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