Abstract 131: Prostaglandin D2 DP1 Receptor Ameliorates Stroke Outcomes Through Cerebral Blood Flow and Hemostasis
Background and Purpose: The association of PGD2 with vasculature and blood makes it a prime candidate to be investigated in stroke. Here, we tested whether selective DP1 receptor agonist BW245C treatment after stroke improves the outcomes by regulating cerebral blood flow (CBF) and hemostasis.
Methods: First, the effect of BW245C on basal CBF was determined by giving a single i.p. injection of vehicle or 0.02, 0.2, 2.0mg/kg BW245C in WT and DP1-/- mice. Mice were given an i.p. injection of the vehicle or 0.2mg/kg BW245C and excised tail tip was placed in PBS to record bleeding time. To test the effect of BW245C on ex-vivo coagulation, mouse blood was mixed with vehicle or BW245C and the un-coagulated content was quantified. Next, to determine whether BW245C can prevent brain damage after MCAO, WT and DP1-/- mice were subjected to MCAO. Immediately at reperfusion mice were given a single i.p. injection of vehicle or 0.02, 0.2, 2.0mg/kg BW245C, and the functional and anatomical outcomes were tested at 96h. Further, to determine if BW245C can improve CBF during or after stroke, BW245C was given during occlusion and changes in CBF in peri-infarct and core were continuously recorded. Finally, the effect of BW245C on stroke outcomes was also tested in DP1-/- mice.
Results: BW245C treatment significantly increased the basal CBF only in WT. Interestingly, the tail bleeding time was significantly higher in BW245C group (29.0±14.7%; p<0.01) as compared with the vehicle group, and similarly the un-coagulated content was also higher in BW245C group (14.9±5.9%; p<0.005). The infarction volume was significantly reduced to 38.7±8.1% in 0.2mg/kg BW245C group as compared with the control (51.2±7.1%) and vehicle (52.7±8.6%) groups. Moreover, a strong correlation was observed between the decrease in infarction and CBF improvement in peri-infarct immediately at reperfusion and at 60min after reperfusion. The infarction in DP1-/- was significantly higher (66.3±11.4%) than the WT control mice and it was unaffected by BW245C treatment.
Conclusions: Overall the data suggests that activation of the DP1 receptor after stroke improves CBF, and minimizes brain damage and functional deficits partially through CBF and hemostasis regulation. [Supported by AHA SDG (ASA) and NIH R01 (SD) funds]
Author Disclosures: A.S. Ahmad: None. S. Narumiya: None. S. Dore: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.