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

Libby RT, Howell GR, Pang IH, Savinova OV, Mehalow AK, Barter JW, Smith RS, Clark AF, John SW - BMC Neurosci (2007)

Bottom Line: The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis.Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease.Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. Richard_Libby@URMC.rochester.edu

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 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.

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Aminoguanidine treatment does not alter IOP or glaucomatous neurodegeneration. (A) Ag-treatment did not affect the pre-glaucomatous IOP of DBA/2J mice (3.5 months: average mmHg ± s.e.m., number of eyes examined; control 11.8 ± 0.2, 19; Ag-treated 11.7 ± 0.2, 23; P = 0.76). Ag-treatment did not affect the ocular hypertension during the key window in disease progression, between 10 and 11 months (control, 18.2 ± 1.0, 31; Ag-treatment, 16.6 ± 1.3, 30; P = 0.334). (B) Ag-treatment from 5 months of age does not alter glaucomatous neurodegeneration (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 10 months, 51 controls, 22,6,23; 51 Ag-treated 21,6,25; P = 0.293; 11.5 months, 55 controls, 18,6,31; 46 Ag-treated, 16,7,23, P = 0.896. (C) Ag-treatment beginning at 3 months of age does not protect from glaucomatous neurodegeneration. Nine months old treated mice actually tended to have more severe damage (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 9 months, 42 controls, 27,7,8; 41 Ag-treated 17,6,18; P = 0.04; 10 months, 43 controls, 10,1,32; 49 Ag-treated, 6,2,41, P = 0.4; 11 months, 43 controls, 4,3,36; 37 Ag-treated, 5,3,29, P = 0.8. The experiments shown in B and C were performed at different institutions (see text).
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Figure 4: Aminoguanidine treatment does not alter IOP or glaucomatous neurodegeneration. (A) Ag-treatment did not affect the pre-glaucomatous IOP of DBA/2J mice (3.5 months: average mmHg ± s.e.m., number of eyes examined; control 11.8 ± 0.2, 19; Ag-treated 11.7 ± 0.2, 23; P = 0.76). Ag-treatment did not affect the ocular hypertension during the key window in disease progression, between 10 and 11 months (control, 18.2 ± 1.0, 31; Ag-treatment, 16.6 ± 1.3, 30; P = 0.334). (B) Ag-treatment from 5 months of age does not alter glaucomatous neurodegeneration (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 10 months, 51 controls, 22,6,23; 51 Ag-treated 21,6,25; P = 0.293; 11.5 months, 55 controls, 18,6,31; 46 Ag-treated, 16,7,23, P = 0.896. (C) Ag-treatment beginning at 3 months of age does not protect from glaucomatous neurodegeneration. Nine months old treated mice actually tended to have more severe damage (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 9 months, 42 controls, 27,7,8; 41 Ag-treated 17,6,18; P = 0.04; 10 months, 43 controls, 10,1,32; 49 Ag-treated, 6,2,41, P = 0.4; 11 months, 43 controls, 4,3,36; 37 Ag-treated, 5,3,29, P = 0.8. The experiments shown in B and C were performed at different institutions (see text).

Mentions: Ag-treatment did not change the time course or the severity of the iris disease (data not shown). We first checked for any affect of Ag-treatment on IOP using young pre-glaucomatous DBA/2J mice. The IOP of young mice was not altered by Ag-treatment from 2 to 3.5 months of age. Similarly long-term Ag-treatment had no affect on IOP when assessed at 10 to 11 months, key ages of elevation in both sexes [39,40]. The IOPs of treated mice were significantly elevated compared to young mice (P < 0.001). Importantly, Ag-treatment did not alter the average IOP or the population distribution (Fig. 4A). The lack of effect of Ag-treatment on IOP is consistent with previous studies [35,51].


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

Libby RT, Howell GR, Pang IH, Savinova OV, Mehalow AK, Barter JW, Smith RS, Clark AF, John SW - BMC Neurosci (2007)

Aminoguanidine treatment does not alter IOP or glaucomatous neurodegeneration. (A) Ag-treatment did not affect the pre-glaucomatous IOP of DBA/2J mice (3.5 months: average mmHg ± s.e.m., number of eyes examined; control 11.8 ± 0.2, 19; Ag-treated 11.7 ± 0.2, 23; P = 0.76). Ag-treatment did not affect the ocular hypertension during the key window in disease progression, between 10 and 11 months (control, 18.2 ± 1.0, 31; Ag-treatment, 16.6 ± 1.3, 30; P = 0.334). (B) Ag-treatment from 5 months of age does not alter glaucomatous neurodegeneration (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 10 months, 51 controls, 22,6,23; 51 Ag-treated 21,6,25; P = 0.293; 11.5 months, 55 controls, 18,6,31; 46 Ag-treated, 16,7,23, P = 0.896. (C) Ag-treatment beginning at 3 months of age does not protect from glaucomatous neurodegeneration. Nine months old treated mice actually tended to have more severe damage (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 9 months, 42 controls, 27,7,8; 41 Ag-treated 17,6,18; P = 0.04; 10 months, 43 controls, 10,1,32; 49 Ag-treated, 6,2,41, P = 0.4; 11 months, 43 controls, 4,3,36; 37 Ag-treated, 5,3,29, P = 0.8. The experiments shown in B and C were performed at different institutions (see text).
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Related In: Results  -  Collection

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Figure 4: Aminoguanidine treatment does not alter IOP or glaucomatous neurodegeneration. (A) Ag-treatment did not affect the pre-glaucomatous IOP of DBA/2J mice (3.5 months: average mmHg ± s.e.m., number of eyes examined; control 11.8 ± 0.2, 19; Ag-treated 11.7 ± 0.2, 23; P = 0.76). Ag-treatment did not affect the ocular hypertension during the key window in disease progression, between 10 and 11 months (control, 18.2 ± 1.0, 31; Ag-treatment, 16.6 ± 1.3, 30; P = 0.334). (B) Ag-treatment from 5 months of age does not alter glaucomatous neurodegeneration (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 10 months, 51 controls, 22,6,23; 51 Ag-treated 21,6,25; P = 0.293; 11.5 months, 55 controls, 18,6,31; 46 Ag-treated, 16,7,23, P = 0.896. (C) Ag-treatment beginning at 3 months of age does not protect from glaucomatous neurodegeneration. Nine months old treated mice actually tended to have more severe damage (given as total number analyzed, treatment group, number of that treatment with mild, moderate, severe glaucoma) 9 months, 42 controls, 27,7,8; 41 Ag-treated 17,6,18; P = 0.04; 10 months, 43 controls, 10,1,32; 49 Ag-treated, 6,2,41, P = 0.4; 11 months, 43 controls, 4,3,36; 37 Ag-treated, 5,3,29, P = 0.8. The experiments shown in B and C were performed at different institutions (see text).
Mentions: Ag-treatment did not change the time course or the severity of the iris disease (data not shown). We first checked for any affect of Ag-treatment on IOP using young pre-glaucomatous DBA/2J mice. The IOP of young mice was not altered by Ag-treatment from 2 to 3.5 months of age. Similarly long-term Ag-treatment had no affect on IOP when assessed at 10 to 11 months, key ages of elevation in both sexes [39,40]. The IOPs of treated mice were significantly elevated compared to young mice (P < 0.001). Importantly, Ag-treatment did not alter the average IOP or the population distribution (Fig. 4A). The lack of effect of Ag-treatment on IOP is consistent with previous studies [35,51].

Bottom Line: The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis.Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease.Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. Richard_Libby@URMC.rochester.edu

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 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.

Show MeSH
Related in: MedlinePlus