P53 knockout mice are protected from cocaine-induced kindling behaviors via inhibiting mitochondrial oxidative burdens, mitochondrial dysfunction, and proapoptotic changes

Huynh Nhu Mai, Naveen Sharma, Ji Hoon Jeong, Eun Joo Shin, Duc Toan Pham, Quynh Dieu Trinh, Yu Jeung Lee, Choon Gon Jang, Seung Yeol Nah, Guoying Bing, Hyoung Chun Kim

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Previously we demonstrated that p53 mediates dopaminergic neurotoxicity via inducing mitochondrial burdens and proapoptotsis. However, little is known about the role of p53 in the excitotoxicity induced by psychostimulant, such as cocaine. Cocaine-induced kindling (convulsive) behaviors significantly increased p53 expression in the brain. Cocaine-induced p53 expression was more pronounced in hippocampus than in striatum or prefrontal cortex. Genetic depletion of p53 significantly attenuated cocaine-induced convulsive behaviors, followed by c-Fos immunoreactivity, and oxidative burdens in the hippocampus of mice. The antioxidant potentials mediated by genetic depletion of p53 were more pronounced in the mitochondrial-than cytosolic-fraction. Depletion of p53 significantly attenuated the changes in mitochondrial transmembrane potential, intramitochondrial Ca2+ level, and mitochondrial oxidative burdens induced by cocaine. Consistently, depletion of p53 significantly inhibited mitochondrial p53 translocation, and cleaved-PKCδ induced by cocaine. In addition, depletion of p53 protected from cytosolic cytochrome c release, and pro-apoptotic changes induced by cocaine. Importantly, the protective/anticonvulsant potentials by genetic depletion of p53 were comparable to those by pifithrin-μ (PFT), a p53 inhibitor. Our results suggest that depletion of p53 offers anticonvulsive and neuroprotective potentials mainly via attenuating mitochondrial oxidative burdens, mitochondrial dysfunction, and pro-apoptotic signalings against cocaine-induced convulsive neurotoxicity.

Original languageEnglish
Pages (from-to)68-81
Number of pages14
JournalNeurochemistry International
Volume124
DOIs
StatePublished - Mar 1 2019

Bibliographical note

Publisher Copyright:
© 2018

Keywords

  • Cocaine-kindling (convulsive) behaviors
  • Hippocampus
  • Mitochondrial dysfunction
  • Oxidative stress
  • Pro-apoptosis
  • p53 knockout mice

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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