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

Abstract

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 microU MPO/tissue g, 30.78 +/- 5.67 microU 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-kappaB activation.

• Authors: Massimo Collino, Sara Castiglia, Marco Manoni, Liana Salsini, Jacopo Chini, Emanuela Masini, Roberto Fantozzi
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 102 Issue 5 Pg. 837-45 (Nov 2009) ISSN: 2567-689X [Electronic] Germany
• PMID: 19888517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Anticoagulants
• BH3 Interacting Domain Death Agonist Protein
• Bid protein, rat
• Polysaccharides
• Proto-Oncogene Proteins c-bcl-2
• Rela protein, rat
• Transcription Factor RelA
• Intercellular Adhesion Molecule-1
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Cyclooxygenase 2
• Ptgs2 protein, rat

Topics

• Animals
• Anti-Inflammatory Agents (chemical synthesis, pharmacology, therapeutic use)
• Anticoagulants (chemical synthesis, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• BH3 Interacting Domain Death Agonist Protein (biosynthesis, genetics)
• Brain Damage, Chronic (etiology, prevention & control)
• Brain Ischemia (drug therapy, etiology, pathology)
• Chemotaxis, Leukocyte (drug effects)
• Cyclooxygenase 2 (biosynthesis, genetics)
• Drug Evaluation, Preclinical
• Hippocampus (blood supply, drug effects, pathology)
• Inflammation (prevention & control)
• Intercellular Adhesion Molecule-1 (biosynthesis, genetics)
• Male
• Neutrophils (enzymology)
• Nitric Oxide Synthase Type II (biosynthesis, genetics)
• Polysaccharides (chemical synthesis, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics)
• Psychomotor Performance (drug effects)
• Random Allocation
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy, pathology)
• Transcription Factor RelA (antagonists & inhibitors)