• Neurological research · Jul 2012

    Combination therapy with glucagon and a novel plasminogen activator inhibitor-1-derived peptide enhances protection against impaired cerebrovasodilation during hypotension after traumatic brain injury through inhibition of ERK and JNK MAPK.

    • William M Armstead, John Riley, Douglas B Cines, and Abd Al-Roof Higazi.
    • Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA. armsteaw@uphs.upenn.edu
    • Neurol. Res. 2012 Jul 1;34(6):530-7.

    ObjectiveOutcome of traumatic brain injury (TBI) is impaired by hypotension and glutamate, and TBI-associated release of endogenous tissue plasminogen activator (tPA) impairs cerebral autoregulation. Glucagon decreases central nervous system glutamate, lessens neuronal cell injury, and improves neurological score in mice after TBI. Glucagon partially protects against impaired cerebrovasodilation during hypotension after TBI in piglets by upregulating cAMP which decreases release of tPA. Pial artery dilation during hypotension is due to release of cAMP-dependent dilator prostaglandins (PG), such as PGE2 and PGI2. TBI impairs PGE2 and PGI2-mediated pial artery dilation, which contributes to disturbed cerebral autoregulation post-insult, by upregulating mitogen-activated protein kinase (MAPK). This study was designed to investigate relationships between tPA, prostaglandins, and MAPK as a mechanism to improve the efficacy of glucagon-mediated preservation of cerebrovasodilation during hypotension after TBI.MethodsLateral fluid percussion brain injury (FPI) was induced in piglets equipped with a closed cranial window. ERK and JNK MAPK concentrations in cerebrospinal fluid were quantified by enzyme-linked immunosorbent assay.ResultsCerebrospinal fluid JNK MAPK was increased by FPI, but blunted by glucagon and the novel plasminogen activator inhibitor-1-derived peptide (PAI-1DP), Ac-RMAPEEIIMDRPFLYVVR-amide. FPI modestly increased, while glucagon and PAI-1DP decreased ERK MAPK. PGE2, PGI2, N-methyl-D-aspartate, and hypotension-induced pial artery dilation was blunted after FPI, partially protected by glucagon, and fully protected by glucagon+PAI-1DP, glucagon+JNK antagonist SP600125 or glucagon+ERK inhibitor U 0126.DiscussionGlucagon+PAI-1DP act in concert to protect against impairment of cerebrovasodilation during hypotension after TBI via inhibition of ERK and JNK MAPK.

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