Phenytoin blocks retinal ganglion cell death after partial optic nerve crush.
Phenytoin is a well-characterized sodium channel blocker in widespread use as an anticonvulsant. In 1972, Becker and co-workers reported that phenytoin could reverse visual field loss from glaucoma. The authors therefore explored whether phenytoin could protect retinal ganglion cells from optic nerve crush. The optic nerve of Long-Evans rats was partially crushed; animals were given a single dose of either intraperitoneal phenytoin or vehicle. A third group underwent sham optic nerve crush. In a second set of experiments, the effect of phenytoin was compared to the N -methyl- D -receptor antagonist, memantine. Retinal ganglion survival was evaluated 1 week later. In addition, the effect of memantine and phenytoin on glutamate-induced intracellular calcium fluxes was evaluated.Phenytoin and memantine significantly reduced ganglion cell loss after optic nerve crush, and blunted the rise in intracellular calcium seen after administration of glutamate. Co-administration of the two agents, however, did not increase ganglion cell survival, and had no effect on ganglion cell calcium fluxes. Phenytoin can preserve retinal ganglion cells after partial optic nerve crush. This effect was not additive with a glutamate antagonist, suggesting that both agents alone are equally protective at saving the same population of ganglion cells at risk. In fact, the neuroprotective effect of the combined administration of phenytoin and memantine was significantly less than either of the two drugs alone. Phenytoin is known to decrease neuronal firing and neurotransmitter release; this may underlie its ability to serve as a neuro-protectant in this experimental paradigm.
Naskar
Rita
R
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia and Veterans Administration Medical Center, Philadelphia, PA 19104, USA. rnaskar@aol.com
Quinto
Kristine
K
Romann
Ilka
I
Schuettauf
Frank
F
Zurakowski
David
D
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005260:Female; D008559:Memantine / Q000627:therapeutic use; D009409:Nerve Crush; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010672:Phenytoin / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010672:Phenytoin; D002118:Calcium; D008559:Memantine