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

Ling Yu Yang, Nigel H. Greig, Ya Ni Huang, Tsung Hsun Hsieh, David Tweedie, Qian Sheng Yu, Barry J. Hoffer, Yu Luo, Yu Chieh Kao, Jia Yi Wang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippocampus 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-α oxygen analogue (PFT-α (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-α (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-α or PFT-α (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-α and, particularly, PFT-α (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-α and especially PFT-α (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-α (O), but not PFT-α, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-α (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-α (O) after TBI. Our data suggest that PFT-α and especially PFT-α (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties.

Original languageEnglish
Pages (from-to)216-226
Number of pages11
JournalNeurobiology of Disease
Volume96
DOIs
Publication statusPublished - Dec 1 2016

Fingerprint

Oxygen
Apoptosis
Hippocampus
Annexin A5
Dentate Gyrus
Wounds and Injuries
Prostaglandin-Endoperoxide Synthases
Caspase 3
Messenger RNA
Fluorescent Antibody Technique
Staining and Labeling
Hippocampal CA1 Region
pifithrin
Traumatic Brain Injury
bcl-2-Associated X Protein
Automatic Data Processing
Superoxide Dismutase
Cause of Death
Cell Death
Coloring Agents

Keywords

  • Apoptosis
  • Controlled cortical impact (CCI)
  • Motor and cognitive deficits
  • p53
  • PFT-α oxygen analogue (PFT-α (O))
  • Pifithrin-α (PFT-α)
  • Puma
  • Traumatic brain injury (TBI)

ASJC Scopus subject areas

  • Neurology

Cite this

Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury. / Yang, Ling Yu; Greig, Nigel H.; Huang, Ya Ni; Hsieh, Tsung Hsun; Tweedie, David; Yu, Qian Sheng; Hoffer, Barry J.; Luo, Yu; Kao, Yu Chieh; Wang, Jia Yi.

In: Neurobiology of Disease, Vol. 96, 01.12.2016, p. 216-226.

Research output: Contribution to journalArticle

Yang, Ling Yu ; Greig, Nigel H. ; Huang, Ya Ni ; Hsieh, Tsung Hsun ; Tweedie, David ; Yu, Qian Sheng ; Hoffer, Barry J. ; Luo, Yu ; Kao, Yu Chieh ; Wang, Jia Yi. / Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury. In: Neurobiology of Disease. 2016 ; Vol. 96. pp. 216-226.
@article{563ce7fbcd94454bba62a42607b4ec1b,
title = "Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury",
abstract = "Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippocampus 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-α oxygen analogue (PFT-α (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-α (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-α or PFT-α (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-α and, particularly, PFT-α (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-α and especially PFT-α (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-α (O), but not PFT-α, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-α (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-α (O) after TBI. Our data suggest that PFT-α and especially PFT-α (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties.",
keywords = "Apoptosis, Controlled cortical impact (CCI), Motor and cognitive deficits, p53, PFT-α oxygen analogue (PFT-α (O)), Pifithrin-α (PFT-α), Puma, Traumatic brain injury (TBI)",
author = "Yang, {Ling Yu} and Greig, {Nigel H.} and Huang, {Ya Ni} and Hsieh, {Tsung Hsun} and David Tweedie and Yu, {Qian Sheng} and Hoffer, {Barry J.} and Yu Luo and Kao, {Yu Chieh} and Wang, {Jia Yi}",
year = "2016",
month = "12",
day = "1",
doi = "10.1016/j.nbd.2016.08.012",
language = "English",
volume = "96",
pages = "216--226",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury

AU - Yang, Ling Yu

AU - Greig, Nigel H.

AU - Huang, Ya Ni

AU - Hsieh, Tsung Hsun

AU - Tweedie, David

AU - Yu, Qian Sheng

AU - Hoffer, Barry J.

AU - Luo, Yu

AU - Kao, Yu Chieh

AU - Wang, Jia Yi

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippocampus 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-α oxygen analogue (PFT-α (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-α (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-α or PFT-α (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-α and, particularly, PFT-α (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-α and especially PFT-α (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-α (O), but not PFT-α, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-α (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-α (O) after TBI. Our data suggest that PFT-α and especially PFT-α (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties.

AB - Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippocampus 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-α oxygen analogue (PFT-α (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-α (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-α or PFT-α (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-α and, particularly, PFT-α (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-α and especially PFT-α (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-α (O), but not PFT-α, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-α (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-α (O) after TBI. Our data suggest that PFT-α and especially PFT-α (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties.

KW - Apoptosis

KW - Controlled cortical impact (CCI)

KW - Motor and cognitive deficits

KW - p53

KW - PFT-α oxygen analogue (PFT-α (O))

KW - Pifithrin-α (PFT-α)

KW - Puma

KW - Traumatic brain injury (TBI)

UR - http://www.scopus.com/inward/record.url?scp=84988019708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988019708&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2016.08.012

DO - 10.1016/j.nbd.2016.08.012

M3 - Article

C2 - 27553877

AN - SCOPUS:84988019708

VL - 96

SP - 216

EP - 226

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -