title: DJ-1-dependent protective activity of DJ-1-binding compound no. 23 against neuronal cell death in MPTP-treated mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is caused by dopaminergic cell death in the substantia nigra, leading to a reduced level of dopamine in the striatum. Oxidative stress is one of the causes of PD. Since symptomatic PD therapies are used, identification of compounds or proteins that inhibit oxidative stress-induced neuronal cell death is necessary. DJ-1 is a causative gene product of familial PD and plays a role in anti-oxidative stress reaction. We have identified various DJ-1-binding compounds, including compound-23, that restored neuronal cell death and locomotion defects observed in neurotoxin-induced PD models. In this study, wild-type and DJ-1-knockout mice were injected intraperitoneally with 1 mg/kg of compound-23 and then with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 1 h after injection. Five days after administration, the effects of compound-23 on MPTP-induced locomotion deficits, on dopaminergic cell death and on brain dopamine levels were analyzed by rotor rod tests, by staining cells with an anti-TH antibody and by an HPLC, respectively. The results showed that compound-23 inhibited MPTP-induced reduction of retention time on the rotor rod bar, neuronal cell death in the substantia nigra and striatum and dopamine content in wild-type mice but not in DJ-1-knockout mice, indicating a DJ-1-dependent effect of compound-23.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Takahashi-Niki
authors.affiliation: Central Research Laboratory, New Drug Research Center, Inc., Toiso, Eniwa 061-1405, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Inafune
authors.affiliation: Central Research Laboratory, New Drug Research Center, Inc., Toiso, Eniwa 061-1405, Japan.
authors.forename: Naruyuki
authors.initials: N
authors.lastname: Michitani
authors.affiliation: Central Research Laboratory, New Drug Research Center, Inc., Toiso, Eniwa 061-1405, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hatakeyama
authors.affiliation: Central Research Laboratory, New Drug Research Center, Inc., Toiso, Eniwa 061-1405, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Central Research Laboratory, New Drug Research Center, Inc., Toiso, Eniwa 061-1405, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Faculty of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niki
authors.affiliation: Faculty of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan.
authors.forename: Sanae M M
authors.initials: SM
authors.lastname: Iguchi-Ariga
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan. Electronic address: hiro@pharm.hokudai.ac.jp.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ariga
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D015513:Oncogene Proteins / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D054464:Peroxiredoxins / Q000502:physiology*; D000071617:Protein Deglycase DJ-1; D011725:Pyridines / Q000494:pharmacology*; D013378:Substantia Nigra / Q000166:cytology / Q000473:pathology
chemical_list: D001549:Benzamides; C000606301:N-(4-(8-methyl(4-hydroimidazo(1,2-a)pyridin-2-yl))phenyl)(3,4,5-trimethoxyphenyl)carboxamide; D018696:Neuroprotective Agents; D009498:Neurotoxins; D015513:Oncogene Proteins; D011725:Pyridines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine
keywords: Compound; DJ-1; MPTP; Neuroprotection; Parkinson's disease