Traumatic injury is the leading cause of death for infants and children and mortality is greatly increased in the presence of head injury. While the effects of brain injury have been extensively investigated in the adult, less is known in the newborn/infant. Cerebral blood flow (CBF) falls and pial arteries constrict more in newborn versus juvenile pigs after fluid percussion brain injury (FPI), supporting the idea that the newborn is more sensitive to traumatic vascular brain injury. Activation of the N-methyl-D-aspartate (NMDA) glutamatergic receptor subtype is thought to play a crucial role in excitotoxic neuronal cell death. Urokinase and tissue plasminogen activator (uPA and tPA) are serine proteases whose contributions to the regulation of cerebral hemodynamics are not well characterized. tPA may contribute to excitoxic neuronal cell death via enhancement of NMDA receptor mediated signaling. The term neurovascular unit (NVU) focuses attention on the interactions between cerebral blood vessels and neurons. The tPA treatment paradox could relate to vasodilation. Plasminogen activator vascular activity is mediated by the low density lipoprotein receptor (LRP). We show tPA and uPA elicit vasodilation at pathophysiologic concentrations while administration of tPA and uPA inhibitors partially prevented FPI induced inhibition of NMDA dilation and reductions in pial artery diameter in an age dependent manner. We propose that plasminogen activators change the MAPK isoform expression/activation profile in an LRP dependent process to elicit both initial hyperemia and NMDA impairment of cerebral hemodynamics producing marked histopathology post insult in the newborn but only NMDA impairment of cerebral hemodynamics and modest histopathology in the juvenile. The hypothesis is that plasminogen activator release following FPI produces hyperemia and inhibits NMDA receptor mediated effects on CBF in an age dependent manner leading to impaired cerebral hemodynamics and edema followed by neuronal cell loss. The tPA therapeutic treatment paradox may relate to changes in the MAPK isoform expression profile.
Three specific aims will be investigated in newborn and juvenile pigs: 1. Characterize the relationship between the plasminogen activators and NMDA receptor activation in cerebral hemodynamics following FPI as a function of age. 2. Investigate the role of MAPK isoforms and LRP as the mechanism by which plasminogen activators and NMDA receptor activation control cerebral hemodynamics following FPI as a function of age;Changes in the MAPK isoform expression profile result in impaired cerebral hemodyanamics and neuron cell loss post insult. And 3. Determine the association between plasminogen activator and NMDA receptor induced impairment of cerebral hemodynamics and histopathology following FPI as a function of age. Immunohistochemistry, detection of plasminogen activator and MAPK expression, and CBF determination by radiolabled microspheres will be performed.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1-BINP-L (01))
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Maholmes, Valerie
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University of Pennsylvania
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Bohman, Leif-Erik; Riley, John; Milovanova, Tatyana N et al. (2016) Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury. J Neurotrauma 33:168-74
Armstead, William M; Riley, John; Cines, Douglas B et al. (2014) PAI-1-derived peptide EEIIMD prevents hypoxia/ischemia-induced aggravation of endothelin- and thromboxane-induced cerebrovasoconstriction. Neurocrit Care 20:111-8
Larusch, Gretchen A; Merkulova, Alona; Mahdi, Fakhri et al. (2013) Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through β1-integrin and VEGFR2. Am J Physiol Heart Circ Physiol 305:H305-20
Armstead, William M; Riley, John; Vavilala, Monica S (2013) Dopamine prevents impairment of autoregulation after traumatic brain injury in the newborn pig through inhibition of Up-regulation of endothelin-1 and extracellular signal-regulated kinase mitogen-activated protein kinase. Pediatr Crit Care Med 14:e103-11
Armstead, William M; Bohman, Leif-Erik; Riley, John et al. (2013) tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1. J Neurotrauma 30:1898-907
Armstead, William M; Riley, John; Cines, Douglas B et al. (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. Neurol Res 34:530-7
Armstead, William M; Ganguly, Kumkum; Riley, John et al. (2012) RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis. Transl Stroke Res 3:114-21
Armstead, William M; Riley, John; Yarovoi, Serge et al. (2012) tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury. J Neurotrauma 29:1794-802
Kosty, Jennifer; Riley, John; Liang, Jiaming et al. (2012) Influence of Sex and ERK MAPK on the Pressure Reactivity Index in Newborn Piglets After Fluid Percussion Injury. Transl Stroke Res 3:460-5
Armstead, William M; Riley, John; Vavilala, Monica S (2012) TBI sex dependently upregulates ET-1 to impair autoregulation, which is aggravated by phenylephrine in males but is abrogated in females. J Neurotrauma 29:1483-90

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