The effects of the phosphodiesterase inhibitor olprinone on global cerebral ischemia.
BACKGROUND
The phosphodiesterase III inhibitor olprinone has been confirmed to improve myocardial function and increase cerebral blood flow; therefore, if olprinone exerts direct neuroprotective effects against global cerebral ischemia to the same degree as cilostazol, olprinone could be useful for cerebral resuscitation after cardiac arrest. We examined whether olprinone directly protected neuronal cells from global cerebral ischemia both in vivo and in vitro.


METHODS
In a rat model of 10-minute global cerebral ischemia induced by 4-vessel occlusion, 0.3, 3, or 30 microg x kg(-1) x min(-1) olprinone or saline was infused for a periischemic period of 40 minutes (n = 6 for each group). Hippocampal CA1 neuronal cells were then counted 3 days after reperfusion, and the phosphorylation of cyclic adenosine 3'5'-monophosphate response element-binding protein was examined using Western blotting analyses of specimens obtained 15 minutes after reperfusion. In vitro, cultured cerebral neurons were exposed to 4 hours of hypoxia and glucose deprivation and then 24 hours of recovery in the absence or presence of olprinone (10(-11)-10(-5) mol x L(-1)). Cell viability was measured using the Cell Counting Kit-8 (Dojindo Molecular Technologies, Gaithersburg, MD).


RESULTS
In the rat model of global ischemia, the number of surviving CA1 neurons counted under a microscopic field in the 30 microg x kg(-1) x min(-1) olprinone-treated group (49.9 +/- 9.2) was significantly higher than that in the saline infusion control group (7.2 +/- 3.4), and olprinone treatment increased the phosphorylation of cyclic adenosine 3'5'-monophosphate response element-binding protein. The survival fraction of the neuronal cells cultured in the presence of olprinone was also significantly higher than that of cells cultured in the absence of olprinone in a dose-dependent manner.


CONCLUSIONS
Our study successfully demonstrated, for the first time, that olprinone had a protective effect on neuronal cells in vitro and in vivo, especially against global cerebral ischemia. These results suggest that olprinone might be useful for the treatment of patients experiencing global cerebral ischemia.
Okayama
Naoko
N
Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Matsunaga
Akira
A
Kakihana
Yasuyuki
Y
Fujikawa
Kohsho
K
Inoue
Kazuhiko
K
Nagayama
Tetsuya
T
Takeyama
Masaharu
M
Miyata
Atsuro
A
Kanmura
Yuichi
Y
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D007093:Imidazoles; D018696:Neuroprotective Agents; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; C059498:olprinone; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005947:Glucose