Therapeutic time window and dose dependence of neuroprotective effects of sodium orthovanadate following transient middle cerebral artery occlusion in rats.
Vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. We previously documented the neuroprotective effect of sodium orthovanadate (SOV) against in rodents i.v. injected with 2 ml/kg 50 mM SOV just after the induction of middle cerebral artery occlusion (MCAO; 0 min post-MCAO). To evaluate its potential clinical use, we determined here therapeutic time window (0, 45, and 90 min post-MCAO) and the neuroprotective dose (2 ml/kg, 12.5, 25, 37.5, and 50 mM) of SOV in rats. A single injection of 50 mM SOV at 0 or 45 min post-MCAO produced similar neuroprotective effects, and even 50 mM delivered 90 min post-MCAO exerted significant neuroprotection. Although the maximal neuroprotective effect was obtained at 50 mM SOV, 25 mM injected once and 12.5 mM delivered at 0 and 45 min post-MCAO significantly reduced the infarct volume. We also documented that SOV treatment ameliorates ischemic neuronal cell injury via the activation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK), inhibits serum glucose, and elicits the gradual recovery of regional cerebral blood flow (rCBF) after transient MCAO in rats. To elucidate the important factor(s) involved in the neuronal protection afforded by SOV, we measured Akt and ERK activity, physiological parameters, blood glucose levels, and rCBF following various SOV treatments. In conclusion, Akt activation was the most important factor in SOV-induced neuroprotection; ERK activation, the gradual recovery of rCBF, and decreased blood glucose were weak contributors.
Hasegawa
Yu
Y
Department of Neurosurgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Morioka
Motohiro
M
Hasegawa
Shu
S
Matsumoto
Jun
J
Kawano
Takayuki
T
Kai
Yutaka
Y
Yano
Shigetoshi
S
Fukunaga
Kohji
K
Kuratsu
Jun-Ichi
J
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014638:Vanadates / Q000008:administration & dosage / Q000627:therapeutic use*
D001786:Blood Glucose; D018696:Neuroprotective Agents; D014638:Vanadates; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases