Abstract W MP47: Mitochondrial P53 Inhibition Abolishes Detrimental Effect of Post-Stroke Isolation on Ischemic Injury
Background: Social isolation is an important contributing risk factor for increased stroke injury and delayed functional recovery. Although previous studies strongly suggest that isolation prior to stroke increase injury in experimental models, little is known regarding the effects of SI after injury. Most patients do not seek medical attention until after the injury occurs; the ability to manipulate post-stroke housing environments has translational significance. In this study, we investigated the effects of post-stroke isolation.
Methods: C57Bl6 mice were housed as pairs (PH), male with ovariectomized female for 2 weeks, then subjected to right middle cerebral artery occlusion and then assigned to single housing (SI) or continued PH. The effects of SI on infarct volumes and neurological deficit scores (NDS) at 72h were assessed. Brain lysates from a separate cohort at 6h post-stroke were used for mitochondrial p53, caspase3 and BCl2 protein levels by western blot. Using pifithrin-μ (PFT-μ), a mitochondrial p53inhibitor (2mg/kg given i.p. at 3h & 24h after stroke) we then explored the role of P53 on infarct in SI mice.
Results: Post-stroke SI exacerbated infarct size compared to PH mice in males (Cortex: 61.6±4.8 vs 38.4±5.1; p<0.05); (Striatum: 79.2±6.1 vs 60.4±5.7; p<0.05); (Total: 58.1±4.6 vs 34.4±5.1; p<0.05). This effect is more pronounced in females (Cortex: 64.3±5.1 vs 37.1±3.1; p<0.01); (Striatum: 82.1±4.6 vs 56.5±4.6; p<0.01); (Total: 51.4±3.4 vs 30.3±3.8; p<0.01). PH mice displayed improved NDS compared to SI mice. The detrimental effects of SI are observed with an increase in mitochondrial p53 translocation (n=6/grp; p<0.05). Inhibition of mitochondrial p53 abolished the effects of SI and reduced TUNEL positive cells, suggesting that p53 plays a critical role in housing effects.
Conclusions: We found that post-stroke SI leads to worse outcome in both males and females, along with increased mitochondrial p53 expression. P53 is a critical stress sensor activated in response to stress and ischemia. Inhibition of mitochondrial P53 by PFT-μ abolished the detrimental effects of SI on stroke volume and reduced apoptotic cell death. These findings suggest that mitochondrial P53 inhibition may minimize the detrimental effects of SI in stroke.
Author Disclosures: V.R. venna: None. L.M. O'Keefe: None. Y. Xu: None. R. Verma: None. A. Patrizz III: None. B. Friedler: None. L.D. McCullough: None.
This research has received full or partial funding support from the American Heart Association, Founders - Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont.
- © 2014 by American Heart Association, Inc.