Effects of a semi-synthetic N-,O-sulfated glycosaminoglycan K5 polysaccharide derivative in a rat model of cerebral ischaemia/ reperfusion injury
| Autor: | Liana Salsini, Emanuela Masini, Marco Manoni, Jacopo Chini, Sara Castiglia, Massimo Collino, Roberto Fantozzi |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Neutrophils Anti-Inflammatory Agents Drug Evaluation Preclinical Ischemia Nitric Oxide Synthase Type II Apoptosis Inflammation Brain damage Pharmacology Hippocampus Brain Ischemia Brain ischemia Lesion Random Allocation Polysaccharides medicine Animals Rats Wistar biology business.industry Transcription Factor RelA Anticoagulants Hematology Heparin Intercellular Adhesion Molecule-1 medicine.disease Rats Chemotaxis Leukocyte Proto-Oncogene Proteins c-bcl-2 Cyclooxygenase 2 Reperfusion Injury Myeloperoxidase Immunology biology.protein Brain Damage Chronic medicine.symptom business Reperfusion injury Psychomotor Performance BH3 Interacting Domain Death Agonist Protein medicine.drug |
| Zdroj: | Thrombosis and Haemostasis. 102:837-845 |
| ISSN: | 2567-689X 0340-6245 |
| DOI: | 10.1160/th09-01-0012 |
| Popis: | SummaryHeparin 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. |
| Databáze: | OpenAIRE |
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