Abstract W P101: Combination of MST-188 and Tissue Plasminogen Activator Extends the Therapeutic Window of Stroke
Background and Purpose: The utilization of tissue plasminogen activator (tPA) for stroke treatment is hampered by its narrow therapeutic window and hemorrhagic complication. MST-188 (Vepoloxamer) is a proprietary tri-block copolymer with rheological and membrane-protective properties. The current study investigated whether MST-188 enhances the therapeutic effect of tPA on ischemic damage in a rat model of embolic focal cerebral ischemia.
Methods: Male Wistar rats (n=10) subjected to embolic middle cerebral artery occlusion (MCAO) were treated post stroke with the combination of MST-188 (300 mg/kg at 3.5h, IV; followed by a second dose of 2,000 mg/kg at 9.5h, IP) and tPA (10 mg/kg at 4h, IV). Ischemic rats treated with tPA (10 mg/kg at 4h, IV) alone, or saline were used as control groups (n=10/group). An array of behavioral tests were performed at 1 and 7 days after MCAO. Ischemic lesion volume was measured 7 days after MCAO.
Results: All rats exhibited neurological deficits measured by the Longa scale 30 min after MCAO. Treatment with tPA alone failed to reduce infarct volume and neurological functional deficits compared with saline treated rats. However, MST-188 in combination with tPA significantly (p<0.05) reduced neurological functional deficits measured by the adhesive removal test (90±29 at 1d and 63±39 seconds at 7d) and modified neurological severity score (mNSS, 9±2 at 1d and 6±3at 7d) compared with rats treated with tPA alone (116±9 at 1d and 96±17 seconds at 7d by adhesive removal test, 11±1 at 1d and 9±1 at 7d by mNSS) and saline (113±12 at 1d and 95±16 seconds at 7d by adhesive removal test, 11±1 at 1d and 8±1 at 7d by mNSS). Histopathological analysis showed that the combination of MST-188 with tPA treatment significantly reduced lesion volume (21±10%, p<0.05) compared with rats treated with tPA alone (35±12%) and saline (34±11%). No significant differences of the incidence of gross hemorrhage were detected among groups.
Conclusions: MST-188 enhances the therapeutic effect of tPA without increasing the incidence of hemorrhagic transformation when tPA is administered 4h after embolic MCAO.
Author Disclosures: L. Zhang: None. Z. Zhang: None. M. Emanuele: Employment; Significant; Dr. Emanuele is a senior vice president of Mast Therapeutics. M. Chopp: None.
- © 2015 by American Heart Association, Inc.