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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.

SUBMITTER: Hammond SL

PROVIDER: S-EPMC4631643 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro.

Hammond Sean L SL Safe Stephen S Tjalkens Ronald B RB

Neuroscience letters 20150914

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 pres ...[more]

PMID: 26383113

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Project description:Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inﬂammation and apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel strategy for neuroprotection. In the present study, sEH inhibitors APAU was screened in silico and further evaluated for their antiparkinson activity against rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and Drosophila melanogaster model of Parkinson disease (PD). In the in vitro study cell viability (MTT and LDH release assay), oxidative stress parameters (total intracellular ROS, hydroperoxides, protein oxidation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, glutathione, total antioxidant status, mitochondrial complex-1activity and mitochondrial membrane potential), inflammatory markers (IL-6, COX-1 and COX-2), and apoptotic markers (JNK, phospho-JNK, c-jun, phospho-c-jun, pro and active caspase-3) were assessed to study the neuroprotective effects. In vivo activity of APAU was assessed in Drosophila melanogaster by measuring survival rate, negative geotaxis, oxidative stress parameters (total intracellular ROS, hydroperoxides, glutathione levels) were measured. Dopamine and its metabolites were estimated by LC-MS/MS analysis. In the in silico study the molecule, APAU showed good binding interaction at the active site of sEH (PDB: 1VJ5). In the in vitro study, APAU significantly attenuated ROT induced changes in oxidative, pro-inflammatory and apoptotic parameters. In the in vivo study, APAU significantly attenuates ROT induced changes in survival rate, negative geotaxis, oxidative stress, dopamine and its metabolites levels (p < 0.05). Our study, therefore, concludes that the molecule APAU, has significant neuroprotection benefits against rotenone induced Parkinsonism.

Dataset Information

A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro.

Publications

A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro.

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