Inhibition of Mitochondrial P53 Abolishes the Detrimental Effects of Social Isolation on Ischemic Brain Injury

Abstract

Background and Purpose Social Isolation (SI) increases stroke incidence and delays post-stroke recovery. Women may be at greater risk from the negative consequences of SI, but few studies have examined both sexes in experimental models, and none have evaluated the effects of isolation initiated after stroke. The effects of post-stroke SI in males and females were examined and the role of mitochondrial P53 was evaluated. Methods C57Bl6 mice were pair-housed (male and ovariectomized female) for 2 weeks, subjected to stroke and then assigned to a housing condition (isolated or pair-housed (PH)). The effects of housing on infarct volume and recovery were examined. Changes in Bcl-2 and mitochondrial p53 were assessed by western blot. A mitochondrial p53 inhibitor (PFT-μ) was given to mice of both sexes. Results Compared to PH mice, post-stroke SI significantly increased infarct size in both sexes; SI mice also had worse neurological deficits. The detrimental effects of SI paralleled increases in mitochondrial p53 levels. Pharmacological inhibition of mitochondrial p53 using PFT-μ abolished the detrimental effects of SI and reduced cell death. Conclusions Post-stroke SI results in increased ischemic injury in both sexes. The effect of housing on infarct was more pronounced in females. Targeting the mitochondrial P53 pathway could minimize the detrimental effects of isolation after stroke.

Neuroprotection with the P53-Inhibitor Pifithrin-μ after Cardiac Arrest in a Rodent Model

“…Dysfunctional p53 can be found in a wide range of cancer cells (21), but p53 is also involved in delayed cell death after traumatic brain injury (22), stroke (20), and contributes to side effects of anti-cancer drugs and irradiation. Inhibition of p53 by either drugs or gene knockout leads to improved survival after irradiation (8,23), anti-cancer treatment (10,24), neuronal ischemia (9,10,20,25), myocardial ischemia (26) and oxidative stress in hepatoma cell lines (27). The small molecule pifithrin-α inhibits the transcription-dependent p53, whereas pifithrin-μ suppresses the p53 binding to the mitochondrial membrane (27).…”

“…Inhibition of p53 restores spontaneous locomotion of the animals after experimental stroke (9), protects neonatal rat brain from hypoxic-ischemic injury (10) and attenuate autophagic and apoptotic cell death in the cortex and hippocampus when given before cardiac arrest in rats (11).…”

One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition

“…See Figure 4 for a comparison of infarct volumes. Though isolation is clearly associated with increased infarct volume in both sexes, the effect may be more pronounced in females [128]. Affiliative interaction prior to stroke improved motor function a week after injury [21].…”

MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke

“…Intervention in p53 interactions represents a new target for unique therapeutic development in ischemic insults [12]. Therefore, targeting the p53 signaling pathway minimized the detrimental effects after stroke [13]. We speculated that MDM2 and p53 signaling pathway is functional and has therapeutic significance in ischemic stroke treatment.…”