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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD057355-05
Application #
8225271
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Maholmes, Valerie
Project Start
2008-03-20
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$318,087
Indirect Cost
$116,127
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Larusch, Gretchen A; Merkulova, Alona; Mahdi, Fakhri et al. (2013) Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through *1-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; Riley, John; Yarovoi, Serge et al. (2012) tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury. J Neurotrauma 29:1794-802
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
Armstead, William M; Riley, John; Cines, Douglas B et al. (2011) tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK. Brain Res 1376:88-93
Armstead, William M; Kiessling, J Willis; Riley, John et al. (2011) Phenylephrine infusion prevents impairment of ATP- and calcium-sensitive potassium channel-mediated cerebrovasodilation after brain injury in female, but aggravates impairment in male, piglets through modulation of ERK MAPK upregulation. J Neurotrauma 28:105-11
Armstead, William M; Kiessling, J Willis; Riley, John et al. (2011) tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK. Neurol Res 33:726-33
Armstead, William M; Kiessling, J Willis; Cines, Douglas B et al. (2011) Glucagon protects against impaired NMDA-mediated cerebrovasodilation and cerebral autoregulation during hypotension after brain injury by activating cAMP protein kinase A and inhibiting upregulation of tPA. J Neurotrauma 28:451-7

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