p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms.
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.
Wang
Yan
Y
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Medicine, Suzhou, China.
Dong
Xiao-Xia
XX
Cao
Yi
Y
Liang
Zhong-Qin
ZQ
Han
Rong
R
Wu
Jun-Chao
JC
Gu
Zhen-Lun
ZL
Qin
Zhen-Hong
ZH
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*
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