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Neurotox Res. 2019 Aug;36(2):347-356. doi: 10.1007/s12640-019-00050-w. Epub 2019 May 8.

Pifithrin-Alpha Reduces Methamphetamine Neurotoxicity in Cultured Dopaminergic Neurons.

Author information

1
Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.
2
Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan.
3
Molecular Mechanisms of Cellular Stress and Inflammation Unit, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, USA.
4
Translational Gerontology Branch, Intramural Research Program, National Institute of Aging, NIH, Baltimore, MD, USA.
5
Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan. ywang@nhri.org.tw.

Abstract

Methamphetamine (Meth) is a widely abused stimulant. High-dose Meth induces degeneration of dopaminergic neurons through p53-mediated apoptosis. A recent study indicated that treatment with the p53 inhibitor, pifithrin-alpha (PFT-α), antagonized Meth-mediated behavioral deficits in mice. The mechanisms underpinning the protective action of PFT-α against Meth have not been identified, and hence, their investigation is the focus of this study. Primary dopaminergic neuronal cultures were prepared from rat embryonic ventral mesencephalic tissue. High-dose Meth challenge reduced tyrosine hydroxylase immunoreactivity and increased terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling. PFT-α significantly antagonized these responses. PFT-α also reduced Meth-activated translocation of p53 to the nucleus, an initial step before transcription. Previous studies have indicated that p53 can also activate cell death through transcription-independent pathways. We found that PFT-α attenuated endoplasmic reticulum (ER) stressor thapsigargin (Tg)-mediated loss of dopaminergic neurons. ER stress was further monitored through the release of Gaussia luciferase (GLuc) from SH-SY5Y cells overexpressing GLuc-based Secreted ER Calcium-Modulated Protein (GLuc-SERCaMP). Meth or Tg significantly increased GLuc release in to the media, with PFT-α significantly reducing GLuc release. Additionally, PFT-α significantly attenuated Meth-induced CHOP expression. In conclusion, our data indicate that PFT-α is neuroprotective against Meth-mediated neurodegeneration via transcription-dependent nuclear and -independent cytosolic ER stress pathways.

KEYWORDS:

Degeneration; Dopaminergic; Methamphetamine; Pifithrin-alpha; p53

PMID:
31069753
DOI:
10.1007/s12640-019-00050-w

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