The effects of the phosphodiesterase inhibitor olprinone on global cerebral ischemia.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 1310650 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1526-7598 (Electronic) Linking ISSN: 00032999 NLM ISO Abbreviation: Anesth Analg Subsets: MEDLINE

Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Cleveland, International Anesthesia Research Society.

Phosphodiesterase 3 Inhibitors*; Brain Ischemia/*drug therapy ; CA1 Region, Hippocampal/*drug effects ; Cerebrovascular Circulation/*drug effects ; Imidazoles/*pharmacology ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Phosphodiesterase Inhibitors/*pharmacology ; Pyridones/*pharmacology; Animals ; Blotting, Western ; Brain Ischemia/enzymology ; Brain Ischemia/pathology ; Brain Ischemia/physiopathology ; CA1 Region, Hippocampal/blood supply ; CA1 Region, Hippocampal/enzymology ; CA1 Region, Hippocampal/pathology ; CA1 Region, Hippocampal/physiopathology ; Cell Hypoxia ; Cell Survival ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Glucose/deficiency ; Male ; Neurons/enzymology ; Neurons/pathology ; Phosphorylation ; Rats ; Rats, Wistar ; Time Factors

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.

0 (Cyclic AMP Response Element-Binding Protein)
0 (Imidazoles)
0 (Neuroprotective Agents)
0 (Phosphodiesterase 3 Inhibitors)
0 (Phosphodiesterase Inhibitors)
0 (Pyridones)
4Y8BMI9YGC (olprinone)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
IY9XDZ35W2 (Glucose)

Date Created: 20100101 Date Completed: 20100319 Latest Revision: 20210103

20221213

10.1213/ANE.0b013e3181cb5cdd

20042441