title: 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).
abstract: 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.
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Gaynor A
authors: GA
authors: Smith
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Emily M
authors: EM
authors: Rocha
authors: Sanofi, Neurodegeneration and Pain Unit, Chilly-Mazarin, France.
authors: Thomas
authors: T
authors: Rooney
authors: Sanofi, Neurodegeneration and Pain Unit, Chilly-Mazarin, France.
authors: Pascal
authors: P
authors: Barneoud
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Jesse R
authors: JR
authors: McLean
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Jonathan
authors: J
authors: Beagan
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Teresia
authors: T
authors: Osborn
authors: Sanofi, Disposition, Safety & Animal Research, Department 1, Chilly-Mazarin, France.
authors: Madeleine
authors: M
authors: Coimbra
authors: Sanofi-Genzyme, Drug Metabolism and Pharmacokinetics Department, Waltham, Massachusetts, United States of America.
authors: Yongyi
authors: Y
authors: Luo
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Penelope J
authors: PJ
authors: Hallett
authors: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, Massachusetts, United States of America.
authors: Ole
authors: O
authors: Isacson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D007093:Imidazoles / Q000008:administration & dosage*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists / Q000235:genetics*; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism; D011070:Poly I-C / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D012330:RNA, Double-Stranded; D051381:Rats; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007093:Imidazoles; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011725:Pyridines; D012330:RNA, Double-Stranded; C000605003:SA00025; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016627:Oxidopamine; D011070:Poly I-C; D004298:Dopamine