Abstract
Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excessive concentrations of glutamate have been reported in various neurological diseases, including glaucomatous optic neuropathy (GON). Glutamate excitotoxicity triggered by overstimulation of N-methyl-d-aspartate (NMDA)-type glutamate receptors may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other retinal neuronal cell death in ischemic insult including diabetic retinopathy. Neuroprotective effects with the blockage of overstimulated NMDA receptors were found in several previous studies in RGC degeneration models, such as the axotomy, ischemia, and laser-induced high intraocular pressure models. Although there is a great deal of evidence for elevated glutamate in GON, a clinical trial of memantine, an NMDA receptor antagonist, was unsuccessful. Thus, excitotoxicity is not recognized as a primary factor in GON, although glutamate leaking from dying/dead RGCs or compromised glia may contribute to the secondary death of neighboring RGCs via excessive activation of NMDA receptors during the development of glaucoma. Therefore, appropriate modulation of NMDA receptor-mediated retinal excitotoxicity remains to be elucidated and may become a possible therapeutic target.
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1 Introduction
Glutamate is an excitatory neurotransmitter in the central nervous system (CNS). Neurotoxicity in the retina caused by elevated glutamate levels was first reported by Lucas and Newhouse in 1957 [1]. This phenomenon is referred to as excitotoxicity and it induces neuronal degeneration. Glutamate stored within cells is not harmful. Currently, excitotoxicity is known to play a role in various neurological disorders, including acute insult and chronic stress [2]. After the original report of Lucas and Newhouse, numerous studies focusing on excitotoxicity have been performed in neurodegenerative diseases including glaucomatous optic neuropathy (GON) [3, 4]. One contested study found higher levels of glutamate in the vitreous of glaucomatous patients than in controls [5, 6]. Therefore, it appears reasonable to suggest that if ganglion cell death in glaucoma is caused by excessive activation of N-methyl-d-aspartate (NMDA) receptors, then the NMDA receptor antagonist memantine would be worth exploring as a potential neuroprotective agent. Based on this reasoning, a clinical trial was conducted to determine the efficacy of memantine as a neuroprotectant against glaucoma. However, that trial was unsuccessful. Unfortunately, one of the authors associated with the reports by Dreyer et al. and Brooks et al. was later discredited, and attempts by others to reproduce some of those findings were not successful [5–8]. As a result, reliance on these data as a basis for undertaking further trials is difficult to justify. However, after those reports, elevated glutamate levels in animal experimental glaucoma models were reported [9, 10]. Furthermore, ectopic vesicular glutamate release at the optic nerve head was observed 2 days after intraocular pressure (IOP) elevation and caused subsequent axonal degeneration and RGC loss [11]. Although the memantine trial failed, understanding RGC degeneration with elevated glutamate levels may be important. This chapter discusses mechanistic insights into excitotoxicity and how excitotoxicity can contribute to GON.
1.1 Physiology
Glutamate is the most abundant excitatory neurotransmitter in the CNS. Nerve impulses trigger the release of glutamate from presynaptic cells [12]. In the opposing postsynaptic cells, glutamate receptors, such as the NMDA receptor, bind glutamate and are activated [13]. Because of its role in synaptic plasticity, glutamate is involved in cognitive functions in the CNS. The form of plasticity known as long-term potentiation occurs at glutamatergic synapses in the brain and retina [14, 15]. Glutamate functions not only as a point-to-point transmitter but also through spillover synaptic cross talk between synapses in which glutamate released from a neighboring synapse creates extrasynaptic signaling/volume transmission. In addition, glutamate plays important roles in the regulation of growth cones and synaptogenesis during development [16, 17].
