As a model system, we used primary rat microglial cells which produce NO synthase and subsequently release NO upon stimulation with lipopolysaccharide (LPS). Among the substances tested, the glucocorticoids prednisone, hydrocortisone, dexamethasone and progesterone as well as transforming growth factor-beta (TGF-beta) dose-dependently inhibited LPS-induced nitric oxide synthase (iNOS) and NO synthesis.
The results showed that DHEA but not DHEAS significantly inhibited the production of nitrite in the LPS-stimulated BV-2 cell cultures. Pretreatment of BV-2 cells with DHEA reduced the LPS-induced iNOS mRNA and protein levels in a dose-dependent manner.
We conclude that the intraspinal injection of LPS results in inﬂammation and subsequently in prominent demyelination. The mech- anisms underlying the demyelination are not clear, but it is notable that it typically begins with disruption of the adaxonal myelin. Indeed, there is an early loss of myelin-associated glycoprotein within the lesion, despite the persistence of proteolipid protein. This combination is a feature of the pattern III lesion recently described in multiple sclerosis (Lucchinetti et al., 2000), and we therefore suggest that LPS-induced demyelination may serve as the ﬁrst experimental model available for the study of this type of multiple sclerosis lesion.
Our in vivo data also demonstrated that LA decreased LPS-induced fractalkine expression in arterial endothelial cells, endocardium, and villous endothelium. Therefore, LA warrants further evaluation as an antiinflammatory drug in endotoxemia. Because current therapy for patients with sepsis is still unsatisfactory, there have been continued efforts to find new and effective means to improve outcome by modulating inflammatory responses. Our results indicate that LA may be promising as an adjunctive treatment for endotoxemia, although the results presented here need further evaluation with other clinically relevant animal models.
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