p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms

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Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
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Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons

Published on: November 6, 2017

Yan Wang1, Xiao-Xia Dong, Yi Cao

  • 1Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou, China.

The European Journal of Neuroscience
|January 23, 2010
PubMed

Insights

p53 activation contributes to excitotoxic neuronal injury via apoptosis and autophagy. Inhibiting nuclear factor-kappaB (NF-kappaB) or p53 reduces neuronal death, suggesting therapeutic targets for excitotoxicity.

Area of Science:

  • Neuroscience
  • Molecular Biology

Background:

  • Excitotoxic neuronal injury is a significant concern in neurological disorders.
  • The role of p53 in neuronal death following excitotoxicity requires further elucidation.

Purpose of the Study:

  • To investigate the mechanisms by which p53 induction contributes to excitotoxic neuronal injury.
  • To assess the involvement of p53-mediated apoptosis and autophagy in neuronal damage.

Main Methods:

  • Rats were administered quinolinic acid (QA) to induce excitotoxicity.
  • Expression of p53, apoptosis-related genes (PUMA, Bax, Bcl-2), and autophagy markers (DRAM, LC3, beclin 1) were analyzed.
  • Inhibitors of NF-kappaB (SN50), p53 (Pifithrin-alpha), and autophagy (3-MA) were used to assess their protective effects.

Main Results:

  • QA administration increased p53, PUMA, and Bax expression while decreasing Bcl-2.
  • QA exposure led to increased autophagosome and lysosome formation, upregulating DRAM, LC3-II/LC3-I ratio, and beclin 1.
  • Pre-treatment with SN50, PFT-alpha, or 3-MA significantly attenuated QA-induced changes and protected against DNA fragmentation and neuronal loss.

Conclusions:

  • NMDA receptor overstimulation induces NF-kappaB-dependent p53 expression.
  • p53 contributes to excitotoxic neuronal death through both apoptotic and autophagic pathways.
  • Targeting NF-kappaB, p53, or autophagy may offer neuroprotective strategies against excitotoxicity.

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