Nitric oxide synthase inhibition delays axonal degeneration and promotes the survival of axotomized retinal ganglion cells.
Nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS) has been implicated in neuronal cytotoxicity following trauma to the central nervous system. The aim of the present study was to examine the role of NO in mediating axotomy-induced retinal ganglion cell (RGC) death. We observed increases in iNOS expression by microglia and Müller cells in the retina after optic nerve transection. This was paralleled by the induced expression of constitutive NOS (cNOS) in RGCs which do not normally express this enzyme. In order to determine if NO is cytotoxic to axotomized RGCs, the nonspecific NOS inhibitors Nomega-nitro-L-arginine (NOLA) or N-nitro-L-arginine methyl ester (L-NAME) were delivered to the vitreous chamber by intraocular injections. Both NOLA and L-NAME significantly enhanced RGC survival at 7, 10, and 14 days postaxotomy. The separate contributions of iNOS and cNOS to RGC degeneration were examined with intraocular injections of the specific iNOS inhibitor L-N(6)-(I-iminoethyl)lysine hydrochloride or the specific cNOS inhibitor L-thiocitrulline. Our results suggest that cNOS plays a greater role in RGC degeneration than iNOS. In addition to enhancing RGC survival, NOS inhibitors delayed the retrograde degeneration of RGC axons after axotomy. We conclude that NO synthesized by retinal iNOS and cNOS plays a major role in RGC death and retrograde axonal degeneration following axotomy.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.
P D
PD
Koeberle
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Ball
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D019771:Axotomy; D002470:Cell Survival / Q000187:drug effects; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D008058:Dihydrolipoamide Dehydrogenase / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007267:Injections; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000517:prevention & control; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology*; D009900:Optic Nerve / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; C086715:thiocitrulline; D019335:Nitroarginine; D002956:Citrulline; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; D008058:Dihydrolipoamide Dehydrogenase; D013890:Thiourea; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester