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Targeting the p53 p...
Targeting the p53 pathway to protect the neonatal ischemic brain.
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Nijboer, Cora H (author)
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Heijnen, Cobi J (author)
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van der Kooij, Michael A (author)
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Zijlstra, Jitske (author)
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van Velthoven, Cindy T J (author)
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Culmsee, Carsten (author)
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van Bel, Frank (author)
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- Hagberg, Henrik, 1955 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi,Institute of Clinical Sciences, Department of Obstetrics and Gynecology
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Kavelaars, Annemieke (author)
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(creator_code:org_t)
- 2011-06-14
- 2011
- English.
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In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134.
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kirurgi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Surgery (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Nijboer, Cora H
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Heijnen, Cobi J
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van der Kooij, M ...
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Zijlstra, Jitske
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van Velthoven, C ...
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Culmsee, Carsten
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show more...
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van Bel, Frank
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Hagberg, Henrik, ...
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Kavelaars, Annem ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Surgery
- Articles in the publication
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Annals of neurol ...
- By the university
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University of Gothenburg