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R.K. Lai, T. Chun, S. Lee; A Comparative Study of the Effect of Use-dependent NMDA Antagonist and Voltage-Sensitive Sodium Channel Blocker in a Rat Acute Retinal Ischemia/Reperfusion Model . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2938.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose Excessive release of the excitatory neurotransmitter glutamate occurs in retinal ischemia. Activation of voltage-dependent sodium channels is believed to play a key role in this release of glutamate. In support of this hypothesis, NMDA receptor antagonist (MK-801) and sodium channel blocker (tetrodotoxin) have been shown to protect retinal cells from ischemic insults. However, these agents cause unacceptable systemic side effects. Newer agents from these drug classes are use-dependent and are believed to have fewer systemic side effects. In this study, we evaluated the efficacy and safety of memantine (a use-dependent NMDA antagonist) and BIII-890-CL (a use-dependent sodium channel blocker) in a rat acute retinal ischemia model. Method: One hour prior to ischemic insult, male Brown Norway rats were dosed with drug or vehicle. They were then anesthetized with isoflurane. One eye was cannulated and connected to a saline reservoir with adjustable pressure. Ischemia was induced by raising IOP to 110 mm Hg and maintained for 50 minutes followed by reperfusion. After seven days of resting, ERG responses were measured from both the ischemic and contralateral non-ischemic eye. Results: In this retinal ischemia model, the extent of inner retinal damage correlates to the amplitude of the ERG b-wave. Ischemia reduces ERG b-wave to 15% that of the non-ischemic control eye. Both memantine and BIII-890-CL dose-dependently protected the retina from ischemia. Memantine (10 mg/kg po) preserved ERG b-wave to 48% that of control and enhanced RGC survival. BIII-890-CL was not effective orally; at 60 mg/kg ip, it preserved ERG b-wave to 36%. Both compounds did not cause any observable cardiovascular or other systemic side effects. Conclusions: Use-dependent NMDA and sodium channel blockers are effective in protecting retinal function after retinal ischemia. Compared to BIII-890-CL, memantine is orally active and more efficacious.
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