Oral administration of diphenylarsinic acid, a degradation product of chemical warfare agents, induces oxidative and nitrosative stress in cerebellar Purkinje cells.
A new clinical syndrome with prominent cerebellar symptoms in patients living in Kamisu City, Ibaraki Prefecture, Japan, is described. Since the patients ingested drinking water containing diphenylarsinic acid (DPA), a stable degradation product of both diphenylcyanoarsine and diphenylchloroarsine, which were developed for use as chemical weapons and cause severe vomiting and sneezing, DPA was suspected of being responsible for the clinical syndrome. The purpose of the present study was to elucidate prominent cerebellar symptoms due to DPA. The aim of the study was to determine if single (15 mg/kg) or continuous (5 mg/kg/day for 5 weeks) oral administration of DPA to ICR-strain mice induced oxidative and/or nitrosative stress in their brain. Significantly positive staining with malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) was observed in the cerebellar Purkinje cells by repeated administration (5 mg/kg/day) with DPA for 5 weeks that led to the cerebellar symptoms from a behavioral pharmacology standpoint and by single administration of DPA (15 mg/kg). Furthermore, it is possible that the production of 3-NT was not caused by peroxynitrite formation. The present results suggest the possibility that arsenic-associated novel active species may be a factor underlying the oxidative and nitrosative stress in Purkinje cells due to exposure to DPA, and that the damage may lead to the cerebellar symptoms.
Kato
Koichi
K
Research Unit of Environmental Toxicology and Carcinogenesis, Nihon University College of Pharmacy, Chiba, Japan.
Mizoi
Mutsumi
M
An
Yan
Y
Nakano
Masayuki
M
Wanibuchi
Hideki
H
Endo
Ginji
G
Endo
Yoko
Y
Hoshino
Mikio
M
Okada
Shoji
S
Yamanaka
Kenzo
K
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002526:Cerebellar Diseases / Q000139:chemically induced / Q000503:physiopathology; D002531:Cerebellum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009249:NADP / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000503:physiopathology; D009584:Nitrogen / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects*; D011689:Purkinje Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D001152:Arsenicals; D002619:Chemical Warfare Agents; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D008315:Malondialdehyde; D009249:NADP; D005979:Glutathione Peroxidase; D009584:Nitrogen; C493087:diphenylarsinic acid