title: N-Methyl, N-propynyl-2-phenylethylamine (MPPE), a Selegiline Analog, Attenuates MPTP-induced Dopaminergic Toxicity with Guaranteed Behavioral Safety: Involvement of Inhibitions of Mitochondrial Oxidative Burdens and p53 Gene-elicited Pro-apoptotic Change.
abstract: Selegiline is a monoamine oxidase-B (MAO-B) inhibitor with anti-Parkinsonian effects, but it is metabolized to amphetamines. Since another MAO-B inhibitor N-Methyl, N-propynyl-2-phenylethylamine (MPPE) is not metabolized to amphetamines, we examined whether MPPE induces behavioral side effects and whether MPPE affects dopaminergic toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Multiple doses of MPPE (2.5 and 5 mg/kg/day) did not show any significant locomotor activity and conditioned place preference, whereas selegiline (2.5 and 5 mg/kg/day) significantly increased these behavioral side effects. Treatment with MPPE resulted in significant attenuations against decreases in mitochondrial complex I activity, mitochondrial Mn-SOD activity, and expression induced by MPTP in the striatum of mice. Consistently, MPPE significantly attenuated MPTP-induced oxidative stress and MPPE-mediated antioxidant activity appeared to be more pronounced in mitochondrial-fraction than in cytosolic-fraction. Because MPTP promoted mitochondrial p53 translocation and p53/Bcl-xL interaction, it was also examined whether mitochondrial p53 inhibitor pifithrin-μ attenuates MPTP neurotoxicity. MPPE, selegiline, or pifithrin-μ significantly attenuated mitochondrial p53/Bcl-xL interaction, impaired mitochondrial transmembrane potential, cytosolic cytochrome c release, and cleaved caspase-3 in wild-type mice. Subsequently, these compounds significantly ameliorated MPTP-induced motor impairments. Neuroprotective effects of MPPE appeared to be more prominent than those of selegiline. MPPE or selegiline did not show any additional protective effects against the attenuation by p53 gene knockout, suggesting that p53 gene is a critical target for these compounds. Our results suggest that MPPE possesses anti-Parkinsonian potentials with guaranteed behavioral safety and that the underlying mechanism of MPPE requires inhibition of mitochondrial oxidative stress, mitochondrial translocation of p53, and pro-apoptotic process.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Yunsung
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.|Hutecs Korea Pharm Co., Ltd., Osan, 18111, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Phuong-Khue Thi
authors.initials: PT
authors.lastname: Nguyen
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Yoo
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: The-Vinh
authors.initials: TV
authors.lastname: Tran
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, Republic of Korea.
authors.forename: Young J
authors.initials: YJ
authors.lastname: Oh
authors.affiliation: Eve Topf Centers of Excellence for Neurodegenerative Diseases Research, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
authors.forename: Moussa B H
authors.initials: MBH
authors.lastname: Youdim
authors.affiliation: National Creative Research Initiative Center for Catalytic Organic Reactions, Department of Chemistry, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Phil Ho
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, 468-8503, Japan.|NPO, Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-8503, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea. kimhc@kangwon.ac.kr.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal; D053148:Caspase 3 / Q000378:metabolism; D003213:Conditioning, Psychological; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D042967:Electron Transport Complex I; D008124:Locomotion / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012642:Selegiline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C545747:2-phenylacetylenesulfonamide; C000626069:N-methyl-N-propynyl-2-phenylethylamine; D010627:Phenethylamines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D000071246:Uncoupling Protein 2; D051020:bcl-X Protein; D012642:Selegiline; D045304:Cytochromes c; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D013482:Superoxide Dismutase; D008995:Monoamine Oxidase; D053148:Caspase 3; D042967:Electron Transport Complex I
keywords: Behavioral safety; Mitochondria; N-Methyl, N-propynyl-2-phenylethylamine; Oxidative stress; Parkinson’s disease; Pro-apoptosis; Selegiline; p53 gene knockout mice