Antithrombin reduces ischemic volume, ameliorates neurologic deficits, and prolongs animal survival in both transient and permanent focal ischemia.
OBJECTIVE
Antithrombin (AT), a glycoprotein belonging to the serpin family, blocks thrombin formation and activity at several steps. Thrombin, beside its relevant role in the coagulation cascade, exerts neurodetrimental effects through the activation of a family of protease-activated receptors, which can be implicated in stroke pathophysiology. The aims of the present study were to evaluate whether AT could reduce brain damage, ameliorate neurologic deficits, and prolong animal survival.


METHODS
Two different doses of AT (10 and 30 IU/kg IP) were administered 3 hours, 6 hours, or 3 and 6 hours after an ischemic insult to mice and rats subjected to either transient or permanent focal ischemia. Ischemic volume was evaluated 24 hours or 7 days after the ischemic insult. Neurologic deficits were also scored.


RESULTS
In mice, 10 or 30 IU/kg AT administered twice, at 3 and 6 hours after transient ischemia, and 30 IU/kg AT administered 3 hours only after transient ischemia substantially reduced total ischemic volume, significantly improved neurologic deficits evaluated 24 hours after the insult, and prolonged animal survival. In rats, the same doses given at the same time intervals significantly reduced ischemic volume, evaluated 24 hours after permanent ischemia.


CONCLUSIONS
These results indicate that AT remarkably reduces infarct volume, ameliorates neurologic deficit scores, and prolongs animal survival in 2 rodent models of brain ischemia. Taken together, our data suggest that AT, delivered via systemic administration, an easily achievable route of administration and in a clinically useful time window, could represent a new therapeutic strategy to be validated for the clinical treatment of human stroke.
Cuomo
Ornella
O
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II, University of Naples, Via S Pansini 5, 80131 Naples, Italy.
Pignataro
Giuseppe
G
Gala
Rosaria
R
Scorziello
Antonella
A
Gravino
Elvira
E
Piazza
Ornella
O
Tufano
Rosalba
R
Di Renzo
Gianfranco
G
Annunziato
Lucio
L
D000818:Animals; D000991:Antithrombins / Q000378:metabolism*; D001784:Blood Gas Analysis; D001921:Brain / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D009422:Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D016896:Treatment Outcome
D000991:Antithrombins; D044462:Receptors, Proteinase-Activated