Czapski Grzegorz A, Cakala Magdalena, Chalimoniuk Malgorzata, Gajkowska Barbara, Strosznajder Joanna B
Department of Cellular Signalling, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
J Neurosci Res. 2007 Jun;85(8):1694-703. doi: 10.1002/jnr.21294.
Although the inducible isoform of nitric oxide synthase (iNOS) is a well-established source of nitric oxide (NO*) during inflammation of the central nervous system (CNS), little is known about the involvement of constitutive isoforms of NOS (cNOS) in the inflammatory process. The aim of this study was to compare the responses of the expression and activity of iNOS and the two cNOS isoforms, neuronal and endothelial (nNOS and eNOS, respectively), in the brain to systemic inflammation and their roles in the cascade of events leading to degeneration and apoptosis. A systemic inflammatory response in C57BL/6 mice was induced by intraperitoneal injection of lipopolysaccharide [LPS; 1 mg/kg body weight (b.w.)]. The relative roles of the NOS isoforms were evaluated after injection of NG-nitro-L-arginine (NNLA; 30 mg/kg b.w.), which preferentially inhibits cNOS, or 1400W (5 mg/kg b.w.), an inhibitor of iNOS. Biochemical and morphological alterations were analyzed up to 48 hr after administration of LPS. Systemic LPS administration evoked significant ultrastructural alterations in brain capillary vessels, neuropils, and intracellular organelles of neurons, astrocytes, and microglia. Apoptotic/autophagic processes occurred in many neurons of the substantia nigra (SN), which coincided with exclusive enhancement of iNOS expression and activity in this brain region. Moreover, inhibitors of both iNOS and cNOS prevented LPS-evoked release of apoptosis-inducing factor (AIF) from SN mitochondria. Collectively, the results indicate that synthesis of NO* by both the inducible and constitutive NOS isoforms contribute to the activation of apoptotic pathways in the brain during systemic inflammation.
尽管一氧化氮合酶（iNOS）的诱导型同工型是中枢神经系统（CNS）炎症期间一氧化氮（NO*）的一个公认来源，但关于一氧化氮合酶（NOS）的组成型同工型（cNOS）在炎症过程中的作用却知之甚少。本研究的目的是比较大脑中iNOS以及两种cNOS同工型（神经元型和内皮型，分别为nNOS和eNOS）的表达和活性对全身炎症的反应，以及它们在导致变性和凋亡的一系列事件中的作用。通过腹腔注射脂多糖 [LPS；1 mg/kg体重（b.w.）] 诱导C57BL/6小鼠的全身炎症反应。在注射优先抑制cNOS的NG-硝基-L-精氨酸（NNLA；30 mg/kg b.w.）或iNOS抑制剂1400W（5 mg/kg b.w.）后，评估NOS同工型的相对作用。在给予LPS后长达48小时分析生化和形态学改变。全身给予LPS引起脑毛细血管、神经纤维网以及神经元、星形胶质细胞和小胶质细胞的细胞内细胞器发生显著的超微结构改变。黑质（SN）的许多神经元中发生凋亡/自噬过程，这与该脑区iNOS表达和活性的特异性增强相一致。此外，iNOS和cNOS的抑制剂均能阻止LPS诱导的SN线粒体释放凋亡诱导因子（AIF）。总体而言，结果表明诱导型和组成型NOS同工型合成的NO*均有助于全身炎症期间大脑中凋亡途径的激活。
