Abstract
Purpose::
Excessive activity of NMDA-type glutamatergic membrane channels has been implicated as a mechanism for neuronal injury in a wide range of CNS disease including glaucoma. Memantine, a use-dependent NMDA-type channel blocker, has recently been approved in the U.S. for treatment of Alzheimer's dementia and is also being evaluated in a multicenter clinical trial for efficacy to prevent glaucomatous vision loss. The experiments summarized here were designed to characterize the effect of memantine on normal retinal light signaling as well as its action to reverse or block NMDA-induced changes in the activity of retinal ganglion cells (RGCs).
Methods::
Simultaneous recordings of the electroretinogram (ERG) and single-unit RGC activity were obtained from rabbit retina using standard methods for electrophysiological recording. The retina preparation was mounted in a chamber inside a light-tight Faraday cage, perfused continuously with Ames medium, and maintained at 350 C. Diffuse light stimuli were generated with a blue-green LED (peak = 505 nm). Test agents were added directly to the perfusion medium.
Results::
Most RGCs tested were sensitive to application of NMDA at concentrations ranging from 30µM to 100µM. For these cells, application of NMDA was followed by an increase in resting action potential (AP) frequency. In some cells, the NMDA-induced AP activity showed a clear bursting or oscillatory pattern while other cells responded with an increase in AP frequency that was maintained at a high rate and was associated with a gradual decrease in AP amplitude and complete block of the light response. Washout of NMDA was followed rapidly by return of AP activity to the control level. Application of memantine (1µM - 30µM) in combination with NMDA resulted in a dose-dependent block of NMDA-induced AP activity and this effect was completely reversed following memantine washout. There was no evidence for an effect of memantine (10µM) on the amplitude or timing of the ERG b-wave nor was there any apparent effect on RGC ON responses. However, this same concentration of memantine was typically associated with a slight delay of RGC OFF responses.
Conclusions::
Memantine is able to block NMDA-induced increases in RGC spiking activity at a concentrations that had little or no effect on retinal light signaling observed under control conditions.
Keywords: neuroprotection • ganglion cells • excitatory amino acid receptors