Mazzio Elizabeth, Becker Allan, Soliman Karam F A
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
J Neuroimmunol. 2002 Oct;131(1-2):70-82. doi: 10.1016/s0165-5728(02)00260-6.
Inducible nitric oxide synthase (iNOS) plays a significant role in the pathology of central nervous system diseases. Inducible NOS expression is regulated by intracellular adenosine 3',5'-cyclic monophosphate (cAMP) signaling, and astrocytes contain both iNOS and adenylate cyclase-coupled neurotransmitter receptors. The data obtained from the present study indicated that acetylcholine, lambda-amino-n-butyric acid, glutamate, quinolinic acid, N-methyl-D-aspartate and aspartate have no effect on NO(2)(-) production in C6 glioma cells stimulated by lipopolysaccharide and interferon-gamma. However, dopamine (DA) caused inhibition of NO(2)(-) production and iNOS transcription. The effects of DA were not due to homovanillic acid/3,4-dihydroxyphenylacetic acid, the autoxidative products superoxide (O(2)(-))/hydrogen peroxide (H(2)O(2)) or direct reactions with NO(2)(-). Forskolin, adenylate cyclase activator, dose-dependently reduced NO(2)(-). Meanwhile, (+/-) SKF-38393 D(1) receptor agonist attenuated iNOS in a similar fashion to DA. In addition, the results indicated that DA attenuation of iNOS was significantly impeded by the adenylate cyclase inhibitor MDL-12,330A, the D(1) antagonist SCH-23390, the beta2 adrenergic receptor antagonist ICI-118,551 and the beta1 adrenergic receptor antagonist atenolol. In conclusion, it appears that DA attenuates iNOS through a D(1), beta1 and beta2 adrenergic receptor-linked adenylate cyclase-mediated cAMP cascade.
诱导型一氧化氮合酶（iNOS）在中枢神经系统疾病的病理过程中发挥着重要作用。诱导型一氧化氮合酶的表达受细胞内3',5'-环磷酸腺苷（cAMP）信号传导调控，星形胶质细胞同时含有诱导型一氧化氮合酶和与腺苷酸环化酶偶联的神经递质受体。本研究获得的数据表明，乙酰胆碱、γ-氨基丁酸、谷氨酸、喹啉酸、N-甲基-D-天冬氨酸和天冬氨酸对脂多糖和干扰素-γ刺激的C6胶质瘤细胞中NO₂⁻的产生没有影响。然而，多巴胺（DA）可抑制NO₂⁻的产生和诱导型一氧化氮合酶的转录。多巴胺的作用并非源于高香草酸/3,4-二羟基苯乙酸、自氧化产物超氧阴离子（O₂⁻）/过氧化氢（H₂O₂）或与NO₂⁻的直接反应。腺苷酸环化酶激活剂福斯可林可剂量依赖性地降低NO₂⁻。同时，（±）SKF-38393 D₁受体激动剂以与多巴胺类似的方式减弱诱导型一氧化氮合酶。此外，结果表明，腺苷酸环化酶抑制剂MDL-12,330A、D₁拮抗剂SCH-23390、β₂肾上腺素能受体拮抗剂ICI-118,551和β₁肾上腺素能受体拮抗剂阿替洛尔可显著阻碍多巴胺对诱导型一氧化氮合酶的减弱作用。总之，多巴胺似乎通过D₁、β₁和β₂肾上腺素能受体连接的腺苷酸环化酶介导的cAMP级联反应减弱诱导型一氧化氮合酶。
