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Editors Selection IGR 7-3

Basic science: Excitotoxicity - glutamate

Comment by William Hare on:

12578 Neurochemical evidence to implicate elevated glutamate in the mechanisms of high intraocular pressure (IOP)-induced retinal ganglion cell death in rat, Nucci C; Tartaglione R; Rombola L et al., Neurotoxicology, 2005; 26: 935-941

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Inner retinal neurons, like neurons in other parts of the CNS, may be injured by excessive activation of glutamate-gated channels in the neuronal membrane. Glutamatergic excitotoxicity has been proposed as a mechanism for injury to retinal ganglion cells (RGCs) in glaucoma and other retinal disease. Nucci et al. (840) have used a rat model of reversible intraocular ischemia to explore the contribution of glutamatergic excitotoxicity to RGC injury resulting from transient (reversible) retinal ischemia. For this study, retinal ischemia was achieved by elevation of IOP to a level (120 mmHg) greater than ophthalmic artery systolic pressure for a duration of 45 minutes. Following this period of complete retinal ischemia, IOP was returned to the normal level and retinal perfusion reestablished (reperfusion). Histological analysis of retinal sections showed that ischemic insult was associated with an approximately 8% or 34% reduction of cells in the RGC layer at six hours or seven days post ischemia, respectively. TUNEL-labeled cells were also observed in the RGC layer and inner nuclear layer; leading the authors to conclude that neuronal death had occurred by apoptosis. Systemic dosing with MK801 (0.3 mg/kg), a selective NMDA-type glutamate channel blocker, at one hour prior to ischemia and 12 hours following ischemia was effective to block almost completely the RGC loss observed at 24 hours following reperfusion. Dosing with either GYKI52466 (3.3 mg/kg), a selective non-NMDA glutamate receptor antagonist, or L-NAME (10 mg/kg), an inhibitor of nitric oxide (NO) synthesis, were less effective to reduce RGC loss. In a different series of experiments, a microdialysis probe was positioned near the vitreo-retinal border and retinal glutamate samples were obtained at baseline, during ischemia, and following ischemia (reperfusion). Retinal glutamate levels increased during reperfusion to a peak, at approximately two hours following ischemic insult, which was 88% greater than baseline. Interestingly, this glutamate increase was almost completely blocked by systemic treatment with MK801.

The results and conclusions of this study confirm results of previous work from other laboratories using this IOP-elevation model for reversible retinal ischemia as well as other models of retinal ischemia. Earlier studies have shown that injury in this model is selective for inner retinal neurons, is strongly attenuated by treatment with NMDA-type glutamatergic channel blockers, is associated with apoptotic neuronal death, and is also associated with release of retinal glutamate into the extracellular space. The observation that blockade of NMDA-type glutamatergic channels is more effective to reduce injury than either antagonism of non-NMDA glutamatergic receptors or inhibition of NO synthesis is also consistent with the notion that excessive activity of non-NMDA channels is relatively less injurious due to the lower calcium permeability of these channels and also that NO-mediated toxicity is a secondary (downstream) effect of increased intracellular calcium resulting from over-activation of NMDA channels. The observation that there is an 8% loss of cells in the RGC layer at 6 hours following ischemia is somewhat surprising. Although retinal neurons may be irreversibly injured and committed to death at this early time point, one might expect that it would require a longer period of time before these cells would disappear from the histological picture. The paper also gives the impression that RGC death occurs entirely through an apoptotic mechanism though an early report by Buchi shows that necrotic neuronal death occurs at a significant level in this model.

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