Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model

Richard T Libby^*¹^,5 , Gareth R Howell^*¹ , Iok-Hou Pang² , Olga V Savinova¹^,3 , Adrienne K Mehalow¹ , Joseph W Barter¹ , Richard S Smith¹^,3 , Abbot F Clark² and Simon WM John¹^,3^,4

¹The Jackson Laboratory, Bar Harbor, ME, 04609, USA

²Alcon Research, Ltd., Ft. Worth, TX 76134, USA

³The Howard Hughes Medical Institute, Bar Harbor, ME, 04609, USA

⁴Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA

⁵University of Rochester Eye Institute, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA

author email corresponding author email* Contributed equally

BMC Neuroscience 2007, 8:108doi:10.1186/1471-2202-8-108


Published:	19 December 2007

Abstract

Background

Nitric oxide synthase 2 (NOS2) contributes to neural death in some settings, but its role in glaucoma remains controversial. NOS2 is implicated in retinal ganglion cell degeneration in a rat glaucoma model in which intraocular pressure (IOP) is experimentally elevated by blood vessel cauterization, but not in a rat glaucoma model where IOP was elevated by injection of hypertonic saline. To test the importance of NOS2 for an inherited glaucoma, in this study we both genetically and pharmacologically decreased NOS2 activity in the DBA/2J mouse glaucoma model.

Methods

The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis. To test the involvement of Nos2 in glaucomatous neurodegeneration, a null allele of Nos2 was backcrossed into DBA/2J mice and the incidence and severity of glaucoma was assessed in mice of each Nos2 genotype. Additionally, DBA/2J mice were treated with the NOS2 inhibitor aminoguanidine and the disease compared to untreated mice.

Results

Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease. Despite the presence of a few NOS2 positive cells in the optic nerve head, NOS2 protein was not substantially increased during the glaucoma. Genetic deficiency of Nos2 or aminoguanidine treatment did not alter the IOP profile of DBA/2J mice. Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

Conclusion

Glaucomatous neurodegeneration in DBA/2J mice does not require NOS2 activity. Further experiments involving various models are needed to assess the general importance of Nos2 in glaucoma.