Document Detail

Protective mechanisms of inosine in platelet activation and cerebral ischemic damage.
MedLine Citation:
PMID:  15976325     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Inosine is a naturally occurring nucleoside degraded from adenosine. Recent studies have demonstrated that inosine has potent immunomodulatory and neuroprotective effects. In the present study, we further investigated the inhibitory effects of inosine on platelet activation in vitro and in vivo, as well as in attenuating middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. METHODS AND RESULTS: Inosine concentration-dependently (0.5 to 6.0 mmol/L) inhibited platelet aggregation stimulated by agonists. Inosine (1.5 and 3.0 mmol/L) inhibited phosphoinositide breakdown, [Ca+2]i, and TxA2 formation in human platelets stimulated by collagen (1 microg/mL). In addition, inosine (1.5 and 3.0 mmol/L) markedly increased levels of cyclic guanylate monophosphate (GMP) and cyclic GMP-induced vasodilator-stimulated phosphoprotein Ser157 phosphorylation. Rapid phosphorylation of a platelet protein of molecular weight 47,000 (P47), a marker of protein kinase C activation, was triggered by collagen (1 microg/mL). This phosphorylation was markedly inhibited by inosine (3.0 mmol/L). Inosine (1.5 and 3.0 mmol/L) markedly reduced hydroxyl radical in collagen (1 microg/mL)-activated platelets. In in vivo studies, inosine (400 mg/kg) significantly prolonged the latency period of inducing platelet plug formation in mesenteric venules of mice, and administration of 2 doses (100 mg/kg) or a single dose (150 mg/kg) of inosine significantly attenuated MCAO-induced focal cerebral ischemia in rats. CONCLUSIONS: Platelet aggregation contributes significantly to MCAO-induced focal cerebral ischemia. The most important findings of this study suggest that inosine markedly inhibited platelet activation in vitro and in vivo, as well as cerebral ischemia. Thus, inosine treatment may represent a novel approach to lowering the risk of or improving function in thromboembolic-related disorders and ischemia-reperfusion brain injury.
George Hsiao; Kuang H Lin; Yi Chang; Ta L Chen; Nien H Tzu; Duen S Chou; Joen R Sheu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-06-23
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  25     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2005 Sep 
Date Detail:
Created Date:  2005-08-29     Completed Date:  2006-01-06     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1998-2004     Citation Subset:  IM    
Graduate Institute of Medical Sciences, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan.
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MeSH Terms
Brain Ischemia / blood,  drug therapy*
Calcium / metabolism
Cell Adhesion Molecules / metabolism
Collagen / pharmacology
Contrast Media
Cyclic AMP / metabolism
Cyclic GMP / metabolism
Free Radical Scavengers / pharmacology
Infarction, Middle Cerebral Artery / blood,  drug therapy*
Inosine / pharmacology*
Microfilament Proteins / metabolism
Phosphatidylinositols / metabolism
Phosphoproteins / metabolism
Phosphorylation / drug effects
Platelet Aggregation / drug effects*
Platelet Aggregation Inhibitors / pharmacology
Protein Kinase C / metabolism
Rats, Wistar
Thrombosis / blood,  drug therapy*
Thromboxane B2 / metabolism
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Contrast Media; 0/Free Radical Scavengers; 0/Microfilament Proteins; 0/Phosphatidylinositols; 0/Phosphoproteins; 0/Platelet Aggregation Inhibitors; 0/vasodilator-stimulated phosphoprotein; 2321-07-5/Fluorescein; 54397-85-2/Thromboxane B2; 58-63-9/Inosine; 60-92-4/Cyclic AMP; 7440-70-2/Calcium; 7665-99-8/Cyclic GMP; 9007-34-5/Collagen; EC Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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