1.2 Glutamate Transporters
In the retina, glutamate transporters that rapidly remove excess glutamate from the extracellular space are found in neuronal and glial membranes. In retinal injury or disease, they can work in reverse, and excess glutamate can accumulate outside cells. It was reported that five distinct excitatory amino acid transporters (EAATs) that transport glutamate have been cloned: the glutamate/aspartate transporter (GLAST) [18], glial glutamate transporter (GLT)-1 [19], excitatory amino acid carrier (EAAC)-1 [20], excitatory amino acid transporter (EAAT)-4 [21], and excitatory amino acid transporter (EAAT)-5 [22]. GLAST and GLT-1, which are exclusively located in glial cells in the brain [23–25], are also present in the retina. In the retina, GLAST is considered to be the major glutamate transporter and is expressed in Müller cells [26–28], while GLT-1, which is known to be responsible for up to 90 % of all glutamate transport in the forebrain region [29], is found in retinal neurons, such as cone photoreceptors and certain types of cone bipolar cell [30].
Little is known concerning the functional significance of GLT-1 expression in these retinal neurons. The elimination of excessive glutamate in the retina and vitreous is also important in slowing retinal neurodegenerative disease. The glutamate transporter is the only mechanism for the removal of glutamate from the extracellular fluid in the retina [31]. Increased glutamate levels may result from a failure of glutamate transporters adjacent to RGCs. Mice deficient in the glutamate transporters GLAST and EAAC-1, which are glutamate transporters, demonstrate spontaneous RGC death and optic nerve degeneration without IOP elevation, suggesting that glutamate transporters are necessary to prevent excitotoxic retinal damage [32, 33]. GLAST immunoreactivity is present throughout the retina and can be double-labeled with glutamine synthetase, a specific marker of Müller glial cells. These observations indicate that the intracellular glutamate concentration is dependent on glutamate uptake via GLAST in Müller glial cells.
1.3 Glutamate Receptors
Glutamate receptors are categorized into two main classes: ionotropic and metabotropic. The ionotropic glutamate receptors, which are all nonselective cation channels, are described as either NMDA or non-NMDA subtypes. NMDA receptors are characterized by a high permeability to Ca2+, voltage-dependent blockage by Mg2+, and slow gating kinetics. These receptors are known to be involved in a variety of physiological processes in the CNS [34–36]. Cloning experiments have demonstrated that there are at least five NMDA receptor subunits: NR1 and NR2A through NR2D [37].
Most recently, the novel subunits NR3A and NR3B have been cloned [38–40]. NR3A and NR3B assemble as heterotetramers in the endoplasmic reticulum to form functional channels through distinct combinations, producing various postsynaptic responses. In the mature nervous system, NMDA receptors are composed primarily of NR1 and NR2A through NR2C [41]. The receptor in some neurons may contain only NR1 combined with either NR2A or NR2B. The NR1 subunit in rats has at least eight splice variant forms [42, 43], and splice variants are also found in the NR2B-D and NR3A subunits [44]. On the other hand, unique genes code for each NR2 subunit [45] and for NR3A [46, 47]. NR1 serves a fundamental subunit of the NMDA receptor, without which the receptor cannot function, whereas NR2A through NR2D can be regarded as modulatory subunits [48, 49]. The NMDA receptor channel is highly permeable to Ca2+ [50, 51]. The increase in intracellular calcium levels ([Ca2+]i) in neuronal cells resulting from the activation of the NMDA receptor channel has been shown to be responsible for modulating neuronal activity and producing neurotoxicity [52, 53]. There is recent evidence that the inclusion of an NR3A subunit attenuates the calcium current [54]. A unique feature of the NMDA receptor channel is the voltage dependence of the receptor-mediated inward ionic currents. This is because the channel becomes clogged by Mg2+ at negative membrane potentials and Mg2+ is driven out of the channel pore when the membrane is depolarized. The NMDA receptor-mediated inward current is maximal between −20 and −30 mV in external medium containing physiological concentrations of Mg2+ (approximately 1 mM), is reduced at more hyperpolarized potentials, and becomes negligible at −80 mV [55]. Therefore, at the resting membrane potentials of most spiking neurons (−70 to −90 mV), NMDA receptors undergo significant channel blockage by Mg2+, and the blockage is relieved in a voltage-dependent manner when the neurons are depolarized by the activation of co-localized postsynaptic non-NMDA receptors. In other words, the NMDA receptor could serve as a molecular apparatus for detecting presynaptic signals occurring along postsynaptic depolarization at the synapse. This voltage dependence is important for synaptic integration in the CNS.
