1. Academic Validation
  2. 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

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

  • J Pharmacol Sci. 2015 Mar;127(3):305-10. doi: 10.1016/j.jphs.2015.01.010.
Kazuko Takahashi-Niki 1 Ayako Inafune 2 Naruyuki Michitani 2 Yoshitaka Hatakeyama 2 Kotaro Suzuki 2 Mai Sasaki 2 Yoshihisa Kitamura 3 Takeshi Niki 4 Sanae M M Iguchi-Ariga 4 Hiroyoshi Ariga 5
Affiliations

Affiliations

  • 1 Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
  • 2 Central Research Laboratory, New Drug Research Center, Inc., Toiso, Eniwa 061-1405, Japan.
  • 3 Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
  • 4 Faculty of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan.
  • 5 Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan. Electronic address: hiro@pharm.hokudai.ac.jp.
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.

Keywords

Compound; DJ-1; MPTP; Neuroprotection; Parkinson's disease.

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