Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma

https://doi.org/10.1016/S0079-6123(08)01134-5Get rights and content

Abstract

Glaucoma is a visual disorder characterized by progressive loss of retinal ganglion cells (RGCs), which is often associated with high intraocular pressure. However, mechanisms of RGC death in glaucoma still remain a mystery. Two theories have been proposed as pathogeneses of glaucoma: mechanical and vascular. We demonstrate that glutamate excitotoxicity triggered by overactivation of the N-methyl-d-aspartate (NMDA)-type glutamate receptors may contribute according to both theories to RGC death in glaucoma and other retinal diseases such as ischemia. From a therapeutic standpoint, NMDA receptors and downstream signaling pathways, triggered by p38 mitogen-activated protein kinase (MAPK) and caspases, are potential targets of intervention to prevent RGC death. Glutamate, however, mediates synaptic transmission essential for normal function of the nervous system. Hence, complete blockade of NMDA receptor activity causes unacceptable side effects. Studies in our laboratory have shown that an open-channel blocker of the NMDA receptors, memantine, blocks only excessive NMDA receptor activity while leaving normal function relatively intact. This characteristic endows memantine with clinical tolerability, as demonstrated by its approval for treatment of Alzheimer's disease and vascular dementia, and clinical trials for glaucoma. In this review, we discuss improved memantine derivatives, p38 MAPK, and caspase inhibitors as plausible therapeutics to prevent RGC death.

Introduction

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. However, the presence of glutamate at excessive concentration or for excessive periods of time can excite neurons to death. This phenomenon was first discovered in the retina (Lucas and Newhouse, 1957) and later named “excitotoxicity” (Olney and Ho, 1970). Excitotoxicity has been thought to participate in etiology of various neurological disorders, ranging from acute insults (e.g., stroke, hypoglycemia, trauma, and epilepsy) to chronic neurodegenerative diseases (e.g., Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and human immunodeficiency virus [HIV]-associated dementia): glaucoma may possibly be among them (Choi, 1988; Lipton, 1993, Lipton, 2001, Lipton, 2003, Lipton, 2004; Lipton and Rosenberg, 1994; Dreyer and Lipton, 1999). In this chapter, we will describe mechanistic insights of excitotoxicity and how excitotoxicity can fit into pathogenesis of glaucoma, at least in part. Thereafter, possible therapeutic interventions to treat glaucoma by interrupting excitotoxic cascades will be discussed.

Section snippets

Channel properties of NMDA receptors correlated with excitotoxicity

The excitatory amino acid, glutamate (glutamic acid), elicits neuronal signaling by binding to glutamate receptors. The glutamate receptors are divided into two major categories, the ionotropic (conducting ions) and metabotropic (triggering biochemical signaling). Excitotoxicity is mediated predominantly through the ionotropic receptors, which comprise of three classes of receptors (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid [AMPA] receptors, kainate receptors, and N-methyl-d

Downstream signaling cascades after overactivation of NMDA receptors

Overactivation of NMDA receptors triggers an excessive Ca2+ influx into neurons, initiating cell death pathways (Lipton and Rosenberg, 1994) (Fig. 1D). As a consequence of the increase in intracellular Ca2+ concentration ([Ca2+]i) and subsequent Ca2+ entry into mitochondria, the mitochondrial membrane potential depolarizes (Ankarcrona et al., 1995; Green and Reed, 1998). Depolarized mitochondria release various bioactive substances into the cytosol. Cytochrome c released from mitochondria

Relevance of excitotoxicity to glaucoma

Whether excitotoxicity participates in the pathophysiology of glaucoma has been a topic of much debate. One contested study detected higher levels of glutamate in the vitreous of glaucoma patients than in controls (Dreyer et al., 1996), while other groups have not replicated this finding (Honkanen et al., 2003). Meanwhile, elevated glutamate levels have been observed in ocular tissues in patients with other retinal diseases in which involvement of glutamate toxicity has been suggested, i.e., in

Therapeutic approaches to prevent RGC death by targeting the pathways involved in NMDA excitotoxicity

In this section, on the basis of laboratory research and clinical trials, we will discuss if NMDA receptors and downstream signaling molecules contributing to excitotoxic pathways can be targets of therapeutic intervention to prevent RGC death in glaucoma. Importantly, glutamate mediates synaptic transmission, which is essential for the normal function of the nervous system. Hence, complete blockade of NMDA receptor activity can be deleterious because physiological activity is impaired. To be

Abbreviations

    AIF

    apoptosis-inducing factor

    CaM

    calmodulin

    EAAT

    excitatory amino acid transporter

    HIV

    human immunodeficiency virus

    IOP

    intraocular pressure

    MAPK

    mitogen-activated protein kinase

    MEF2C

    myocyte enhancer factor 2C

    NMDA

    N-methyl-d-aspartate

    NMDAR

    NMDA receptor

    nNOS

    neuronal nitric oxide synthase

    NO

    nitric oxide

    PARP

    poly(ADP-ribose) polymerase

    PSD-95

    postsynaptic density-95

    RGC

    retinal ganglion cell

    ROS

    reactive oxygen species

Acknowledgments

We thank our collaborators and colleagues, present and former, for their contributions to this work. We are especially grateful to J. Bormann, Y.-B. Choi, H.-S. V. Chen, M. Kikuchi, S. Manabe, C. M. Troy, and M. L. Shelanski. This work was supported in part by National Institutes of Health grants R01 EY05477 and R01 EY09024 (to S.A.L), Allergan, Inc. (to S.A.L.), Astellas Foundation for Research on Metabolic Disorders (to M.S.), and the Japanese Society for the Promotion of Science (JSPS

References (98)

  • G.E. Hardingham et al.

