Hiraku Akiho (#), Akihiko Iwai, Mika Katoh-Sudoh, Shin-ichi Tsukamoto,
Kazuo Koshiya and Tokio Yamaguchi
Neuroscience Research, Pharmacology Laboratories, Institute for Drug
Discovery Research, Yomanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki
305-8585, Japan
(#) Present address for correspondence: Clinical Development Department
I, Clinical Development Division, Yamanouchi Pharmaceutical Co., Ltd., 17-1,
Hasune 3-chome, Itabashi-ku, Tokyo 174-8612, Japan
Abstract: We studied the effects of orotic acid and YM-39558
(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid ethyl ester),
orotic acid ethylester, on delayed neuronal death of hippocampal CA1 neurons
induced by transient forebrain ischemia. Our data indicated that YM-39558
had high permeability across the blood brain barrier and was hydrolyzed
to orotic acid, the active substance, in the brain. The neuronal damage
was reduced significantly in animals intraperitoneally treated with YM-39558
(100 mg/kg x 3) after ischemia, but not with orotic acid in the same way.
The results also suggested that the maintenance of a few ten micromolar
orotic acid in cerebrospinal fluid were needed for its neuroprotective effects.
Keywords: Orotic acid, YM-39558, Cerebral ischemia