Isolation of a diterpenoid substance with potent neuroprotective activity from fetal calf serum.
Excess activation of glutamate receptors and production of free radicals including nitric oxide may result in severe and irreversible damage to the mammalian central nervous system (CNS), but endogenous defense systems that protect neurons from these insults are poorly understood. Here, we purified and isolated a neuroprotective substance, which has been named "serofendic acid," from a lipophilic fraction of FCS based on the ability to protect rat primary cortical neurons against nitric oxide cytotoxicity. Mass spectrometry and NMR spectroscopy revealed the chemical structure of serofendic acid (15-hydroxy-17-methylsulfinylatisan-19-oic acid) as a sulfur-containing atisane-type diterpenoid, which is unique among known endogenous substances. Synthetic serofendic acid exhibited potent protective actions on cortical neurons against cytotoxicity of a nitric oxide donor as well as of glutamate, although it did not show appreciable influences on glutamate receptor-mediated responses in these neurons. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on nitric oxide radicals but was capable of inhibiting the generation of hydroxyl radical, a presumed "executor" radical in the nitric oxide-mediated neurotoxic cascade. These findings suggest that serofendic acid is a low-molecular-weight bioactive factor that promotes survival of CNS neurons, probably through the attenuation of free radical-mediated insults.
Kume
Toshiaki
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Asai
Naoki
N
Nishikawa
Hiroyuki
H
Mano
Nariyasu
N
Terauchi
Taro
T
Taguchi
Ryota
R
Shirakawa
Hisashi
H
Osakada
Fumitaka
F
Mori
Hiroki
H
Asakawa
Naoki
N
Yonaga
Masahiro
M
Nishizawa
Yukio
Y
Sugimoto
Hachiro
H
Shimohama
Shun
S
Katsuki
Hiroshi
H
Kaneko
Shuji
S
Akaike
Akinori
A
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats
D004224:Diterpenes; D018696:Neuroprotective Agents; C452642:serofendic acid