title: p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms.
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-kappaB) inhibitor SN50, the p53 inhibitor Pifithrin-alpha (PFT-alpha) 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-alpha or 3-MA. SN50, PFT-alpha 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-alpha or 3-MA. These results suggest that overstimulation of NMDA receptors can induce NF-kappaB-dependent expression of p53. p53 participates in excitotoxic neuronal death probably through both apoptotic and autophagic mechanisms.
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Dong
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhong-Qin
authors.initials: ZQ
authors.lastname: Liang
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.forename: Jun-Chao
authors.initials: JC
authors.lastname: Wu
authors.forename: Zhen-Lun
authors.initials: ZL
authors.lastname: Gu
authors.forename: Zhen-Hong
authors.initials: ZH
authors.lastname: Qin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D052160:Benzothiazoles / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D053938:DNA Fragmentation / Q000187:drug effects; D016158:Genes, p53; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009498:Neurotoxins / Q000633:toxicity*; D010455:Peptides / Q000633:toxicity; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D014050:Toluene / Q000031:analogs & derivatives / Q000633:toxicity; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D016328:NF-kappa B; D009498:Neurotoxins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C118258:SN50 peptide; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C025946:3-methyladenine; C121565:pifithrin; D017378:Quinolinic Acid; D000225:Adenine