Targeting the p53 pathway to protect the neonatal ischemic brain

Authors


Abstract

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

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