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

Authors

  • Yan Wang,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Xiao-Xia Dong,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Yi Cao,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Zhong-Qin Liang,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Rong Han,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Jun-Chao Wu,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Zhen-Lun Gu,

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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  • Zhen-Hong Qin

    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou 215123, China
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Dr Z.-H. Qin, as above.
E-mail: zhqin5@hotmail.com

Abstract

The present study sought to investigate mechanisms by which p53 induction contributes to excitotoxic neuronal injury. Rats were intrastriatally administered the N-methyl-d-aspartate (NMDA) receptor agonist quinolinic acid (QA), the changes in the expression of p53 and its target genes involved in apoptosis and autophagy, including p53-upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, damage-regulated autophagy modulator (DRAM) and other autophagic proteins including microtubule-associated protein 1 light chain 3 (LC3) and beclin 1 were assessed. The contribution of p53-mediated autophagy activation to apoptotic death of striatal neurons was assessed with co-administration of the nuclear factor-kappaB (NF-κB) inhibitor SN50, the p53 inhibitor Pifithrin-alpha (PFT-α) or the autophagy inhibitor 3-methyladenine (3-MA). The increased formation of autophagosomes and secondary lysosomes were observed with transmission electron microscope after excitotoxin exposure. QA induced increases in the expression of p53, PUMA, Bax and a decrease in Bcl-2. These changes were significantly attenuated by pre-treatment with SN50, PFT-α or 3-MA. SN50, PFT-α or 3-MA also reversed QA-induced upregulation of DRAM, the ratio of LC3-II/LC3-I and beclin 1 protein levels in the striatum. QA-induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by SN50, PFT-α or 3-MA. These results suggest that overstimulation of NMDA receptors can induce NF-κB-dependent expression of p53. p53 participates in excitotoxic neuronal death probably through both apoptotic and autophagic mechanisms.

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