A new poly(ADP-ribose) polymerase inhibitor, FR261529 [2-(4-chlorophenyl)-5-quinoxalinecarboxamide], ameliorates methamphetamine-induced dopaminergic neurotoxicity in mice.
Methamphetamine (METH) administration in mice, results in a chronic dopamine (DA) depletion associated with nerve terminal damage, with DA oxidation and generation of reactive oxygen species (ROS) primarily mediating this neurotoxicity. The oxidative stress induced by METH putatively activates nuclear enzyme poly(ADP-ribose) polymerase (PARP), with excessive PARP activation eventually leading to cell death. In this study, we show that prevention of PARP activation by treatment with FR261529 [2-(4-chlorophenyl)-5-quinoxalinecarboxamide], the compound that was recently identified as a novel PARP inhibitor (IC50 for PARP-1 = 33 nM, IC50 for PARP-2 = 7 nM), protects against both ROS-induced cells injury in vitro and METH-induced dopaminergic neuronal damage in an in vivo Parkinson's disease (PD) model. In PC12 cells, exposure of hydrogen peroxide or METH markedly induced PARP activation, and treatment with FR261529 (1 microM) significantly reduced PARP activation and attenuated cell death. In the mouse METH model, METH (15 mg/kg x 2 i.p., 2 h apart) intoxication accelerated DA metabolism and oxidation in the striatum, with subsequent cell damage in nigrostriatal dopaminergic neurons after 4 days. Oral administration of FR261529 (10 or 32 mg/kg) attenuated the damage of dopaminergic neurons via marked reduction of PARP activity and not via changes in dopamine metabolism or body temperature. These findings indicate that the neuroprotective effects of a novel PARP inhibitor, FR261529, were accompanied by inhibition of METH-induced PARP activation, suggesting that METH induces nigrostriatal dopaminergic neurodegeneration involving PARP activation and also orally active and brain-penetrable PARP inhibitor FR261529 could be a novel attractive therapeutic candidate for neurodegenerative disorders such as PD.
Iwashita
Akinori
A
Department of Neuroscience, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. aki_iwashita@po.fujisawa.co.jp
Mihara
Kayoko
K
Yamazaki
Syunji
S
Matsuura
Shigeru
S
Ishida
Junya
J
Yamamoto
Hirofumi
H
Hattori
Kouji
K
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D016716:PC12 Cells; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
C492671:2-(4-chlorophenyl)-5-quinoxalinecarboxamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011810:Quinoxalines; D008694:Methamphetamine; C025160:3-aminobenzamide; D004298:Dopamine