Acute enoxaparin treatment widens the therapeutic window for tPA in a mouse model of embolic stroke.
OBJECTIVE
The purpose of this experiment was to determine if the low molecular weight heparin (LMWH) enoxaparin could extend the treatment window for thrombolysis in a mouse model of embolic stroke.


METHODS
To establish the treatment window, mice were treated with tPA 2, 3 or 4 hours after clot insertion. Results showed that only the 2 hour treatment group exhibited infarct volumes significantly smaller than untreated controls. We attempted to widen this window by pre-treating mice with enoxaparin (10 mg/kg, s.c.; n=36) 1 hour before embolization. A control group (n=24) was given a saline injection. The enoxaparin-treated animals were subdivided and treated with tPA either 4 (n=12) or 6 hours (n=12) after clot insertion, while the third group (n=12) was given saline. The saline-pre-treated mice were dived into two groups: one group (n=12) received tPA and the other group (n=12) received saline 4 hours post-stroke. Embolization was confirmed by laser Doppler flowmetry and the effects of the resulting infarcts were evaluated by triphenyltetrazolium chloride staining and by behavioral testing.


RESULTS
Results showed large infarcts and impaired sensorimotor coordination in the saline pre-treated animals confirming the narrow treatment window. Enoxaparin pre-treatment produced significantly smaller infarcts and improved motor behavior in groups treated with tPA both 4 and 6 hours after embolization. Neither the 4 nor the 6 hour tPA-treated groups showed evidence of intracerebral hemorrhage or external bleeding.


CONCLUSIONS
These data indicate that the LMWH enoxaparin can significantly increase the therapeutic time window in a mouse model of embolic stroke.
Quartermain
David
D
Department of Neurology, New York University School of Medicine, New York, NY 10016, USA. quartd01@med.nyu.edu
Li
Yong-Sheng
YS
Jonas
Saran
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004347:Drug Interactions; D017984:Enoxaparin / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy*; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D013778:Tetrazolium Salts; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D017984:Enoxaparin; D005343:Fibrinolytic Agents; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D010959:Tissue Plasminogen Activator