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Pentoxifylline Alleviates Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage

  • Experimental Research - Brain Injury
  • Published:
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Abstract

Background

Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease frequently caused by ruptured aneurysms. Early brain injury (EBI) is the primary cause of morbidity and mortality in patients diagnosed with SAH and is associated with increased intracranial pressure, decreased cerebral blood flow and cerebral ischemia. Pentoxifylline (PTX) is a methylxanthine derivative clinically proven to improve perfusion in the peripheral microcirculation and has been shown to have neuroprotective effects in brain trauma and global cerebral ischemia in experimental animal models. This study aimed to determine the effect of PTX in experimental SAH, which has not been investigated yet.

Methods

An experimental SAH model was induced in male Wistar rats by autologous blood injection into the prechiasmatic cistern, and PTX was injected intraperitoneally immediately after SAH. The effects of PTX were evaluated 24 h after SAH via assessing the cerebral ultrastructure via transmission electron microscopy (TEM). Brain edema, blood-brain barrier (BBB) permeability, red blood cell deformability, tumor necrosis factor-alpha (TNF-alpha), nitrite-nitrate levels and apoptotic neuron death were also determined 24 h after SAH. The BBB permeability was measured by Evans blue (EB) extravasation, erythrocyte deformability was determined by filtration technique, and TNF-alpha and reactive nitrogen metobolites were analyzed in brain tissue by ELISA and spectral analysis, respectively. Apoptotic neurons were determined in brain sections by cleaved caspase-3 immunohistochemical analysis, and expression intensity was quantified using image J software.

Results

Cerebral ultrastructure in SAH group animals revealed intense perivascular edema and distortion in the astrocyte foot processes. PTX treatment attenuated structural deterioration due to SAH. Brain water content, BBB permeability, TNF-alpha, nitrite-nitrate levels and apoptotic neuronal death were significantly increased 24 h after SAH and were significantly alleviated by PTX treatment. There was no significant change in red cell deformability after SAH.

Conclusions

Our results show that PTX reduces brain edema, BBB permeability, TNF-alpha expression, reactive nitrogen metobolites and apopotosis in experimental SAH. Based on our findings we suggest that PTX exerts neuroprotection against SAH-induced EBI, which might be associated with the inhibition of inflammation and apoptotic neuronal cell death.

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Authors and Affiliations

  1. Department of Neurosurgery, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey

    Ethem Goksu

  2. Division of Neurosurgery, Denizli State Hospital, Denizli, 20125, Turkey

    Ozgur Dogan

  3. Department of Physiology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey

    Pınar Ulker

  4. Department of Histology, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey

    Gamze Tanrıover, Esma Konuk, Sayra Dilmac & Necdet Demır

  5. Medical Biochemistry, Akdeniz University Faculty of Medicine, Antalya, 07070, Turkey

    Ebru Kirac & Mutay Aslan

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  1. Ethem Goksu
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Correspondence to Mutay Aslan.

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Funding

Akdeniz University Research Foundation provided financial support in the form of grant funding (no: TSA-2015-925). The sponsor had no role in the design or conduct of this research.

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Goksu, E., Dogan, O., Ulker, P. et al. Pentoxifylline Alleviates Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage. Acta Neurochir 158, 1721–1730 (2016). https://doi.org/10.1007/s00701-016-2866-5

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  • DOI: https://doi.org/10.1007/s00701-016-2866-5

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