Abstract WMP78: Prostaglandin D2 DP1 Receptor Attenuates the Effects of Post-stroke Sleep Disturbance on Stroke Outcomes

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Abstract

Background: Post-stroke sleep disturbance is reported to be an indicator of poor stroke outcomes. The strategic location of the PGD2 DP1 receptor in specific brain regions regulating cerebrospinal fluid and sleep led us to hypothesize that the DP1 receptor may attenuate the deleterious effects associated with post-stroke sleep disturbance.

Methods: First, to test the effect of sleep deprivation on locomotor activity, wildtype mice were individually housed and their activity was monitored 20h/d for 3d. Day zero was used to obtain baseline, while for the next two days, mice were subjected to sleep disturbance for 10h during the sleep phase followed by 10h of no sleep. Second, to test whether a selective DP1 receptor agonist decreases locomotor activity, mice were given an intraperitoneal injection of the agonist and locomotor activity was monitored. Third, to test the effect of post-stroke sleep disturbance on stroke outcomes, wildtype and DP1-/- mice were subjected to 45min of MCAO and 7d of reperfusion. After MCAO, mice were subjected to post-stroke sleep disturbance for 12h/d for 3d during the mouse sleep phase.

Results: Sleep disturbance resulted in higher activity (awake like) during the sleep phase and lower activity during the awake phase. The distance travelled during the awake phase after sleep deprivation was significantly lower (P<0.001). These data suggest that sleep deprivation attenuated locomotor activity. The total ambulatory distance covered by DP1 agonist-treated group 4h post-treatment was 2161.2±846.4cm compared with the vehicle group activity of 7093.5±1953cm (P<0.01), suggesting that the selective pharmacological agent induced sleep. Analysis of the Cresyl violet-stained sections revealed a significantly larger (P<0.05) infarction volume and neurologic deficit in post-stroke, sleep-disturbed DP1-/- mice compared to similarly treated WT mice.

Conclusion: These data show that the PGD2 DP1 receptor plays a vital role in attenuating the deleterious effects of sleep disturbance on stroke outcomes. Additional studies are underway to further investigate mechanisms and optimal therapeutic conditions. [This work was supported by UF-CTSI (to A.S.A.) and R01NS046400, R01AT007429 (to S.D.)]

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