1.4 Downstream Signaling Cascade After Stimulation of NMDA Receptors
Stimulation of NMDA receptors is observed in the retina in various animal models of neurodegeneration, such as experimental glaucoma, axotomy, ischemia-reperfusion, and NMDA injection [56–59]. Intravitreal injection of NMDA causes relatively acute neuronal death, especially in the inner retina, through several molecular pathways (Fig. 1.1). The increase in Ca2+[i] influx is the initial key molecular event in NMDA receptor-mediated cell death [60]. Ca2+[i] overload activates Ca2+-dependent enzyme systems such as calpain- and calcium-/calmodulin-dependent kinase 2 (CaMK2) [61, 62]. Calpain is localized in TUNEL-positive apoptotic cells in the inner retina after NMDA injection, and the inhibition of calpain results in less NMDA-induced neuronal cell death, suggesting a proapoptotic role of calpain in NMDA-induced neurotoxicity. In contrast, phosphorylation of CaMK2 is observed in the retina relatively early after NMDA injection, and inhibition of CaMK2 synthesis accelerates NMDA-induced RGC loss, indicating an antiapoptotic role of CaMK2 [62]. Ca2+[i] influx also affects mitochondrial activity, such as the release of cytochrome C and reactive oxygen species, and results in the activation of several apoptotic pathways. Apoptosis-inducing factor is one key factor released from mitochondria and also contributes to DNA damage with overactivation of NMDA receptors [63]. PARP-1 activation occurs in the retina after NMDA injection in the vitreous and is accompanied by a decrease in ATP levels [64]. Conversely, a PARP inhibitor protects RGCs from NMDA-induced excitotoxicity. Our previous studies on the downstream Ca2+[i] influx led us to propose that the activation of proapoptotic molecules, such as nuclear factor-κB p65 and p38, c-Jun N-terminal kinase, and c-Jun, plays a role in NMDA-induced neurotoxicity [65–68] (Fig. 1.2). An inflammatory response, i.e., the upregulation of interleukin-1β, is also observed in the glia and RGCs after NMDA administration, suggesting the involvement of inflammation in response to excitotoxicity [69]. Our previous study showed that axonal degeneration with neurofilament loss is evident 3 days after intravitreal injection of NMDA [70]. Although NMDA penetrates into the inner retina after intravitreal injection and induces various molecular changes in the glia and RGCs which lead to RGC apoptotic degeneration and inner retinal thinning, those changes occur after TUNEL-positive DNA fragmentation in RGCs, indicating anterograde degenerative change in NMDA-induced neurotoxicity. Furthermore, apoptotic cell body death affects axonal transport to axons through the disruption of kinesin-1 activity, an anterograde axonal motor protein related to microtubules and neurofilament. These findings indicate anterograde neurodegeneration in NMDA-induced neurotoxicity [70].
2 Future Perspectives
Glutamate levels in the vitreous have been measured under the premise that the vitreous represents the extracellular space of the retina. The true extracellular space is the intracellular space between retinal cells. Because of technical difficulties in measuring such glutamate concentrations in the human retina, it has not been confirmed whether glutamate levels are elevated in human patients with glaucoma. The epicenter of GON is proposed to be the optic nerve head or lamina cribrosa, where soft tissues, including RGC axons and blood vessels circulating the optic nerve head, are likely to be compressed as a result of deformation of the laminar structure [71, 72]. Excitotoxicity may play a role in the pathophysiology of glaucoma by causing secondary RGC death because of glutamate leaking from injured cells, thereby triggering the activation of the apoptotic pathway. Harada and coworkers found that mice deficient in the glutamate transporters GLAST or EAAC-1 demonstrate spontaneous RGC and optic nerve degeneration without elevated IOP [33]. The retinas of glaucoma patients showed lower immunoreactivity of the EAAT-1 [73]. Furthermore, other studies showed that the optic nerve head is ischemic in glaucoma [74, 75]. Excitotoxicity can also contribute to the development of glaucomatous axonal degeneration because glutamate clearance by the glia decreases under ischemic conditions [76]. Although excitotoxicity is not a primary event in GON, glutamate leaking from dying/dead RGCs or compromised glia may contribute to the secondary death of neighboring RGCs via excessive activation of NMDA receptors in the development of glaucoma (Fig. 1.2). Therefore, the more appropriate therapeutic modulation of NMDA receptor-mediated retinal excitotoxicity remains to be elucidated and may become a potential therapeutic target.
