title: Substance P exacerbates dopaminergic neurodegeneration through neurokinin-1 receptor-independent activation of microglial NADPH oxidase.
abstract: Although dysregulated substance P (SP) has been implicated in the pathophysiology of Parkinson's disease (PD), how SP affects the survival of dopaminergic neurons remains unclear. Here, we found that mice lacking endogenous SP (TAC1(-/-)), but not those deficient in the SP receptor (neurokinin-1 receptor, NK1R), were more resistant to lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neurodegeneration than wild-type controls, suggesting a NK1R-independent toxic action of SP. In vitro dose-response studies revealed that exogenous SP enhanced LPS- and 1-methyl-4-phenylpyridinium (MPP(+))-induced dopaminergic neurodegeneration in a bimodal manner, peaking at submicromolar and subpicomolar concentrations, but was substantially less effective at intermediate concentrations. Mechanistically, the actions of submicromolar levels of SP were NK1R-dependent, whereas subpicomolar SP-elicited actions required microglial NADPH oxidase (NOX2), the key superoxide-producing enzyme, but not NK1R. Subpicomolar concentrations of SP activated NOX2 by binding to the catalytic subunit gp91(phox) and inducing membrane translocation of the cytosolic subunits p47(phox) and p67(phox). The importance of NOX2 was further corroborated by showing that inhibition or disruption of NOX2 blocked subpicomolar SP-exacerbated neurotoxicity. Together, our findings revealed a critical role of microglial NOX2 in mediating the neuroinflammatory and dopaminergic neurodegenerative effects of SP, which may provide new insights into the pathogenesis of PD.
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, wangq4@niehs.nih.gov hong3@niehs.nih.gov.
authors.forename: Qingshan
authors.identifier: http://orcid.org/0000-0002-8724-7465
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chu
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Shih-Heng
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Esteban
authors.initials: E
authors.lastname: Oyarzabal
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Lulu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079, and.
authors.forename: Syed
authors.initials: S
authors.lastname: Ali
authors.affiliation: Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079, and.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, wangq4@niehs.nih.gov hong3@niehs.nih.gov.
authors.forename: Jau-Shyong
authors.identifier: http://orcid.org/0000-0002-3056-8401
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004789:Enzyme Activation; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D018040:Receptors, Neurokinin-1; D013373:Substance P; D019255:NADPH Oxidases; D004298:Dopamine
keywords: GPCR independence; NADPH oxidase; Parkinson's disease; neuroinflammation; substance P