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Targeting the p53 pathway to protect the neonatal ischemic brain
Author(s) -
Nijboer Cora H.,
Heijnen Cobi J.,
van der Kooij Michael A.,
Zijlstra Jitske,
van Velthoven Cindy T.J.,
Culmsee Carsten,
van Bel Frank,
Hagberg Henrik,
Kavelaars Annemieke
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22413
Subject(s) - neuroprotection , oxidative stress , apoptosis , mitochondrion , lipid peroxidation , cytochrome c , pharmacology , downregulation and upregulation , caspase 3 , biology , chemistry , medicine , endocrinology , microbiology and biotechnology , biochemistry , programmed cell death , gene
Objective: To investigate whether inhibition of mitochondrial p53 association using pifithrin‐μ (PFT‐μ) represents a potential novel neuroprotective strategy to combat perinatal hypoxic‐ischemic (HI) brain damage. Methods: Seven‐day‐old rats were subjected to unilateral carotid artery occlusion and hypoxia followed by intraperitoneal treatment with PFT‐μ, an inhibitor of p53 mitochondrial association or PFT‐α an inhibitor of p53 transcriptional activity. Cerebral damage, sensorimotor and cognitive function, apoptotic pathways (cytosolic cytochrome c , Smac/DIABLO, active caspase 3), and oxidative stress (lipid peroxidation and PARP‐1 cleavage) were investigated. Results: PFT‐μ treatment completely prevented the HI‐induced increase in mitochondrial p53 association at 3 hours and reduced neuronal damage at 48 hours post‐HI. PFT‐μ had long‐term (6–10 weeks post‐HI) beneficial effects as sensorimotor and cognitive outcome improved and infarct size was reduced by ∼79%. Neuroprotection by PFT‐μ treatment was associated with strong inhibition of apoptotic pathways and reduced oxidative stress. Unexpectedly, PFT‐μ also inhibited HI‐induced upregulation of p53 target genes. However, the neuroprotective effect of inhibiting only p53 transcriptional activity by PFT‐α was significantly smaller and did not involve reduced oxidative stress. Interpretation: We are the first to show that prevention of mitochondrial p53 association by PFT‐μ strongly improves functional outcome and decreases lesion size after neonatal HI. PFT‐μ not only inhibits mitochondrial release of cytochrome c , 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‐μ may develop into a novel and powerful neuroprotective strategy. ANN NEUROL 2011;00:000–000