References
Lucas DR, Newhouse JP (1957) The toxic effect of sodium l-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 58:193–201
Tapia R (1996) Release and uptake of glutamate as related to excitotoxicity. Rev Bras Biol 56:165–174
Kalloniatis M (1995) Amino acids in neurotransmission and disease. J Am Optom Assoc 66:750–757
Haefliger IO, Fleischhauer JC, Flammer J (2000) In glaucoma, should enthusiasm about neuroprotection be tempered by the experience obtained in other neurodegenerative disorders? Eye 14:464–472
Dreyer EB, Zurakowski D, Schumer RA et al (1996) Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol 114:299–305
Brooks DE, Garcia GA, Dreyer EB et al (1997) Vitreous body glutamate concentration in dogs with glaucoma. Am J Vet Res 58:864–867
Levkovitch-Verbin H, Martin KR, Quigley HA et al (2002) Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection. J Glaucoma 11:396–405
Wamsley S, Gabelt BT, Dahl DB et al (2005) Vitreous glutamate concentration and axon loss in monkeys with experimental glaucoma. Arch Ophthalmol 123:64–70
Kim JH, Lee NY, Jung SW et al (2007) Expression of N-methyl-d-aspartate receptor 1 in rats with chronic ocular hypertension. Neuroscience 149:908–916
Luo XG, Chiu K, Lau FH et al (2009) The selective vulnerability of retinal ganglion cells in rat chronic ocular hypertension model at early phase. Cell Mol Neurobiol 29:1143–1151
Fu CT, Sretavan DW (2012) Ectopic vesicular glutamate release at the optic nerve head and axon loss in mouse experimental glaucoma. J Neurosci 32:15859–15876
Hamberger A, Nyström B, Sellström A et al (1976) Amino acid transport in isolated neurons and glia. Adv Exp Med Biol 69:221–236
Garcia-Munoz M, Young SJ, Groves PM (1991) Terminal excitability of the corticostriatal pathway. II. Regulation by glutamate receptor stimulation. Brain Res 551:207–215
Sugioka M, Fukuda Y, Yamashita M (1998) Development of glutamate-induced intracellular Ca2+ rise in the embryonic chick retina. J Neurobiol 34:113–125
King AE, Chung RS, Vickers JC et al (2006) Localization of glutamate receptors in developing cortical neurons in culture and relationship to susceptibility to excitotoxicity. J Comp Neurol 498:277–294
Herkert M, Röttger S, Becker CM (1998) The NMDA receptor subunit NR2B of neonatal rat brain: complex formation and enrichment in axonal growth cones. Eur J Neurosci 10:1553–1562
Haberecht MF, Redburn DA (1996) High levels of extracellular glutamate are present in retina during neonatal development. Neurochem Res 21:285–291
Storck T, Schulte S, Hofmann K (1992) Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 89:10955–10959
Pines G, Danbolt NC, Bjørås M et al (1992) Cloning and expression of a rat brain l-glutamate transporter. Nature 360:464–467
Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471
Fairman WA, Vandenberg RJ, Arriza JL et al (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375:599–603
Arriza JL, Eliasof S, Kavanaugh MP et al (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94:4155–4160
Danbolt NC, Storm-Mathisen J, Kanner BI (1992) An [Na++ K+]-coupled l-glutamate transporter purified from rat brain is located in glial cell processes. Neuroscience 2:295–310
Lehre KP, Levy LM, Ottersen OP et al (1995) Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 15:1835–1853
Levy LM, Lehre KP, Rolstad B et al (1993) A monoclonal antibody raised against an [Na(+)+K+]coupled l-glutamate transporter purified from rat brain confirms glial cell localization. FEBS Lett 317:79–84
