Small molecule selectin inhibitor in global cerebral ischemia and controlled hemorrhagic shock.
BACKGROUND
The clinical and experimental management of stroke has not reached the therapeutic success seen in other medical conditions associated with ischemia/reperfusion. In this work, we investigated the effect of a small molecule selectin inhibitor TBC-1269, in animals subjected to global cerebral ischemia (GCI) and controlled hemorrhagic shock (CHS).


METHODS
Forty-eight male Sprague-Dawley rats weighting between 275 g and 300 g were subjected to a model of GCI and CHS. Three groups of animals were included in this study (n = 16 per group): sham/saline (group 1); GCI/CHS/Saline (group 2); GCI/CHS/TBC-1269 (group 3). Experimental design consisted of bilateral carotid artery occlusion for 20 minutes, and the development of CHS until a mean arterial pressure of 50 mm Hg was reached. At 20 minutes, clamps were released, and resuscitation was achieved with normal saline, and the end point was to attain a mean arterial pressure of 80 mm Hg. Treatment at the beginning of resuscitation included either normal saline (groups 1 and 2) or TBC-1269 (25 mg/kg, group 3). The following indices were evaluated: brain tissue myeloperoxidase, average numbers of ischemic neurons, and 7-day survival.


RESULTS
Brain myeloperoxidase was decreased in animals treated with TBC-1269, although this difference was not statistically significant. Treated animals demonstrated a significant smaller amount of ischemic neurons than the controls. Survival was also improved from 40% in controls to 80% with TBC-1269 treatment. This difference was statistically significant.


CONCLUSIONS
The use of a small molecule selectin inhibitor, TBC-1269, had a protective effect in this model of GCI and CHS, as evidenced by decreased numbers of ischemic neurons and improved survival rates.
Anaya-Prado
Roberto
R
Borgess Research Institute, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI 49048, USA.
Pérez-Gomez
Nahum
N
Toledo-Pereyra
Luis H
LH
Walsh
John
J
Jordan
Jackie
J
Ward
Peter A
PA
D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000627:therapeutic use*; D020556:Neutrophil Infiltration; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D008362:Mannosides; C108700:bimosiamose disodium; D009195:Peroxidase; D008358:Mannose