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Suppression of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Nitric-Oxide Synthase 2 Expression in Astrocytes by a Novel Diindolylmethane Analog Protects Striatal Neurons against Apoptosis

Department of Environmental and Radiological Health Sciences (D.L.C., K.A.P., J.A.M., R.B.T.) and Program in Molecular, Cellular and Integrative Neurosciences (D.L.C., J.A.M., R.B.T.), Colorado State University, Fort Collins, Colorado; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)

The progressive debilitation of motor functions in Parkinson's disease (PD) results from degeneration of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Long-term inflammatory activation of microglia and astrocytes plays a central role in the progression of PD and is characterized by activation of the nuclear factor-B (NF-B) signaling cascade and subsequent overproduction of inflammatory cytokines and nitric oxide (NO). Suppression of this neuroinflammatory phenotype has received considerable attention as a potential target for chemotherapy, but there are no currently approved drugs that sufficiently address this problem. The data presented here demonstrate the efficacy of a novel anti-inflammatory diindolylmethane class compound, 1,1-bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu), in suppressing NF-B-dependent expression of inducible nitric-oxide synthase (NOS2) and NO production in astrocytes exposed to the parkinsonian neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through a mechanism distinct from that described for the thiazolidinedione-class compound, rosiglitazone. Chromatin immunoprecipitations revealed that micromolar concentrations of DIM-C-pPhtBu prevented association of the p65 subunit of NF-B with enhancer elements in the Nos2 promoter but had little effect on DNA binding of either peroxisome proliferator-activated receptor- (PPAR-) or the nuclear corepressor NCoR2. Treatment with DIM-C-pPhtBu concomitantly suppressed NO production and protein nitration in MPTP-activated astrocytes and completely protected cocultured primary striatal neurons from astrocyte-dependent apoptosis. These data demonstrate the efficacy of DIM-C-pPhtBu in preventing the activation of NF-B-dependent inflammatory genes in primary astrocytes and suggest that this class of compounds may be effective neuroprotective anti-inflammatory agents in vivo.

Address correspondence to: Dr. Ronald B. Tjalkens, Associate Professor, Department of Environmental and Radiological Health Sciences, Colorado State University, Campus Delivery 1680, Ft. Collins, CO 80523. E-mail: ron.tjalkens{at}colostate.edu