omega-agatoxin IVA-sensitive Ca(2+) channel blocker, alpha-eudesmol, protects against brain injury after focal ischemia in rats.
omega-Agatoxin IVA-sensitive Ca(2+) channels have been thought to be involved in physiological excitatory amino acid glutamate release and these channels may also contribute to the development of ischemic brain injury. Recently, we demonstrated that alpha-eudesmol from Juniperus virginiana Linn. (Cupressaceae) inhibits potently the presynaptic omega-agatoxin IVA-sensitive Ca(2+) channels. In the present study, we investigated the effects of alpha-eudesmol on brain edema formation and infarct size determined after 24 h of reperfusion following 1 h of middle cerebral artery occlusion in rats. We first found that alpha-eudesmol concentration-dependently inhibited glutamate release from rat brain synaptosomes and that its inhibitory effect was Ca(2+)-dependent. In the middle cerebral artery occlusion study, intracerebroventricular (i.c.v.) treatment with alpha-eudesmol significantly attenuated the post-ischemic increase in brain water content. alpha-Eudesmol also significantly reduced the size of the infarct area determined by triphenyltetrazolium chloride staining after 24 h of reperfusion. Using a microdialysis technique, we further demonstrated that alpha-eudesmol inhibits the elevation of the extracellular concentration of glutamate during ischemia. From these results, we suggest that alpha-eudesmol displays an ability to inhibit exocytotic glutamate release and to attenuate post-ischemic brain injury.
Asakura
K
K
Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Japan.
Matsuo
Y
Y
Oshima
T
T
Kihara
T
T
Minagawa
K
K
Araki
Y
Y
Kagawa
K
K
Kanemasa
T
T
Ninomiya
M
M
D000818:Animals; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D045787:Sesquiterpenes, Eudesmane; D013729:Terpenes / Q000494:pharmacology*; D020867:omega-Agatoxin IVA / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D045787:Sesquiterpenes, Eudesmane; D013729:Terpenes; D020867:omega-Agatoxin IVA; D018698:Glutamic Acid; C118684:alpha-eudesmol; D011188:Potassium