Abstract TP260: Efficacy of Laropiprant in Ameliorating Hyperglycemia-mediated Intracerebral Hemorrhage
Introduction: The respective importance of PGD2 and its receptor DP1 in the vasculature, the blood, and the brain warrants further examination of their role in hyperglycemia-mediated intracerebral hemorrhage (ICH).
Hypothesis: In this study, we tested whether deletion of the DP1 receptor or its blockade by the selective antagonist Laropiprant improves functional and anatomical outcomes following ICH in hyperglycemic mice.
Methods: Wildtype (WT) and DP1-/- C57BL/6 mice were given 2g/kg glucose; blood glucose levels and c-peptide levels were monitored over 4h. In the second cohort, WT and DP1-/- mice treated with saline or the DP1 receptor antagonist were given 2g/kg glucose and ICH was induced at 1h by giving a single dose of collagenase in the striatum. Neurologic deficits, brain injury volume, and edema volume were calculated at 72h. Further, the brain sections from these groups were subjected to Perls’ staining and Iba1 and GFAP immunoreactivity to determine the effect of Laropiprant on the modulation of iron levels and gliosis.
Results: Acute injection of glucose led to a significant increase in the glucose level in WT and DP1-/- mice. DP1-/- mice exhibited faster clearance of glucose overload compared with the WT mice. Similarly, WT mice treated with Laropiprant also exhibited faster clearance of glucose. Similar patterns were observed in c-peptide levels of these groups. The injury volume in DP1-/- mice compared with WT was significantly lower (8.3±1.8 vs 19.3±5.6mm3; p<0.01). Furthermore, WT mice treated with Laropiprant also exhibited significantly lower brain lesion volume (9.1±3.2 vs 19.3±5.6mm3; p<0.01). Interestingly, a significant decrease in Iba1 immunoreactivity and Perls’-labelled iron content was observed in hyperglycemic DP1-/- compared with the hyperglycemic WT mice.
Conclusion: Together, the data suggest that inhibition of the DP1 receptor improves glucose tolerance/clearance and attenuates functional and anatomical deficits following hyperglycemia-mediated ICH. Additional studies are underway to investigate further mechanisms.
[This work was supported by NIH R01 NS046400 (to S.D.).]
Author Disclosures: M. Mendes: None. S. Ali: None. S. Dore: Research Grant; Significant; R01NS046400. A. Ahmad: None.
- © 2016 by American Heart Association, Inc.