Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-α

Lital Rachmany, David Tweedie, Vardit Rubovitch, Qian Sheng Yu, Yazhou Li, Jia Yi Wang, Chaim G. Pick, Nigel H. Greig

Research output: Contribution to journalArticle

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Abstract

With parallels to concussive mild traumatic brain injury (mTBI) occurring in humans, anesthetized mice subjected to a single 30 g weight drop mTBI event to the right parietal cortex exhibited significant diffuse neuronal degeneration that was accompanied by delayed impairments in recognition and spatial memory. To elucidate the involvement of reversible p53-dependent apoptosis in this neuronal loss and associated cognitive deficits, mice were subjected to experimental mTBI followed by the systemic administration of the tetrahydrobenzothiazole p53 inactivator, PFT-α, or vehicle. Neuronal loss was quantified immunohistochemically at 72 hr. post-injury by the use of fluoro-Jade B and NeuN within the dentate gyrus on both sides of the brain, and recognition and spatial memory were assessed by novel object recognition and Y-maze paradigms at 7 and 30 days post injury. Systemic administration of a single dose of PFT-α 1 hr. post-injury significantly ameliorated both neuronal cell death and cognitive impairments, which were no different from sham control animals. Cellular studies on human SH-SY5Y cells and rat primary neurons challenged with glutamate excitotoxicity and H2O2 induced oxidative stress, confirmed the ability of PFT-α and a close analog to protect against these TBI associated mechanisms mediating neuronal loss. These studies suggest that p53-dependent apoptotic mechanisms underpin the neuronal and cognitive losses accompanying mTBI, and that these are potentially reversible by p53 inactivation.

Original languageEnglish
Article numbere79837
JournalPLoS One
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 28 2013

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Brain Concussion
Cell death
cell death
Rodentia
Brain
Cell Death
rodents
neurons
brain
Wounds and Injuries
Parietal Lobe
Aptitude
Dentate Gyrus
Data storage equipment
Oxidative stress
mice
Object recognition
Glutamic Acid
Oxidative Stress
glutamates

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-α. / Rachmany, Lital; Tweedie, David; Rubovitch, Vardit; Yu, Qian Sheng; Li, Yazhou; Wang, Jia Yi; Pick, Chaim G.; Greig, Nigel H.

In: PLoS One, Vol. 8, No. 11, e79837, 28.11.2013.

Research output: Contribution to journalArticle

Rachmany, Lital ; Tweedie, David ; Rubovitch, Vardit ; Yu, Qian Sheng ; Li, Yazhou ; Wang, Jia Yi ; Pick, Chaim G. ; Greig, Nigel H. / Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-α. In: PLoS One. 2013 ; Vol. 8, No. 11.
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