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

摘要

ObjectiveThe outcome 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 CNS 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.