{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:00:37Z","timestamp":1790164837437,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,6,14]],"date-time":"2011-06-14T00:00:00Z","timestamp":1308009600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2011,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>To investigate whether inhibition of mitochondrial p53 association using pifithrin\u2010\u03bc (PFT\u2010\u03bc) represents a potential novel neuroprotective strategy to combat perinatal hypoxic\u2010ischemic (HI) brain damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Seven\u2010day\u2010old rats were subjected to unilateral carotid artery occlusion and hypoxia followed by intraperitoneal treatment with PFT\u2010\u03bc, an inhibitor of p53 mitochondrial association or PFT\u2010\u03b1 an inhibitor of p53 transcriptional activity. Cerebral damage, sensorimotor and cognitive function, apoptotic pathways (cytosolic cytochrome <jats:italic>c<\/jats:italic>, Smac\/DIABLO, active caspase 3), and oxidative stress (lipid peroxidation and PARP\u20101 cleavage) were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>PFT\u2010\u03bc treatment completely prevented the HI\u2010induced increase in mitochondrial p53 association at 3 hours and reduced neuronal damage at 48 hours post\u2010HI. PFT\u2010\u03bc had long\u2010term (6\u201310 weeks post\u2010HI) beneficial effects as sensorimotor and cognitive outcome improved and infarct size was reduced by \u223c79%. Neuroprotection by PFT\u2010\u03bc treatment was associated with strong inhibition of apoptotic pathways and reduced oxidative stress. Unexpectedly, PFT\u2010\u03bc also inhibited HI\u2010induced upregulation of p53 target genes. However, the neuroprotective effect of inhibiting only p53 transcriptional activity by PFT\u2010\u03b1 was significantly smaller and did not involve reduced oxidative stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>We are the first to show that prevention of mitochondrial p53 association by PFT\u2010\u03bc strongly improves functional outcome and decreases lesion size after neonatal HI. PFT\u2010\u03bc not only inhibits mitochondrial release of cytochrome <jats:italic>c<\/jats:italic>, but also inhibits oxidative stress. We propose that as a consequence nuclear accumulation of p53 and transcription of proapoptotic target genes are prevented. In conclusion, targeting p53 mitochondrial association by PFT\u2010\u03bc may develop into a novel and powerful neuroprotective strategy. 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