Reactive astrogliosis is a prominent neuropathologic feature of manganism, a neurodegenerative disorder caused by excessive accumulation of manganese (Mn) in the basal ganglia. Activation of astrocytes has been linked to neuronal injury in manganism resulting from overproduction of inflammatory mediators, including tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), interleukin-1β (IL-1β), and nitric oxide (NO), but the signaling mechanisms by which Mn regulates these factors remain poorly understood. We previously reported that Mn enhances production of NO in activated astrocytes that promotes apoptosis in cocultured neuronal cells by a mechanism involving the transcription factor nuclear factor-κB (NF-κB) (Liu et al., 2005). Because NF-κB-dependent expression of inducible nitric oxide synthase (NOS2) can be antagonized by the nuclear orphan receptor peroxisome proliferator-activated receptor-γ (PPARγ), we postulated that a novel agonist of this receptor, 1,1-bis(3′-indolyl)-1- (p-trifluoromethylphenyl)methane (cDIM1), would suppress expression of NOS2 in astrocytes and protect cocultured neuronal cells from apoptosis. Submicromolar concentrations of cDIM1 potently suppressed production of NO and expression of NOS2 in cultured astrocytes exposed to Mn and IFNγ/TNFα and prevented apoptosis in cocultures of differentiated PC12 cells, but this neuroprotective effect was lost in the absence of astrocytes. By using fluorescence reporter and chromatin immunoprecipitation (ChIP) assays, we found that cDIM1 prevented activation of NF-κB in astrocytes by a mechanism involving stabilization of the nuclear corepressor 2 (NCoR2) on the proximal NF-κB binding site of the NOS2 promoter. These data suggest that PPARγ may be an effective target for limiting inflammatory activation of astrocytes during neurologic injury. © 2007 Wiley-Liss, Inc.