Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity.
OBJECTIVE
Heparin and heparinoids have long been proposed for stroke treatment. This study investigates the effect of enoxaparin (Lovenox, Clexane), a low-molecular-weight heparin, on functional outcome (neuroscore) and lesion size in stroke models with reversible and irreversible cerebral ischemia using middle cerebral artery occlusion (MCAO) in the rat.


METHODS
Ischemia was induced in rats by transient occlusion for 2 hours or by permanent electrocoagulation of the left MCA. Forty-eight hours after ischemia, neurological deficit was evaluated by scoring sensorimotor functions and ischemic damage was quantified by histological evaluation of lesion volumes.


RESULTS
After transient MCAO, enoxaparin at 2x1.5 mg/kg IV (2 and 24 hours after insult) significantly reduced lesion size by 30% (P<0.05) and improved neuroscore (P<0.01). This significant effect on lesion size and neuroscore was still evident when treatment was started 5 hours after insult. Administered under the same protocol with a 5 hours delay post permanent MCAO, enoxaparin reduced lesion size by 49% (P<0.05) and improved neuroscore (P<0.01).


CONCLUSIONS
This study indicates that standard nonhemorrhagic doses of enoxaparin reduce ischemic damage with a wide therapeutic window. In addition to its anticoagulant properties, other properties of enoxaparin could act in synergy to explain its neuroprotective profile in ischemia. Thus clinical application of enoxaparin treatment in stroke warrants serious consideration.
Mary
V
V
CNS Research, Aventis Pharma, CRVA, Vitry-sur-seine, France. veronique.mary@aventis.com
Wahl
F
F
Uzan
A
A
Stutzmann
J M
JM
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000008:administration & dosage*; D006493:Heparin / Q000008:administration & dosage; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010314:Partial Thromboplastin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013997:Time Factors; D016896:Treatment Outcome
D017984:Enoxaparin; D018696:Neuroprotective Agents; D006493:Heparin