Izumi Y, Shimamoto K, Benz AM et al (2002) Glutamate transporters and retinal excitotoxicity. Glia 39:58–68
Pow DV (2001) Visualising the activity of the cystine-glutamate antiporter in glial cells using antibodies to aminoadipic acid, a selectively transported substrate. Glia 34:27–38
Rauen T, Wiessner M (2000) Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS. Neurochem Int 37:179–189
Robinson MB (1998) The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype. Neurochem Int 33:479–491
Rauen T, Rothstein JD, Wässle H (1996) Differential expression of three glutamate transporter subtypes in the rat retina. Cell Tissue Res 286:325–336
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
Harada T, Harada C, Watanabe M et al (1998) Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Proc Natl Acad Sci USA 95:4663–4666
Harada T, Harada C, Nakamura K et al (2007) The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma. J Clin Invest 117:1763–1770
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39
Carroll RC, Zukin RS (2002) NMDA receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Neurosci 25:571–577
Li B, Chen N, Luo T, Otsu Y et al (2002) Differential regulation of synaptic and extra-synaptic NMDA receptors. Nat Neurosci 5:833–834
Ozawa S, Kamiya H, Tsuzuki K (1998) Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 54:581–618
Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11:327–335
Sucher NJ, Kohler K, Tenneti L et al (2003) N-methyl-d-aspartate receptor subunit NR3A in the retina: developmental expression, cellular localization, and functional aspects. Invest Ophthalmol Vis Sci 44:4451–4456
Prybylowski K, Wenthold RJ (2004) N-Methyl-d-aspartate receptors: subunit assembly and trafficking to the synapse. J Biol Chem 279:9673–9676
Dingledine R, Borges K, Bowie D et al (1999) The glutamate receptor ion channels. Pharmacol Rev 51:7–61
Durand GM, Gregor P, Zheng X et al (1992) Cloning of an apparent splice variant of the rat N-methyl-d-aspartate receptor NMDAR1 with altered sensitivity to polyamines and activators of protein kinase C. Proc Natl Acad Sci USA 89:9359–9363
Sugihara H, Moriyoshi K, Ishii T et al (1992) Structures and properties of seven isoforms of the NMDA receptor generated by alternative splicing. Biochem Biophys Res Commun 185:826–832
Chatterton JE, Awobuluyi M, Premkumar LS et al (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415:793–798
Monyer H, Burnashev N, Laurie DJ et al (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540
Yao Y, Harrison CB, Freddolino PL et al (2008) Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors. EMBO J 27:2158–2170
Das S, Sasaki YF, Rothe T et al (1998) Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393:377–381
Chazot PL (2004) The NMDA receptor NR2B subunit: a valid therapeutic target for multiple CNS pathologies. Curr Med Chem 11:389–396
Luo J, Wang Y, Yasuda RP et al (1997) The majority of N-methyl-d-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B). Mol Pharmacol 51:79–86
Cline HT, Tsien RW (1991) Glutamate-induced increases in intracellular Ca2+ in cultured frog tectal cells mediated by direct activation of NMDA receptor channels. Neuron 6:259–267
MacDermott AB, Mayer ML, Westbrook GL et al (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321:519–522
Siliprandi R, Canella R, Carmignoto G et al (1992) N-methyl-d-aspartate-induced neurotoxicity in the adult rat retina. Vis Neurosci 8:567–573
Sucher NJ, Wong LA, Lipton SA (1990) Redox modulation of NMDA receptor-mediated Ca2+ flux in mammalian central neurons. Neuroreport 1:29–32
