Libby Richard T, Howell Gareth R, Pang Iok-Hou, Savinova Olga V, Mehalow Adrienne K, Barter Joseph W, Smith Richard S, Clark Abbot F, John Simon W M
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
BMC Neurosci. 2007 Dec 19;8:108. doi: 10.1186/1471-2202-8-108.
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.
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.
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.
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.
一氧化氮合酶2（NOS2）在某些情况下会导致神经死亡，但其在青光眼中的作用仍存在争议。在通过血管烧灼实验性升高眼压的大鼠青光眼模型中，NOS2与视网膜神经节细胞变性有关，但在通过注射高渗盐水升高眼压的大鼠青光眼模型中则不然。为了测试NOS2对遗传性青光眼的重要性，在本研究中，我们在DBA/2J小鼠青光眼模型中通过基因和药理学方法降低了NOS2活性。
在疾病发病机制的不同阶段，从RNA和蛋白质水平分析视神经乳头中Nos2的表达。为了测试Nos2是否参与青光眼性神经变性，将Nos2的无效等位基因回交到DBA/2J小鼠中，并评估每种Nos2基因型小鼠的青光眼发病率和严重程度。此外，用NOS2抑制剂氨基胍治疗DBA/2J小鼠，并与未治疗的小鼠进行疾病比较。
视神经乳头Nos2 RNA水平在疾病中度时有所变化并升高，但在疾病早期和严重阶段降低。尽管视神经乳头中有一些NOS2阳性细胞，但在青光眼期间NOS2蛋白并未显著增加。Nos2基因缺陷或氨基胍治疗并未改变DBA/2J小鼠的眼压情况。此外，Nos2缺陷和氨基胍对青光眼性视神经损伤均无任何可检测到的影响。
DBA/2J小鼠的青光眼性神经变性不需要NOS2活性。需要进行涉及各种模型的进一步实验，以评估Nos2在青光眼中的总体重要性。
