A prodrug of a selective inhibitor of inducible nitric oxide synthase is neuroprotective in the rat model of glaucoma.
OBJECTIVE
To test the hypothesis that nitric oxide, synthesized by inducible nitric oxide synthase, causes degeneration of retinal ganglion cells in an animal model of glaucoma.


METHODS
Rats with unilateral, chronic, moderately elevated intraocular pressure were treated orally with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of inducible nitric oxide synthase. The loss of retinal ganglion cells was quantitated as an indicator of glaucomatous damage.


RESULTS
At the end of seven months, rat eyes with chronic, moderately elevated intraocular pressure lost approximately 20,000 retinal ganglion cells. Treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide for seven months completely prevented the loss of retinal ganglion cells in eyes with chronic, moderately elevated intraocular pressure. When treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide was delayed and started after three months of chronic, moderately elevated intraocular pressure, further loss of retinal ganglion cells was prevented.


CONCLUSIONS
Pharmacological neuroprotection with a selective inhibitor of inducible nitric oxide synthase may be useful for the treatment of glaucoma.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA. neufeld@vision.wustl.edu
Arthur H
AH
Neufeld
Sucharita
S
Das
Smita
S
Vora
Elizabeth
E
Gachie
Shin-Ichiro
S
Kawai
Pamela T
PT
Manning
Jane R
JR
Connor
D000284:Administration, Oral; D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005901:Glaucoma / Q000188:drug therapy*; D006709:Homoarginine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009798:Ocular Hypertension / Q000188:drug therapy; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology
D004791:Enzyme Inhibitors; C446200:L-N(6)-(1-iminoethyl)lysine tetrazole-amide; D018696:Neuroprotective Agents; D011355:Prodrugs; D006709:Homoarginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat