Suppression of Manganese-dependent Production of Nitric Oxide in Astrocytes: Implications for Therapeutic Modulation of Glial-derived Inflammatory Mediators

Suppression of Manganese-Dependent Production of Nitric Oxide in Astrocytes: Implications for Therapeutic Modulation of Glial-Derived Inflammatory Mediators. (December 2006) Tyler T Wright, B.S., Brigham Young University Co-Chairs of Advisory Committee: Dr. Ronald B. Tjalkens Dr. Mark J. Zoran Primary cultured astrocytes were treated with Mn in the absence and presence of proinflammatory cytokines to determine their effect upon stimulation of nitric oxide (NO) production. Treatments of manganese and cytokines raised NO production to intermediate levels, whereas combined treatment raised NO creation to much greater levels. Furthermore, this combined treatment differed from control only in its ability to elevate cellular NO levels at 24 hours, but not at earlier time points. Combined exposure in astrocytes derived from mice lacking the nos2 gene prevented any increase in production of NO. Thus, manganese and cytokines enhance NO production through activation of the nos2 gene. Additionally, pharmacologic ligands of the peroxisome proliferator-activated receptor gamma (PPARγ) were used to test the role of this orphan nuclear receptor in modulating Mn-dependent production of NO. The agonist, 1,1-Bis(3’-indolyl)-1-(p-trifluormethylphenyl) methane (cDIM1) diminished NO in a dose-dependent manner, whereas addition of the PPARγ antagonist, GW 9662, amplified cellular NO production, also in a dose-dependent fashion. Moreover, it was observed that NO production was both attenuated and augmented at similar