Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation.
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.
Czapski
Grzegorz A
GA
Department of Cellular Signalling, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. grzegorz@cmdik.pan.pl
Cakala
Magdalena
M
Chalimoniuk
Malgorzata
M
Gajkowska
Barbara
B
Strosznajder
Joanna B
JB
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008636:Mesencephalon / Q000201:enzymology; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D013378:Substantia Nigra / Q000473:pathology / Q000648:ultrastructure; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism* / Q000473:pathology
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III