A Nurr1 agonist causes neuroprotection in a Parkinson's disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C)

• Published in: PloS one Vol. 10; no. 3; p. e0121072
• Main Authors: Smith, Gaynor A, Rocha, Emily M, Rooney, Thomas, Barneoud, Pascal, McLean, Jesse R, Beagan, Jonathan, Osborn, Teresia, Coimbra, Madeleine, Luo, Yongyi, Hallett, Penelope J, Isacson, Ole
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.03.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Astrocytes; Brain; Brain research; Cytokines; Degeneration; Disease Models, Animal; Dopamine; Dopamine - biosynthesis; Dopamine receptors; Dopamine transporter; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Double-stranded RNA; Gene Expression; Genes; Genotype & phenotype; Glial cell line-derived neurotrophic factor; Glial fibrillary acidic protein; Health aspects; Imidazoles - administration & dosage; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Injection; Interleukin 6; Intermediate filament proteins; Kinases; Male; Medical schools; Microglia; Microglia - metabolism; Microglia - pathology; Movement disorders; Mutation; Nerve Degeneration - drug therapy; Nerve Degeneration - pathology; Neurodegeneration; Neurodegenerative diseases; Neurons; Neuroprotection; Neuroprotection - drug effects; Neurotoxicity; Nuclear Receptor Subfamily 4, Group A, Member 2 - agonists; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear receptors; Nurr1 protein; Oxidopamine - toxicity; Parkinson Disease, Secondary - drug therapy; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - pathology; Parkinson's disease; Pars Compacta - drug effects; Pars Compacta - metabolism; Pathogenesis; Phenotypes; Poly I-C - administration & dosage; Polyinosinic:polycytidylic acid; Priming; Pyridines - administration & dosage; Rats; RNA, Double-Stranded; Rodents; Staining; Substantia nigra; TLR3 protein; Toll-Like Receptor 3 - biosynthesis; Toll-Like Receptor 3 - genetics; Toll-like receptors; Transcription; France; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0121072

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1). Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson's disease (PD) pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o.) entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg) for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly(I:C) and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were associated with changes in microglial morphology indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced. We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD.