Sir,
The recently published study by Kwon et al provides some interesting and valuable data concerning the possible role of glutamate in neuronal cell death in glaucoma.1 As pointed out in the accompanying editorial, this is a field of study that has been bedevilled by conflicting results and even scientific fraud.2 The editorial2 is right to draw attention to these matters and to state that ‘it is important to re-evaluate the evidence for and against glutamate being causal in the development of glaucoma.’ Additionally, the editorial goes on to imply that there is thus no role for glutamate and its receptors (particularly NMDA receptors) in glaucomatous neuronal death. However, it may be wise to urge caution in the interpretation of these new data, as the lack of vitreal glutamate elevation does not necessarily mean that there is no role for glutamate and its receptors in glaucoma. Indeed, Kwon et al1 clearly discuss some of the relevant issues. Although an elevation of vitreal glutamate might be expected in glaucoma models, there is no a priori reason for assuming that this must be so, and indeed it may be that such an increase is not as central to the disease as implied in the editorial:2 there is a danger here of throwing the baby out with the bathwater.
It is well known that glutamate is an amino acid that is abundant in all cells and that it is intimately involved in many metabolic processes, with only a relatively small proportion being involved in neurotransmission and the activation of the receptors involved in this.3 This compartmentalisation of glutamate, maintained by active transport processes, makes it difficult to measure changes in tissue levels of glutamate related to activation of glutamate receptors unless relatively noninvasive sampling techniques with good temporal resolution are applied close to the source of glutamate (eg micro-dialysis or push–pull perfusion). Thus, sampling of retinal tissue post-mortem or sampling of vitreal glutamate, as performed by Kwon et al,1 might not yield information directly relevant to the activation of glutamate receptors on threatened neurones.
A second issue is the nature of the NMDA receptor (the glutamate receptor that is thought to be involved in the neurodegenerative aspects of glutamate pathophysiology) itself. A feature of the NMDA receptor is that its ion channel is largely blocked by magnesium ions when cell membranes are maintained at a healthy resting membrane potential.4 If tissue is compromised (eg injury or anoxia), then the membrane potential will depolarise and this will then relieve the magnesium ion block of the NMDA receptors: the consequence of this is that even relatively ‘normal’ levels of glutamate will have a much greater effect and there will be a substantial inward current into cells carried by sodium and calcium ions. Thus, large increases in glutamate levels may not be necessary in order to have sustained enhanced activation of NMDA receptors leading to the start of neurodegenerative processes.
Therefore, looking for increases in vitreal or retinal glutamate levels in glaucoma or glaucoma models may not be the correct question. What will be more telling and significant is to see whether antagonists of NMDA receptors are effective treatments in such conditions. Experimental work shows some promise in this regard,5 and the forthcoming clinical trials data with memantine will be of great significance here.
References
Kwon YH, Rickman DW, Baruah S, Zimmerman MB, Kim CS, Boldt HC et al. Vitreous and retinal amino acid concentrations in experimental central retinal artery occlusion in the primate. Eye 2005; 19: 455–463.
Lotery AJ . Glutamate excitotoxicity in glaucoma: truth or fiction? Eye 2005; 19: 369–370.
Meldrum BS . Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 2000; 130: 1007S–1015S.
Mayer ML, Westbrook GL . The physiology of excitatory amino acids in the vertebrate central nervous system. Progr Neurobiol 1987; 28: 197–276.
Hare WA, WoldeMussie E, Weinreb RN, Ton H, Ruiz G, Wijono M 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; 45: 2640–2651.
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Salt, T., Cordeiro, M. Glutamate excitotoxicity in glaucoma: throwing the baby out with the bathwater?. Eye 20, 730–731 (2006). https://doi.org/10.1038/sj.eye.6701967
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DOI: https://doi.org/10.1038/sj.eye.6701967
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