Effects of a semi-synthetic N-,O-sulfated glycosaminoglycan K5 polysaccharide derivative in a rat model of cerebral ischaemia/ reperfusion injury

Massimo Collino; Sara Castiglia; Marco Manoni; Liana Salsini; Jacopo Chini; Emanuela Masini; Roberto Fantozzi

doi:10.1160/TH09-01-0012

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 102(05): 837-845
DOI: 10.1160/TH09-01-0012

Theme Issue Article

Schattauer GmbH

Effects of a semi-synthetic N-,O-sulfated glycosaminoglycan K5 polysaccharide derivative in a rat model of cerebral ischaemia/ reperfusion injury

Massimo Collino

¹Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy

,

Sara Castiglia

¹Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy

,

Marco Manoni

²INALCO RSM S.p.A, Research Center, Montale, Pistoia, Italy

,

Liana Salsini

²INALCO RSM S.p.A, Research Center, Montale, Pistoia, Italy

,

Jacopo Chini

²INALCO RSM S.p.A, Research Center, Montale, Pistoia, Italy

,

Emanuela Masini

³Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy

,

Roberto Fantozzi

¹Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy

› Author Affiliations

Abstract

Summary

Heparin and low molecular weight heparins may reduce brain damage evoked by ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhage. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility to produce heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of transient cerebral I/R, we investigated the effects of an epimerised N-,O-sulfated K5 polysaccharide derivative, K5-N,OSepi, on the infarct size, motor activity and injury caused by ischaemia (30 min) and reperfusion. Reperfusion was allowed for 60 min or 1–5 days. Rats reperfused for 5 days showed an infarct volume of 30.7 ±3.1% and K5-N,OSepi (0.1–1 mg/kg) caused dose-dependent reduction in infarct size (maximum at 1 mg/kg: 13.1 ±2.1% infarct volume). This effect was associated with a significant improvement in motor performance. In the rat hippocampus, one of the brain areas most sensitive to I/R injury, I/R induced a robust increase in myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, that was halved by K5-N,OSepi administration (66.38 ±7.75 µU MPO/tissue g, 30.78 ±5.67 µU MPO/tissue g, respectively). K5-N,OSepi drastically reduced the expression of cyclooxygenase-2,inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1. I/R-induced activation of nuclear factor-kB was attenuated by drug treatment. Furthermore, K5-N,OSepi administration was associated with a significant modulation of apoptosis markers, such as Bid and Bcl-2. In conclusion, the results demonstrated that the sulfated semi-synthetic K5 derivative K5-N,OSepi protects the brain against I/R injury by disrupting multiple levels of the apoptotic and inflammatory cascade, including inhibition of NF-κB activation.

Keywords

Heparin-like derivative - hippocampus - cerebral ischaemia/reperfusion - inflammation

Full Text

References

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