Neuroprotection by sodium channel blockade with phenytoin in an experimental model of glaucoma.
OBJECTIVE
Sustained influx of intracellular sodium through voltage-gated sodium channels is an important event in the cascade leading to degeneration of axons. This study tested the hypothesis that sodium channel blockade with phenytoin would result in neuroprotection of retinal ganglion cells (RGCs) and optic nerve axons in an experimental model of glaucoma.


METHODS
Chronic elevation of rat intraocular pressure (IOP) leading to optic nerve damage was induced using the episcleral vein occlusion model. Before induction of glaucoma, a subset of animals was placed on phenytoin-containing chow; this treatment continued for 8 weeks. Quantitative counts of backfilled RGCs and optic nerve axons was performed to examine the effects of phenytoin on glaucoma-induced adverse neurodegeneration.


RESULTS
Elevated IOP resulted in a significant decrease in density of RGCs, as well as dropout of axons within the optic nerve at 8 weeks after induction. In phenytoin-treated animals, however, the loss of RGCs was significantly reduced compared to vehicle-treated glaucomatous animals. Axon loss in the optic nerve was also reduced in phenytoin-treated animals, compared to controls.


CONCLUSIONS
Orally delivered phenytoin was effective in protecting neurons in an animal model of glaucoma, and merits further examination as a potential therapeutic strategy.
Hains
Bryan C
BC
Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.
Waxman
Stephen G
SG
D000284:Administration, Oral; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D007429:Intraocular Pressure; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D009901:Optic Nerve Diseases / Q000473:pathology / Q000517:prevention & control*; D010672:Phenytoin / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D026941:Sodium Channel Blockers / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D010672:Phenytoin