Abstract W P231: Efficacy Of Clinically Tested Laropiprant In Minimizing Brain Injury Following Intracerebral Hemorrhage
Background and Purpose: The significant association of PGD2 and its receptor DP1 in vasculature, blood, and brain warrants further examination of their role in intracerebral hemorrhage. In this study, we tested whether deletion of DP1 receptor or its inhibition by selective antagonist Laropiprant improves functional and anatomical outcomes following ICH by limiting intracranial bleeding.
Methods: Wildtype (WT) and DP1-/- C57Bl/6 mice were subjected to ICH by giving a single dose of collagenase in the striatum. Neurologic deficits, brain injury volume, and edema volume were calculated at 72h. In another set of cohorts, WT mice were subjected to ICH followed by single i.p. injection of Laropiprant. To test whether the beneficial effects of DP1 receptor inhibition could be through reduced intracranial bleeding, non-ICH WT and DP1-/- mice were tested for tail bleeding time following the Laropiprant treatment. To further test the effect of Laropiprant on ex-vivo coagulation, mouse blood was mixed with vehicle or Laropiprant and the uncoagulated content was quantified. Finally, the role of DP1 inhibition in modulation gliosis was also tested by performing immunoreactivity for Iba1 on the brain sections of WT and DP1-/- mice.
Results: A significant decrease in the injury volume (4.8±1.7mm3 vs 14.1±4.5mm3; p<0.001) and edema volume (4.5±1.8mm3 vs 13.2±4.1mm3; p<0.001) in DP1-/- was observed. Similarly, WT mice treated with Laropiprant also exhibited significantly lower brain damage (6.2±2.2mm3 vs 12.7±5.1mm3; p<0.01) as compared with the vehicle treated group. Interestingly, the tail bleeding time was also significantly lower in Laropiprant group (219.4±75.2sec; p<0.001) as compared with the vehicle group (345.2±45.6sec), and similarly the uncoagulated content was also lower in Laropiprant group (356.2±53.6μL; p<0.001) as compared with the vehicle group (486.4±26.7μL). Interestingly, a significant decrease in Iba1 immunoreactivity was observed in DP1-/-.
Conclusions: Together, the data suggests that inhibition of the DP1 receptor after ICH attenuates functional and anatomical deficits partially by minimizing intracranial bleeding and neuroinflammation.
Author Disclosures: A.S. Ahmad: None. M. Mendes: None. S. Dore: None.
- © 2015 by American Heart Association, Inc.