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Intracisternal Administration of Tissue Plasminogen Activator Improves Cerebrospinal Fluid Flow and Cortical Perfusion After Subarachnoid Hemorrhage in Mice

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Abstract

Early brain injury (EBI) during the first 72 h after subarachnoid hemorrhage (SAH) is an important determinant of clinical outcome. A hallmark of EBI, global cerebral ischemia, occurs within seconds of SAH and is thought to be related to increased intracranial pressure (ICP). We tested the hypothesis that ICP elevation and cortical hypoperfusion are the result of physical blockade of cerebrospinal fluid (CSF) flow pathways by cisternal microthrombi. In mice subjected to SAH, we measured cortical blood volume (CBV) using optical imaging, ICP using pressure transducers, and patency of CSF flow pathways using intracisternally injected tracer dye. We then assessed the effects of intracisternal injection of recombinant tissue plasminogen activator (tPA). ICP rose immediately after SAH and remained elevated for 24 h. This was accompanied by a decrease in CBV and impaired dye movement. Intracisternal administration of tPA immediately after SAH lowered ICP, increased CBV, and partially restored CSF flow at 24 h after SAH. Lowering ICP without tPA, by draining CSF, improved CBV at 1 h, but not 24 h after SAH. These findings suggest that blockade of CSF flow by microthrombi contributes to the early decline in cortical perfusion in an ICP-dependent and ICP-independent manner and that intracisternal tPA may reduce EBI and improve outcome after SAH.

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Conflict of Interest

Dominic A. Siler declares that he has no conflict of interest.

Jorge A. Gonzalez declares that he has no conflict of interest.

Ruikang K. Wang declares that he has no conflict of interest.

Justin S. Cetas declares that he has no conflict of interest.

Nabil J. Alkayed declares that he has no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed.

Funding Sources

Dominic A. Siler—NHLBI F30 HL108624, Oregon Brain Institute.

Nabil J. Alkayed—NINDS R01 NS044313 and NS070837

Ruikang K. Wang—NHLBI R01 HL093140 and NIBIB R01 EB009682

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Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR, 97239-3098, USA

    Dominic A. Siler, Jorge A. Gonzalez & Nabil J. Alkayed

  2. Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, 97239-3098, USA

    Dominic A. Siler, Justin S. Cetas & Nabil J. Alkayed

  3. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA

    Ruikang K. Wang

  4. Neurological Surgery, Portland VA Medical Center, Portland, OR, 97239-3098, USA

    Justin S. Cetas

  5. The Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, 97239-3098, USA

    Nabil J. Alkayed

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  1. Dominic A. Siler
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Correspondence to Nabil J. Alkayed.

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Siler, D.A., Gonzalez, J.A., Wang, R.K. et al. Intracisternal Administration of Tissue Plasminogen Activator Improves Cerebrospinal Fluid Flow and Cortical Perfusion After Subarachnoid Hemorrhage in Mice. Transl. Stroke Res. 5, 227–237 (2014). https://doi.org/10.1007/s12975-014-0329-y

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