    The Yin and Yang of NMDA receptor signalling

    Trends Neurosci.

    (2003)
  • W. Hare et al.

    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.

    (2001)
  • H. Kawasaki et al.

    Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells

    J. Biol. Chem.

    (1997)
  • B.E. Klein et al.

    Prevalence of glaucoma. The beaver dam eye study

    Ophthalmology

    (1992)
  • S.A. Lipton

    Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide

    Trends Neurosci.

    (1993)
  • S.A. Lipton

    Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage

    Surv. Ophthalmol.

    (2003)
  • S.A. Lipton

    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

    (2004)
  • S.A. Lipton et al.

    Redox modulation of the NMDA receptor by NO-related species

    Prog. Brain Res.

    (1998)
  • H.A. Quigley

    Neuronal death in glaucoma

    Prog. Retin. Eye Res.

    (1999)
  • J.M. Sullivan et al.

    Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor

    Neuron

    (1994)
  • M. Szatkowski et al.

    Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms

    Trends Neurosci.

    (1994)
  • K.P. Wilson et al.

    The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase

    Chem. Biol.

    (1997)
  • S.W. Yu et al.

    Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity

    Neurobiol. Dis.

    (2003)
  • D. Zurakowski et al.

    Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors

    Vision Res.

    (1998)
  • E. Aizenman et al.

    Responses mediated by excitatory amino acid receptors in solitary retinal ganglion cells from rat

    J. Physiol.

    (1988)
  • J. Ambati et al.

    Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy

    Arch. Ophthalmol.

    (1997)
  • M. Arundine et al.

    Enhanced vulnerability to NMDA toxicity in sublethal traumatic neuronal injury in vitro

    J. Neurotrauma

    (2003)
  • B. Billups et al.

    Modulation of non-vesicular glutamate release by pH

    Nature

    (1996)
  • E. Bonfoco et al.

    Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • J.H. Brandstatter et al.

    Expression of NMDA and high-affinity kainate receptor subunit mRNAs in the adult rat retina

    Eur. J. Neurosci.

    (1994)
  • J. Cao et al.

    The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death

    J. Cell Biol.

    (2005)
  • H.-S.V. Chen et al.

    Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism

    J. Physiol.

    (1997)
  • H.-S.V. Chen et al.

    The chemical biology of clinically tolerated NMDA receptor antagonists

    J. Neurochem.

    (2006)
  • H.-S.V. Chen et al.

    Open-channel block of N-methyl-d-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity

    J. Neurosci.

    (1992)
  • Y.-B. Choi et al.

    Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation

    Nat. Neurosci.

    (2000)
  • V.L. Dawson et al.

    Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures

    J. Neurosci.

    (1993)
  • V.L. Dawson et al.

    Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures

    Proc. Natl. Acad. Sci. U.S.A.

    (1991)
  • E.F. Domino et al.

    Abnormal mental states induced by phencyclidine as a model of schizophrenia

  • E.B. Dreyer et al.

    New perspectives on glaucoma

    JAMA

    (1999)
  • E.B. Dreyer et al.

    Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma

    Arch. Ophthalmol.

    (1996)
  • D.J. Goebel et al.

    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.

    (2006)
  • D.R. Green et al.

    Mitochondria and apoptosis

    Science

    (1998)
  • T. Grunder et al.

    The distribution and developmental regulation of NMDA receptor subunit proteins in the outer and inner retina of the rat

    J. Neurobiol.

    (2000)
  • H. Guo et al.

    Alteration in the voltage dependence of NMDA receptor channels in rat dorsal horn neurones following peripheral inflammation

    J. Physiol.

    (2001)
  • J.S. Hahn et al.

    Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-d-aspartate antagonist MK-801

    Proc. Natl. Acad. Sci. U.S.A.

    (1988)
  • T. Harada et al.

    The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma

    J. Clin. Invest.

    (2007)
  • W.A. Hare et al.

    Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: Functional measures

    Invest. Ophthalmol. Vis. Sci.

    (2004)
  • W.A. Hare et al.

    Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: Structural measures

    Invest. Ophthalmol. Vis. Sci.

    (2004)
  • E. Hartveit et al.

    Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina

    J. Comp. Neurol.

    (1994)
  • Cited by (133)

    View all citing articles on Scopus
    View full text