The reactive nitrogen species, nitric oxide (NO), plays an important role in the pathogenesis of neurodegenerative diseases. The suppression of NO production may be fundamental for survival of neurons. Here, we report that pretreatment of human ramified microglial cells with nearly physiological levels of exogenous NO prevents lipopolysaccharide (LPS)/tumor necrosis factor ␣ (TNF␣)-inducible NO synthesis, because by affecting NF-B activation it inhibits inducible Ca 2؉ -independent NO synthase isoform (iNOS) mRNA expression. Using reverse transcriptase polymerase chain reaction, we have found that both NO donor sodium nitroprusside (SNP) and authentic NO solution are able to inhibit LPS/ TNF␣-inducible iNOS gene expression; this effect was reversed by reduced hemoglobin, a trapping agent for NO. The early presence of SNP during LPS/TNF␣ induction is essential for inhibition of iNOS mRNA expression. Furthermore, SNP is capable of inhibiting LPS/ TNF␣-inducible nitrite release, as determined by Griess reaction. Finally, using electrophoretic mobility shift assay, we have shown that SNP inhibits LPS/TNF␣-elicited NF-B activation. This suggests that inhibition of iNOS gene expression by exogenous NO may be ascribed to a decreased NF-B availability. Nitric oxide (NO)1 is a major messenger molecule playing key roles in many physiological and pathological processes (1). NO production is catalyzed by at least two major forms of the NO synthase (NOS) enzyme: a constitutive Ca 2ϩ -dependent NOS isoform (cNOS) and an inducible Ca 2ϩ -independent NOS isoform (iNOS), which is expressed after stimulation with Escherichia coli lipopolysaccharide (LPS) and cytokines. Recently, we have demonstrated that LPS and/or TNF␣ are able to induce iNOS in human ramified microglia leading to a high NO output (2). On the other hand, NO release from mouse microglia is thought to play an important role in neuronal cell death (3-5). In a recent work, Meda et al. (6) suggested a possible involvement of NO produced by rat microglia after activation with ␤-amyloid protein and IFN-␥ in the pathogenesis of neuronal degradation occurring with age and in Alzheimer's disease.Preserving iNOS gene from its undesirable induction may be important for neuronal survival. Down-regulation of iNOS expression was reported to be achieved by some factors such as dexamethasone, interleukin-4, transforming growth factor-␤, and basic fibroblast growth factor (7-9). Recently, Griscavage et al. However, little is known about the regulatory effects on the mechanism by the variable low concentrations of the available NO before iNOS induction. Recently, we have observed that sodium nitroprusside (SNP), a well known NO donor, elicited inhibition of LPS-induced iNOS expression in rat neutrophils, suggesting a possible suppressive effect on iNOS gene expression by exogenous NO (12). The promoter region of human iNOS gene in vascular smooth muscle cells was shown to contain the consensus sequences for the binding of NFB, a nuclear transcriptional factor (13), and iNOS transc...

No abstract

No abstract

Based on these findings, we postulate a new mechanism of cardiac toxicity based on the PTM-driven accumulation of desmin amyloid-like oligomers. Phosphorylation and cleavage as well as oligomers formation are reduced by treatment (CRT) indicating a relationship between the three. Finally, the decrease of desmin amyloid-like oligomers with CRT or small molecules points both to a general mechanism of HF based on desmin toxicity that is independent of protein mutations and to novel potential therapies.

No abstract