Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat.
Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.
Cervera
Alvaro
A
Stroke Unit, Neurology Service, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer, Barcelona, Spain.
Justicia
Carles
C
Reverter
Joan C
JC
Planas
Anna M
AM
Chamorro
Angel
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D020520:Brain Infarction / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006493:Heparin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016753:Interleukin-10 / Q000097:blood; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D019010:Vascular Cell Adhesion Molecule-1; D016753:Interleukin-10; D006493:Heparin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1