Neuroprotective effect of YM-39558, orotic acid ethylester, in gerbil forebrain ischemia.
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.
Akiho
H
H
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Iwai
A
A
Katoh-Sudoh
M
M
Tsukamoto
S
S
Koshiya
K
K
Yamaguchi
T
T
D000818:Animals; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D005849:Gerbillinae; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016548:Prosencephalon / Q000098:blood supply*; D011743:Pyrimidines / Q000627:therapeutic use*; D013056:Spectrophotometry, Ultraviolet
D018696:Neuroprotective Agents; D011743:Pyrimidines; C113467:YM 39558