The peroxisome proliferator‐activated receptor‐γ agonist 1,1‐bis(3′‐indolyl)‐1‐(p‐trifluoromethylphenyl)methane suppresses manganese‐induced production of nitric oxide in astrocytes and inhibits apoptosis in cocultured PC12 cells

Abstract

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-alpha (TNFalpha), interferon-gamma (IFNgamma), interleukin-1beta (IL-1beta), 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-kappaB (NF-kappaB) (Liu et al., 2005). Because NF-kappaB-dependent expression of inducible nitric oxide synthase (NOS2) can be antagonized by the nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), 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 IFNgamma/TNFalpha 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-kappaB in astrocytes by a mechanism involving stabilization of the nuclear corepressor 2 (NCoR2) on the proximal NF-kappaB binding site of the NOS2 promoter. These data suggest that PPARgamma may be an effective target for limiting inflammatory activation of astrocytes during neurologic injury.

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

“…Mn also strongly potentiates NO production in cytokine-stimulated astrocytes, leading to apoptosis in co-cultured neurons Spranger et al 1998;Tjalkens et al 2008). This observation is supported by studies demonstrating increased expression of NOS2 in activated astrocytes surrounding degenerating neurons in the striatum and globus pallidus of Mn-treated mice .…”

The role of peroxisome proliferator-activated receptor γ, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage

“…Recently, it has been suggested that PPARγ agonists, including RSG, 1,1-bis(3′-indolyl)-1-(p-trifluoromethylphenyl)methane and pioglitazone, regulate inflammatory processes in the CNS and have neuroprotective effects against neurological and neurodegenerative disorders [17][18][19][20][21][22][23][24]. There are many reports on neuroprotective effects against ischemic damage using various drugs or materials [25][26][27][28].…”

Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-InflammatoryPara-Phenyl Substituted Diindolylmethanes in a Mouse Model of Parkinson’s Disease

“…The selected C-DIM compounds examined in this model, particularly C-DIM5 and 12, had excellent pharmacokinetic behavior after oral administration and were effective at inhibiting progressive loss of dopamine neurons in a postlesioning model of PD. In previous in vitro studies with two other C-DIM analogs in this series, 1,1-bis(39-indolyl)-1-(p-trifluoromethylphenyl)methane (C-DIM1) and 1,1-bis(39-indolyl)-1-(p-t-butylphenyl)methane (C-DIM4), we reported that these compounds suppressed activation of NF-kB in mixed glial cultures exposed to inflammatory stimuli that prevented expression of inducible nitric oxide synthase (NOS2) and protected cocultured neurons from apoptosis (Tjalkens et al, 2008;Carbone et al, 2009). The mechanism underlying this anti-inflammatory activity in glia involved stabilization of nuclear corepressor proteins that prevented DNA binding of NF-kB at cis elements in the Nos2 promoter.…”

“…The anti-inflammatory and neuroprotective efficacy of C-DIM compounds in neural cells was demonstrated by the capacity of selected para-phenyl-substituted analogs in this series to inhibit NF-kB-dependent expression of NOS2 in astrocytes and subsequent neuronal injury after inflammatory stimulation with cytokines and neurotoxins (Tjalkens et al, 2008;Carbone et al, 2009). On the basis of these in vitro findings, we generated pharmacokinetic data for each of the C-DIM compounds to determine their potential neuroprotective use in vivo.…”