue Res., 320(1): 51–59.

Morioka, M., Fukunaga, K., Nagahiro, S., Kurino, M., Ushio, Y. and Miyamoto, E. (1995) Glutamate-induced loss of Ca2+/calmodulin-dependent protein kinase II activity in cultured rat hippocampal neurons. J. Neurochem., 64: 2132–2139.

Murphy, J.A. and Clarke, D.B. (2006) Target-derived neurotrophins may influence the survival of adult retinal ganglion cells when local neurotrophic support is disrupted: implications for glaucoma. Med. Hypotheses, 67: 1208–1212.

Namura, N., Zhu, J., Fink, K., Endres, M., Srinivasan, A., Tomaselli, K.J., Yuan, J. and Moskowitz, M.A. (1998) Activation and cleavage of caspase-3 in apoptosis induced by

experimental cerebral ischemia. J. Neurosci., 18(10): 3659–3668.

Nickells, R.W. (1999) Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv. Ophthalmol., 43: 151–161.

Nucci, C., Tartaglione, R., Rombola, L., Morrone, L.A., Fazzi, E. and Bagetta, G. (2005) Neurochemical evidence to implicate elevated glutamate in the mechanisms of high intraocular pressure (IOP)-induced retinal ganglion cell death in rat. Neurotoxicology, 26: 935–941.

Ochiishi, T., Terashima, T., Sugiura, H. and Yamauchi, T. (1994) Immunohistochemical localization of Ca2+/calmodulindependent protein kinase II in the rat retina. Brain Res., 634: 257–265.

Osborne, N.N., Casson, R.J., Wood, J.P.M., Chidlow, G., Graham, M. and Melena, J. (2004) Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog. Retin. Eye Res., 23: 91–147.

Osborne, N.N., Ugarte, M., Chao, M., Bae, J.H., Wood, J.P. and Nash, M.S. (1999) Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv. Ophthalmol., 43(Suppl 1): S102–S128.

Pang, I.H., Wexler, E.M., Nawys, S., Desantis, L. and Kapin, M.A. (1999) Protection by eliprodil against excitotoxicity in cultured rat retinaganglion cells. Invest. Ophthalmol. Vis. Sci., 40: 1170–1176.

Pease, M.E., McKinnon, S.J., Quigley, H.A., KerriganBaumrind, L.A. and Zack, D.J. (2000) Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest. Ophthalmol. Vis. Sci., 41: 764–774.

Peinado-Ramon, P., Salvador, M., Villegas-Perez, M.P. and Vidal-Sanz, M. (1996) Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells: a quantitative in vivo study. Invest. Ophthalmol. Vis. Sci., 37: 489–500.

Pizzi, M., Goffi, F., Boroni, F., Benarese, M., Perkins, S.E., Liou, H.C. and Spano, P. (2002) Opposing roles for NFkappa B/Rel factors p65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1beta. J. Biol. Chem., 277: 20717–20723.

Pollock, G.S., Vernon, E., Forbes, M.E., Yan, Q., Ma, Y.T., Hsieh, T., Robichon, R., Frost, D.O. and Johnson, J.E. (2001) Effects of early visual experience and diurnal rhythms on BDNF mRNA and protein levels in the visual system, hippocampus, and cerebellum. J. Neurosci., 21: 3923–3931.

Posner, A. (1958) Ischemia and the glaucoma syndrome. The Eye, Ear, Nose and Throat Monthly, 37: p. 528.

Quigley, H.A. (1995) Ganglion cell death in glaucoma: pathology recapitulates ontogeny. Aust. N.Z. J. Ophthalmol., 23: 85–91.

Quigley, H.A., McKinnon, S.J., Zack, D.J., Pease, M.E., Kerrigan-Baumrind, L.A., Kerrigan, D.F. and 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.

Rao, P.V., Deng, P.F., Kumar, J. and Epstein, D.L. (2001) Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest. Ophthalmol. Vis. Sci., 42: 1029–1037.

Robinson, M., Adu, J. and Davies, A.M. (1996) Timing and regulation of TrkB and BDNF mRNA expression in placodederived sensory neurons and their targets. Eur. J. Neurosci., 8: 2399–2406.

Roux, P.P. and Barker, P.A. (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol., 67: 203–233.

Rudzinski, M., Wong, T.P. and Saragovi, H.U. (2004) Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension. J. Neurobiol., 58: 341–354.

Sabel, B.A., Sautter, J., Stoehr, T. and Siliprandi, R.A. (1995) A behavioral model of excitotoxicity: retinal degeneration loss of vision, and subsequent recovery after intraocular NMDAadministration in adult rats. Exp. Brain. Res., 106: 93–105.

Saido, T.C., Sorimachi, H. and Suzuki, K. (1994) Calpain: new perspectives in molecular diversity and physiologicalpathological involvement. FASEB J., 8: 814–822.

Sandoval, M., Sandoval, R., Thomas, U., Spilker, C., Small, K.H., Falcon, R., Marengo, J.J., Caldero´n, R., Saavedra, V., Heumann, R., Bronfman, F., Garner, C.C., Gundelfinger, E.D. and Wyneken, U. (2007) Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes. J. Neurochem., 101: 1672–1684.

Schulman, H. (2004) Activity-dependent regulation of calcium/ calmodulin-dependent protein kinase II localization. J. Neurosci., 24: 8399–8403.

Shimomura, A., Ogawa, Y., Kitani, T., Fujisawa, H. and Hagiwara, M. (1996) Calmodulin-dependent protein kinase II potentiates transcriptional activation through activating transcription factor 1 but not cAMP response elementbinding protein. J. Biol. Chem., 271: 17957–17960.

