title: Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson's disease models.
abstract: Nicotinamide adenine dinucleotide phosphate oxidase, a key superoxide-producing enzyme, plays a critical role in microglia-mediated chronic neuroinflammation and subsequent progressive dopaminergic neurodegeneration in Parkinson's disease. Although nicotinamide adenine dinucleotide phosphate oxidase-targeting anti-inflammatory therapy for Parkinson's disease has been proposed, its application in translational research remains limited. The aim of this study was to obtain preclinical evidence supporting this therapeutic strategy by testing the efficacy of an ultra-low dose of the nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium in both endotoxin (lipopolysaccharide)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using post-treatment regimens. Our data revealed that post-treatment with diphenyleneiodonium significantly attenuated progressive dopaminergic degeneration and improved rotarod activity. Remarkably, post-treatment with diphenyleneiodonium 10 months after lipopolysaccharide injection when mice had 30% loss of nigral dopaminergic neurons, showed high efficacy in protecting the remaining neuronal population and restoring motor function. Diphenyleneiodonium-elicited neuroprotection was associated with the inhibition of microglial activation, a reduction in the expression of proinflammatory factors and an attenuation of α-synuclein aggregation. A pathophysiological evaluation of diphenyleneiodonium-treated mice, including assessment of body weight, organs health, and neuronal counts, revealed no overt signs of toxicity. In summary, infusion of ultra-low dose diphenyleneiodonium potently reduced microglia-mediated chronic neuroinflammation by selectively inhibiting nicotinamide adenine dinucleotide phosphate oxidase and halted the progression of neurodegeneration in mouse models of Parkinson's disease. The robust neuroprotective effects and lack of apparent toxic side effects suggest that diphenyleneiodonium at ultra-low dose may be a promising candidate for future clinical trials in Parkinson's disease patients.
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA wangq4@niehs.nih.gov hong3@niehs.nih.gov.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Shih-Heng
authors.initials: SH
authors.lastname: Chen
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chu
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Oyarzabal
authors.affiliation: 2 Neurochemistry Laboratory, Division of Neurotoxicology, National Centre for Toxicological Research/USFDA, Jefferson, AR 72079, USA.
authors.forename: Syed
authors.initials: S
authors.lastname: Ali
authors.affiliation: 2 Neurochemistry Laboratory, Division of Neurotoxicology, National Centre for Toxicological Research/USFDA, Jefferson, AR 72079, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Robinson
authors.affiliation: 3 National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rao
authors.affiliation: 1 Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA wangq4@niehs.nih.gov hong3@niehs.nih.gov.
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009861:Onium Compounds / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009861:Onium Compounds; C007517:diphenyleneiodonium; D019255:NADPH Oxidases
keywords: NADPH oxidase; Parkinson’s disease; microglia; neuroinflammation; superoxide