Post-traumatic administration of the p53 inactivator pifithrin-α, oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury

NEUROBIOLOGY OF DISEASE

卷:96

Article

Yang, Ling-Yu¹  Greig, Nigel H.²  Huang, Ya-Ni^1,3  Hsieh, Tsung-Hsun^4,5,6  Tweedie, David²  Yu, Qian-Sheng²  Hoffer, Barry J.⁷  Luo, Yu⁷  Kao, Yu-Chieh^8,9  Wang, Jia-Yi^1,10 

[1] Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Hsing St, Taipei 110, Taiwan

[2] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA

[3] Hsin Sheng Jr Coll Med Care & Management, Dept Nursing, Taoyuan, Taiwan

[4] Chang Gung Univ, Coll Med, Dept Phys Therapy, Taoyuan, Taiwan

[5] Chang Gung Univ, Coll Med, Grad Inst Rehabil Sci, Taoyuan, Taiwan

[6] Taipei Med Univ, Grad Inst Neural Regenerat Med, Taipei, Taiwan

[7] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA

[8] Taipei Med Univ, Sch Med, Translat Imaging Res Ctr, Taipei, Taiwan

[9] Taipei Med Univ, Sch Med, Dept Radiol, Taipei, Taiwan

[10] Taipei Med Univ, Sch Med, Dept Physiol, Coll Med, Taipei, Taiwan

关键词: Traumatic brain injury (TBI);    p53;    Pifithrin-alpha (PFT-alpha);    PFT-alpha oxygen analogue (PFT-alpha (o));    Apoptosis;    Motor and cognitive deficits;    Puma;    Controlled cortical impact (CCI);   

DOI  :  10.1016/j.nbd.2016.08.012

来源: Elsevier

【 摘 要 】

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippo campus has been detected after TBI. The hippocampal dysfunction may result in cognitive deficits in learning, memory, and spatial information processing. Our previous studies demonstrated that a p53 inhibitor, pifithrin-alpha oxygen analogue (PFT-alpha (O)), significantly reduced cortical cell death, which is substantial following controlled cortical impact (CCI) TBI, and improved neurological functional outcomes via anti-apoptotic mechanisms. In the present study, we examined the effect of PFT-alpha (O) on CCI TBI-induced hippocampal cellular pathophysiology in light of this brain region's role in memory. To investigate whether p53-dependent apoptosis plays a role in hippocampal neuronal loss and associated cognitive deficits and to define underlying mechanisms, SD rats were subjected to experimental CCI TBI followed by the administration of PFT-alpha or PFT-alpha (O) (2 mg/kg, i.v.) or vehicle at 5 h after TBI. Magnetic resonance imaging (MRI) scans were acquired at 24 h and 7 days post-injury to assess evolving structural hippocampal damage. Fluoro-Jade C was used to stain hippocampal sub-regions, including CA1 and dentate gyrus (DG), for cellular degeneration. Neurological functions, including motor and recognition memory, were assessed by behavioral tests at 7 days post injury. p53, p53 upregulated modulator of apoptosis (PUMA), 4-hydroxynonenal (4-HNE), cyclooxygenase-IV (COX IV), annexin V and NeuN were visualized by double immunofluorescence staining with cell-specific markers. Levels of mRNA encoding for caspase-3, p53, PUMA, Bcl-2, Bcl-2-associated X protein (BAX) and superoxide dismutase (SOD) were measured by RT-qPCR. Our results showed that post-injury administration of PFT-alpha and, particularly, PFT-alpha (O) at 5 h dramatically reduced injury volumes in the ipsilateral hippocampus, improved motor outcomes, and ameliorated cognitive deficits at 7 days after TBI, as evaluated by novel object recognition and open-field test. PFT-alpha and especially PFT-alpha (O) significantly reduced the number of FJC-positive cells in hippocampus CA1 and DG subregions, versus vehicle treatment, and significantly decreased caspase-3 and PUMA mRNA expression. PFT-alpha (O), but not PFT-alpha, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-alpha (O) treatment decreased p53, annexin V and 4-HNE positive neurons in the hippocampal CA1 region. Furthermore, PUMA co-localization with the mitochondrial maker COX IV, and the upregulation of PUMA were inhibited by PFT-alpha (O) after TBI. Our data suggest that PFT-alpha and especially PFT-alpha (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties. (C) 2016 Published by Elsevier Inc.

【 授权许可】

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