Siliprandi, R., Canella, R., Carmignoto, G., Schiavo, N., Zanellato, N., Zanoni, R. and Vantini, G. (1991) N-methyl- D-aspartate-induced neurotoxicity in the adult rat retina. Vis. Neurosci., 8: 567–573.

Sisk, D.R. and Kuwabara, T. (1985) Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium l-glutamate. Graefes Arch. Clin. Exp. Ophthalmol., 223: 250–258.

Stroman, G.A., Stewart, W.C., Golnik, K.C., Cure´, J.K. and Olinger, R.E. (1995) Magnetic resonance imaging in patients with low-tension glaucoma. Arch. Ophthalmol., 113: 168–172.

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

Sun, P., Enslen, H., Myung, P.S. and Maurer, R.A. (1994) Differential activation of CREB by Ca2+/calmodulindependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev., 8: 2527–2539.

539

Sun, P., Lou, L. and Maurer, R.A. (1996) Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca/calmodulin-dependent protein kinases type I, II, and IV. J. Biol. Chem., 271: 3066–3073.

Tan, S.E., Robert, J.W. and Soderling, T.R. (1994) Phosphorylation of AMPA-type glutamate receptors by calcium/ calmodulin-dependent protein kinase II and protein kinase C in cultured hippocampal neurons. J. Neurosci., 14: 1123–1129.

Tatton, W.G. (1999) Apoptosis mechanisms in neurodegeneration: possible relevance to glaucoma. Eur. J. Ophthalmol., 9(suppl 1): S22–S29.

Tenneti, L. and Lipton, S.A. (2000) Involvement of activated caspase-3-like proteases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons. J. Neurosci., 74: 134–142.

Terashima, T., Ochiishi, T. and Yamauchi, T. (1994) Immunocytochemical localization of calcium/calmodulin-dependent protein kinase II isoforms in the ganglion cells of the rat retina: immunofluorescence histochemistry combined with a fluorescent retrograde tracer. Brain Res., 650: 133–139.

Thanos, S., Bahr, M., Barde, Y.A. and Vanselow, J. (1989) Survival and axonal elongation of adult rat retinal ganglion cells. In vitro effects of lesioned sciatic nerve and brain derived neurotrophic factor. Eur. J. Neurosci., 1: 19–26.

Tian, B., Gabelt, B.T., Peterson, J.A., Kiland, J.A. and Kaufman, P.L. (1999) H7 increases trabecular facility and facility after ciliary muscle disinsertion in monkeys. Invest. Ophthalmol. Vis. Sci., 40: 239–242.

Ullian, E.M., Barkis, W.B., Chen, S., Diamond, J.S. and Barres, B.A. (2004) Invulnerability of retinal ganglion cells to NMDA excitotoxicity. Mol. Cell. Neurosci., 26: 544–557.

Unoki, K. and LaVail, M.M. (1994) Protection of the rat retina from ischemic injury by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor. Invest. Ophthalmol. Vis. Sci., 35: 907–915.

Vecino, E., Caminos, E., Ugarte, M., Martin-Zanca, D. and Osborne, N.N. (1998) Immunohistochemical distribution of neurotrophins and their receptors in the rat retina and the effects of ischemia and reperfusion. Gen. Pharmacol., 30: 305–314.

Vecino, E., Garcia-Grespo, D., Garcia, M., Martinez-Millan, L., Sharma, S.C. and Carrascal, E. (2002) Rat retinal ganglion cells co-express brain derived neurotrophic factor (BDNF) and its receptor TrkB. Vis. Res., 42: 151–157.

Vecino, E., Ugarte, M., Nash, M.S. and Osborne, N.N. (1999) NMDA induces BDNF expression in the albino rat retina in vivo. Neuroreport, 10: 1103–1106.

Vorverk, C.K., Gorla, M.S. and Dreyer, E.B. (1999) An experimental basis for implicating excitotoxicity in glaucomatous optic neuropathy. Surv. Ophthalmol., 43(suppl 1): S142–S150.

Vorverk, C.K., Lipton, S.A., Zurakowski, D., Hyman, B.T. and Sabel, B.A. (1996) Chronic low-dose glutamate is toxic to retinal ganglion cells: toxicity blocked by memantine. Invest. Ophthalmol. Vis. Sci., 37: 1618–1624.

540

Waldmann, E., Gasser, P., Dubler, B., Huber, C. and Flammer, J. (1996) Silent myocardial ischemia in glaucoma and cataract patients. Graefes. Arch. Clin. Exp. Ophthalmol., 234: 595–598.

Waki, M., Yoshida, Y., Oka, T. and Azuma, M. (2001) Reduction of intarocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase. Curr. Eye Res., 22: 470–474.

Wegner, M., Cao, Z. and Rosenfeld, M.G. (1992) Calciumregulated phosphorylation within the leucine zipper of C/EBP beta. Science, 256: 370–373.

Xue, J., Li, G., Laabich, A. and Cooper, N.G. (2001) Visualmediated regulation of retinal CaMKII and its GluR1 substrate is age-dependent. Brain Res. Mol. Brain Res., 93: 95–104.

Yamamoto, T. (2001) The dawn of neuroprotective therapy for glaucomatous optic neuropathy. Nippon Ganka Gakkai Zasshi, 105: 866–883.

Yano, S., Fukunaga, K., Takiguchi, M., Ushio, Y., Mori, M. and Miyamoto, E. (1996) Regulation of CCAAT/Enhancerbinding protein family members by stimulation of glutamate receptors in cultured rat cortical astrocytes. J. Biol. Chem., 271: 23520–23527.