Babies are frequently exposed to hypoxia and ischemia during the perinatal period due to stroke or problems with delivery or respiratory management post delivery. Neonatal stroke incidence can be as high as 1 in 4000 births. One contributor to neurologic damage is cerebrovascular dysfunction. The only FDA approved treatment for acute stroke is the administration of tPA. Nonetheless, in basic science studies, tPA has been observed to exhibit a dual beneficial/deleterious effect. In addition to its salutary role in reperfusion, tPA may contribute to neuronal cell death. A potential explanation for the tPA therapeutic treatment paradox could relate to the vascular activity (dilation) of tPA. The term neurovascular unit (NVU) focuses attention on the interactions between cerebral blood vessels and neurons. Mitogen activated protein kinase (MAPK) expression is enhanced after cerebral ischemia and may be one of the most distal systems affecting both the vasculature and genomics. The hypothesis is that plasminogen activator production following cerebral hypoxia/ischemia contributes to impaired cerebral hemodynamics and neuronal cell loss post insult. Plasminogen activators are hypothesized to impair reactivity to vascular stimuli and produce hyperemia which results in edema causing neuronal cell loss. Dynamic interactions between cerebral blood vessels and neurons thus result in an integrated response to the insult, consistent with the NVU concept. To address this hypothesis, three specific aims will be pursued in newborn pigs: 1. Characterize the relationship between plasminogen activators and cerebral hemodynamics after hypoxia/ischemia, 2. Investigate the role of MAPK as the mechanism by which plasminogen activators control cerebral hemodynamics post insult; Changes in the MAPK isoform expression profile result in impaired cerebral hemodynamics and neuron cell loss. 3. Determine the association between impaired cerebral hemodynamics and histopathology post insult. The closed cranial window technique will be used to measure pial artery diameter and determine CSF plasminogen activator concentration via ELISA. CBF will be determined by the radiolabeled microsphere method. Immunohistochemistry and techniques for detection of plasminogen activator and MAPK expression will be used to achieve an integrated whole animal/molecular perspective on the relationship between plasminogen activators, cerebral hemodynamics, and histopathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS053410-02S1
Application #
7436890
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Jacobs, Tom P
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$78,750
Indirect Cost
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; Yarovoi, Serge et al. (2016) Tissue-Type Plasminogen Activator-A296-299 Prevents Impairment of Cerebral Autoregulation After Stroke Through Lipoprotein-Related Receptor-Dependent Increase in cAMP and p38. Stroke 47:2096-102
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
Ji, Fang; Wang, Zhenhong; Ma, Nan et al. (2013) Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model. Brain Res 1490:95-100
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
Su, Diansan; Riley, John; Armstead, William M et al. (2012) Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets. Anesth Analg 114:200-4
Wang, Zhenhong; Ma, Nan; Riley, John et al. (2012) Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets. PLoS One 7:e41724
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) tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK. Neurol Res 33:726-33

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