Protective effects of a non-anticoagulant heparin-like polysaccharide derivative on cerebral and myocardial ischemia/reperfusion injury.

Heparin and low molecular weight heparins have been demon- strated to reduce cerebral and myocardial ischemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhage. Recent findings suggest that heparin effects not related to its anti- coagulant property, such as anti-adhesion effect, exert a pivotal role in counteracting I/R-induced organ damage. Chemical and enzymatic modifications of the Escherichia coli capsular K5 polysaccharide have led to the synthesis of a heparin-like compound with low an- ticoagulant activity: the epimerised N-,O-sulfated K5 derivative, K5-N,OSepi. Using rat models of cerebral or myocardial I/R, we investigated the effects of K5-N,OSepi on infarct size and injury caused by, respectively, 30 min bilateral occlusion of common carotid arteries + 60 min-5 days reperfusion and 30 min ligature of the left anterior descending coronary artery + 60 min reperfusion. In both the experimental models, K5-N,OSepi (0.1Y1 mg/kg) caused dose- dependent reduction in infarct size. This effect was associated with a significant reduction in local neutrophil infiltration, adhesion mole- cules expression and cardiac mast cell degranulation. Furthermore, K5-N,OSepi administration attenuated the increase in caspase-3 activity, Bid and Bax activation and ameliorated the decrease in Bcl-2 expression within the ischemic tissue. Overall, these results demon- strate that the non-anticoagulant heparin-like derivative K5-N,OSepi protects both the brain and the heart against I/R injury by disrupting multiple levels of the inflammatory and apoptotic cascade