Abstract 3511: Potential Physiological Pathway Through Which PGD2 DP1 Receptor Is Preventing Ischemic Brain Damage
Background and Purpose: Being the most abundant prostaglandin in brain, PGD2 serves as a prime candidate to be investigated in neurologic conditions. Previously we have shown that DP1-/- mice have greater brain damage after middle cerebral artery occlusion (MCAO) and NMDA-induced acute excitotoxicity. Characterization of cerebral vessels in C57BL/6 wildtype (WT) and DP1-/- mouse brain shows no major differences. In the present study we are testing whether post-treatment with DP1 agonist BW245C improves cerebral blood flow (CBF), and minimizes brain damage and behavioral deficits after MCAO.
Methods: To determine if BW245C can change basal CBF, WT and DP1-/- mice were anesthetized with isoflurane and a laser Doppler flow (LDF) probe was affixed to the skull to record CBF. Once the baseline was obtained, mice were given a single i.p. injection of vehicle or 0.2mg/kg BW245C, and CBF was recorded for 2h at 10min intervals. To determine if BW245C can prevent brain damage after MCAO, separate cohorts of WT and DP1-/- mice were subjected to 60min MCAO and 96h reperfusion. Immediately at reperfusion, mice were given a single i.p. injection of vehicle or 0.2mg/kg BW245C. These mice were also tested for (a) open field activity, (b) cylinder test, (c) hanging wire test, and (d) neurologic deficit. Finally to determine the selectivity of BW245C, DP1-/- mice were subjected to MCAO and immediately at reperfusion vehicle or 0.2mg/kg BW245C was given i.p. and brains were harvested at 96h.
Results: BW245C treatment increased the CBF significantly in WT and in DP1-/- it remained unchanged. The infarction volume was significantly reduced to 38.7±8.1% in BW245C treatment group (n=8) as compared with the control group (51.2±7.1%; n=13) and vehicle group (52.7±8.6%; n=8). The attenuation in cerebral infarction by BW245C correlated with significant improvement in behavioral deficit outcomes. Moreover, the results were extended in the DP1-/- where we found a significant increase in infarction volume (66.3±11.4%) as compared with the WT control mice (51.2±7.1%; n=13). Furthermore, the pharmacologic effects of BW245C were found to be absent in DP1-/- suggesting that the protective effect of BW245C is through DP1 receptor.
Conclusions: Overall the data suggests that stimulation of the DP1 receptor improves CBF, and minimizes brain damage and functional deficits after ischemia. This ongoing work is enabling us to provide mechanisms through which DP1 receptor is exerting its neuroprotective effects. Further work is underway to determine the PGD2 DP1 action in regulating the vascular unit.
- © 2012 by American Heart Association, Inc.