Sucher NJ, Aizenman E, Lipton SA (1991) N-methyl-d-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro. J Neurosci 11:966–971
Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263
Dong CJ, Guo Y, Agey P et al (2008) Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. Invest Ophthalmol Vis Sci 49:4515–4522
Kikuchi M, Tenneti L, Lipton SA (2000) Role of p38 mitogen-activated protein kinase in axotomy-induced apoptosis of rat retinal ganglion cells. J Neurosci 20:5037–5044
Lam TT, Abler AS, Kwong JM et al (1999) N-methyl-d-aspartate (NMDA)-induced apoptosis in rat retina. Invest Ophthalmol Vis Sci 40:2391–2397
Lam TT, Siew E, Chu R et al (1997) Ameliorative effect of MK-801 on retinal ischemia. J Ocul Pharmacol Ther 13:129–137
Laabich A, Li G, Cooper NG (2001) Characterization of apoptosis-genes associated with NMDA mediated cell death in the adult rat retina. Brain Res Mol Brain Res 91:34–42
Chiu K, Lam TT, Ying Li WW et al (2005) Calpain and N-methyl-d-aspartate (NMDA)-induced excitotoxicity in rat retinas. Brain Res 1046:207–215
Takeda H, Kitaoka Y, Hayashi Y et al (2007) Calcium/calmodulin-dependent protein kinase II regulates the phosphorylation of CREB in NMDA-induced retinal neurotoxicity. Brain Res 1184:306–315
Yu SW, Wang H, Dawson TM et al (2003) Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. Neurobiol Dis 14:303–317
Goebel DJ, Winkler BS (2006) Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina. J Neurochem 98:1732–1745
Munemasa Y, Ohtani-Kaneko R, Kitaoka Y et al (2005) Contribution of mitogen-activated protein kinases to NMDA-induced neurotoxicity in the rat retina. Brain Res 1044:227–240
Kitaoka Y, Kumai T, Kitaoka Y et al (2004) Nuclear factor-kappa B p65 in NMDA-induced retinal neurotoxicity. Brain Res Mol Brain Res 131:8–16
Munemasa Y, Ohtani-Kaneko R, Kitaoka Y (2006) Pro-apoptotic role of c-Jun in NMDA-induced neurotoxicity in the rat retina. J Neurosci Res 83:907–918
Takada K, Munemasa Y, Kuribayashi J et al (2011) Protective effect of thalidomide against N-methyl-d-aspartate-induced retinal neurotoxicity. J Neurosci Res 89:1596–1604
Kitaoka Y, Munemasa Y, Nakazawa T et al (2007) NMDA-induced interleukin-1beta expression is mediated by nuclear factor-kappa B p65 in the retina. Brain Res 1142:247–255
Kuribayashi J, Kitaoka Y, Munemasa Y et al (2010) Kinesin-1 and degenerative changes in optic nerve axons in NMDA-induced neurotoxicity. Brain Res 1362:133–140
Quigley HA, Nickells RW, Kerrigan LA et al (1995) Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 36:774–786
Quigley HA (1999) Neuronal death in glaucoma. Prog Retin Eye Res 18:39–57
Naskar R, Vorwerk CK, Dreyer EB (2000) Concurrent downregulation of a glutamate transporter and receptor in glaucoma. Invest Ophthalmol Vis Sci 41:1940–1944
Flammer J, Orgül S (1998) Optic nerve blood-flow abnormalities in glaucoma. Prog Retin Eye Res 17:267–289
Osborne NN, Melena J, Chidlow G et al (2001) A hypothesis to explain ganglion cell death caused by vascular insults at the optic nerve head: possible implication for the treatment of glaucoma. Br J Ophthalmol 85:1252–1259
Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–622
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Munemasa, Y. (2014). Molecular Architecture of Glutamate Signaling Pathway in Glaucomatous Optic Neuropathy. In: Nakazawa, T., Kitaoka, Y., Harada, T. (eds) Neuroprotection and Neuroregeneration for Retinal Diseases. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54965-9_1
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