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Aspects to Consider in Assessing the Role of Glutamate in Glaucoma based on Glutamate Assays in Monkeys with Experimental Glaucoma

Michal Schwartz

In a recent report, Dawson et al. claim that vitreal glutamate concentrations are not increased in monkeys with experimental glaucoma¹. This contradicts earlier reports². I would like to discuss some aspects that might explain contradictory findings on vitreal levels of glutamate, and their implications for our view of the role of glutamate in the ongoing pathology of glaucoma.
Glutamate is a pivotal amino acid that normally functions as an essential neurotransmitter in the central nervous system (CNS). When its concentration exceeds physiological levels, however, it becomes toxic to neurons (depending on the extent and duration of the concentration increase). Moreover, glutamate is known to occur at abnormally high concentrations in several neurodegenerative conditions, including glaucoma. The day-to-day activity of glutamate is tightly regulated, and its physiological concentration is maintained by local mechanisms of transport of extracellular glutamate and by enzymatic processes. These buffering mechanisms help to avoid long-lasting retention of the transient sharp rise in glutamate associated with synaptic activity. Not surprisingly, many researchers have addressed the question if whether glutamate contributes to the pathogenesis of glaucoma. In considering this possibility, several factors should be taken into account.

1. An increase in glutamate concentration adjacent to retinal ganglion cells might be missed because of the dilution factor within the vitreous. A small signal might therefore reflect a large increase in a few cells, and thus be of biological significance. In this case, data should be obtained from a large group of animals in order to reach statistical significance.
2. It is possible that glutamate levels, though increased in patients with neurodegenerative diseases (including glaucoma), vary with time³. Therefore, a measurement taken at a single time point might be misleading. This was recently found to be the case in a rodent model of optic nerve insult⁴. Follow-up should therefore include repeated measurements.
3. Even if its concentration is not increased, glutamate might contribute to the pathogenesis of neurodegenerative diseases (including glaucoma) if its clearance from the extracellular space is defective. This might occur if there is a deficiency of astrocytes or microglia⁵, or if these glial cells, due to the stressful conditions, fail to express the glutamate transporters GLAST or GLT-1, respectively, which act as buffering mechanisms.⁶. Alternatively, vulnerability to glutamate might result from changes in the type of glutamate receptor subunit expressed⁷.
4. Glutamate antagonists protect against the loss of retinal ganglion cells in animal models of increased intraocular pressure^8,9. The effect of such antagonists in vivo might therefore provide a more reliable way to assess glutamate involvement in the pathology of glaucoma than measurement of intravitreal glutamate.

In light of the factors listed above, caution is needed when interpreting discrepancies in the data from different laboratories that report an increase in glutamate elevations levels in monkey models of increased intraocular pressure, especially if their experimental protocols are not identical. Failure to detect glutamate elevation in the vitreous at one time point does not necessarily exclude glutamate involvement in the ongoing pathology of glaucoma.

References

1. Carter-Dawson L, Crawford ML, Harwerth RS, et al. Vitreal glutamate concentration in monkeys with experimental glaucoma. Invest Ophthalmol Vis Sci. 2002; 43: 2633-2637.
2. Dreyer EB, Zurakowski D, Schumer RA, Podos SM, Lipton SA. Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996; 114: 299-305.
3. Dkhissi O, Chanut E, Wasowicz M, et al. Retinal TUNEL-positive cells and high glutamate levels in vitreous humor of mutant quail with a glaucoma-like disorder. Invest Ophthalmol Vis Sci. 1999;40:990-995.
4. Yoles E, Schwartz M. Elevation of intraocular glutamate levels in rats with partial lesion of the optic nerve. Arch Ophthalmol. 1998; 116: 906-910.
5. Kawasaki A, Otori Y, Barnstable CJ. Muller cell protection of rat retinal ganglion cells from glutamate and nitric oxide neurotoxicity. Invest Ophthalmol Vis Sci. 2000; 41: 3444-3450.
6. Martin KR, Levkovitch-Verbin H, Valenta D, et al. Retinal glutamate transporter changes in experimental glaucoma and after optic nerve transection in the rat. Invest Ophthalmol Vis Sci. 2002; 43: 2236-2243.
7. Hof PR, Lee PY, Yeung G, et al. Glutamate receptor subunit GluR2 and NMDAR1 immunoreactivity in the retina of macaque monkeys with experimental glaucoma does not identify vulnerable neurons. Exp Neurol. 1998; 153: 234-241.
8. Gu Z, Yamamoto T, Kawase C, et al. [Neuroprotective effect of N-methyl-D-aspartate receptor antagoinists in an experimental glaucoma model in the rat]. Nippon Ganka Gakkai Zasshi. 2000; 104: 11-16.
9. Hare W, WoldeMussie E, Lai R, 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; 45; Suppl.3: S284-289; Discussion: S295-286.