title: A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro.
abstract: Degeneration of dopaminergic neurons in Parkinson's disease (PD) is associated with decreased expression of the orphan nuclear receptor Nurr1 (NR4A2), which is critical for both homeostasis and development of dopamine (DA) neurons. The synthetic, phytochemical-based compound, 1,1-bis (3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) activates Nurr1 in cancer cells and prevents loss of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. In the present study, we examined the capacity of C-DIM12 to induce expression of Nurr1-regulated genes in two dopaminergic neuronal cell lines (N2A, N27) and to protect against 6-hydroxydopamine (6-OHDA) neurotoxicity. C-DIM12 induced expression of Nurr1-regulated genes that was abolished by Nurr1 knockdown. C-DIM12 increased expression of transfected human Nurr1, induced Nurr1 protein expression in primary dopaminergic neurons and enhanced neuronal survival from exposure to 6-OHDA. These data indicate that C-DIM12 stimulates neuroprotective expression Nurr1-regulated genes in DA neurons.
authors.affiliation: Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.
authors.forename: Sean L
authors.initials: SL
authors.lastname: Hammond
authors.affiliation: Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA. Electronic address: Ron.Tjalkens@colostate.edu.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Tjalkens
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D061251:Primary Cell Culture
chemical_list: C534880:1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane; D007211:Indoles; D018696:Neuroprotective Agents; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016627:Oxidopamine; D004298:Dopamine
keywords: Dopamine; NR4A receptors; Neuroprotection; Nurr1; Transcriptional regulation