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Neuroprotective Effect of Plasminogen Activator Inhibitor-1 Antagonist in the Rat Model of Mild Traumatic Brain Injury

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Abstract—

Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model. Sprague–Dawley male rats were grouped as sham (n = 7), TBI (n = 9), and TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n = 6–7). Under anesthesia, TBI was induced by dropping a metal 300-g weight from a height of 1 m on the skull. Before and 24-h after trauma neurological examination, tail suspension, Y-maze, and novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol-, and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1β, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-β, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin–eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3, and nuclear factor-κB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant. Higher levels of myeloperoxidase activity in the TBI group (p < 0.05) were found to be suppressed in 5 and 10 mg/kg TM5441 treatment groups (p < 0.05–p < 0.01). The tail suspension test score was increased in the TBI group (p < 0.001) and decreased in all treatment groups (p < 0.05–0.001). The histologic damage score was increased statistically significantly in the cortex, dentate gyrus, and CA3 regions in the TBI group (p < 0.01–0.001), decreased in the treatment groups in the cortex and dentate gyrus (p < 0.05–0.001). PAI antagonists, especially TM5441, have antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.

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Abbreviations

CL:

Chemiluminescence

DG:

Dentate gyrus

DI:

Discrimination index

DS:

Difference score

IL:

Interleukin

LDLR:

Low-density lipoprotein receptor

MMP3:

Matrix metalloproteinase-3

MPO:

Myeloperoxidase

NF-κB:

Nuclear factor-κB

NO:

Nitric oxide

PAI-1:

Plasminogen activator inhibitor-1

PBS:

Phosphate-buffered saline

PMNs:

Polymorphonuclear leukocytes

RI:

Recognition index

ROM:

Reactive oxygen metabolites

ROS:

Reactive oxygen species

TBI:

Traumatic brain injury

TGF:

Tumor growth factor

TNF:

Tumor necrosis factor

tPA:

Tissue plasminogen activator

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Acknowledgements

We would like to thank Prof. Toshio Miyata and Takashi Dan for their generous support in sending us PAI antagonists.

Turkan Koyuncuoglu: data curation.

Selin Akbulut: data curation.

Dilek Akakın: data curation, writing–reviewing and editing.

İrem Peker Eyüboğlu: data curation.

Can Erzik: data curation.

Meral Yüksel: data curation, writing–reviewing and editing.

Hizir Kurtel: visualization, investigation, supervision, writing–reviewing and editing.

Funding

This work was supported by Marmara University Scientific Research Projects Coordination Unit.

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Authors and Affiliations

  1. Department of Physiology, Marmara University Institute of Health Sciences, Istanbul, Turkey

    Pınar Kuru Bektaşoğlu & Hızır Kurtel

  2. Department of Neurosurgery, University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey

    Pınar Kuru Bektaşoğlu

  3. Department of Physiology, Biruni University School of Medicine, Istanbul, Turkey

    Türkan Koyuncuoğlu

  4. Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey

    Selin Akbulut & Dilek Akakın

  5. Department of Medical Biology, Marmara University School of Medicine, Istanbul, Turkey

    İrem Peker Eyüboğlu & Can Erzik

  6. Department of Medical Laboratory Techniques, Marmara University Vocational School of Health Services, Istanbul, Turkey

    Meral Yüksel

  7. Department of Physiology, Marmara University Institute of Health Sciences, Istanbul, Turkey

    Pınar Kuru Bektaşoğlu

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Pınar Kuru Bektaşoğlu: conceptualization, methodology, data curation, writing–original draft preparation, writing–reviewing and editing.

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Correspondence to Pınar Kuru Bektaşoğlu.

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All experimental procedures used in this investigation were reviewed and approved by the Marmara University Animal Care and Use Committee (March 12, 2019).

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Highlights

•After mild TBI, PAI-1 antagonists TM5441 and TM5484 were used for the first time in the literature.

•PAI-1 inhibition reduced oxidative stress, inflammation, and neuronal damage in a TBI model.

•PAI antagonist treatment also improved corticospinal pathway functions and behavioral results.

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Kuru Bektaşoğlu, P., Koyuncuoğlu, T., Akbulut, S. et al. Neuroprotective Effect of Plasminogen Activator Inhibitor-1 Antagonist in the Rat Model of Mild Traumatic Brain Injury. Inflammation 44, 2499–2517 (2021). https://doi.org/10.1007/s10753-021-01520-0

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  • DOI: https://doi.org/10.1007/s10753-021-01520-0

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