EndothelinA receptor antagonist BSF-208075 causes immune modulation and neuroprotection after stroke in gerbils.
Leukocytes contribute to the ischemia-reperfusion injury. Recent studies suggested endothelins could be important mediators for leukocyte activation in stroke. We tested if the endothelinA receptor antagonist BSF-208075 (ambrisentan) could reduce an ischemic lesion by modulation of leukocyte-endothelium interactions. Twenty-four gerbils underwent either a sham operation (n=6) or 15 min of bilateral carotid artery occlusion resulting in global cerebral ischemia. Ischemic animals received normal saline (n=6), 5 mg/kg BSF-208075 (n=6) or 30 mg/kg (n=6) administered intravenously at 10 min of reperfusion. Leukocytes rolling or adhering to endothelium were counted by intravital microscopy in parietal subsurface venules through a closed cranial window. BSF-208075 dose-dependently reduced postischemic leukocytes rolling (7.3+/-2.3 vs. 3.3+/-1.4 vs. 0.7+/-0.7 [n/100 microm/min]; p<0.05) and adhering (5.3+/-1.4 vs. 2.7+/-1.6 vs. 1.3+/-0.5 [n/100 microm/min]; p<0.05). Cerebral blood flow was not significantly changed by BSF-208075. Cortical neurons [n/mm2] in an area corresponding to the in vivo microscopy were dose-dependently preserved 7 days after ischemia (2456+/-687 vs. 3254+/-245 vs. 3780+/-168; p<0.05).


CONCLUSIONS
Endothelins mediate leukocyte activation in ischemic stroke. The endothelinA receptor antagonist BSF-208075 administered during reperfusion reduces the postischemic leukocyte activation and causes neuroprotection.
Hauck
Erik F
EF
Division of Neurosurgery, University of Texas Medical Branch, Galveston, USA.
Hoffmann
Julie F
JF
Heimann
Axel
A
Kempski
Oliver
O
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D005849:Gerbillinae; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D044022:Receptor, Endothelin A / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016896:Treatment Outcome
D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D007155:Immunologic Factors; D018696:Neuroprotective Agents; D010666:Phenylpropionates; D011724:Pyridazines; D044022:Receptor, Endothelin A; C467894:ambrisentan