Our goal is to understand the mechanisms by which cerebrovascular insult induced by neonatal seizures causes sustained loss of cerebral blood flow regulation. Circulating endothelial cells (CECs) in the peripheral blood are indicative of vascular damage in cardiovascular disease, but relationships between CECs and cerebrovascular insults have not been investigated. Cerebral blood flow regulation is compromised following seizures in newborn pigs. This proposal is based on our exciting preliminary data suggesting seizures cause appearance of brain-derived circulating endothelial cells (BCECs) in blood coincident with cerebrovascular endothelial injury and a loss endothelial cerebrovascular dilatory function. Further, in newborn pig cerebral vascular endothelial cells, the seizure-inducing excitatory neurotransmitter, glutamate, causes oxidative stress, apoptosis, and cell detachment. We hypothesize that seizure-evoked BCECs are systemic biomarkers of cerebral vascular damage that originate from oxidative stress-induced endothelial apoptosis and endothelial sloughing from cerebral vessels that contributes to sustained loss of endothelial-dependent vasodilator functions in the neonatal cerebral circulation. To test this hypothesis, four specific aims will be addressed using in vivo and in vitro approaches in newborn pigs: 1) Characterize, in vivo, time-dependent relationships among seizures, cerebrovascular events, oxidative stress, and BCECs. 2) Test, in vivo, the hypothesis that BCECs originate via seizure-induced endothelial apoptosis leading to sloughing of cerebral vascular endothelial cells;3) Test, in cerebral vascular endothelial cells, the hypothesis that glutamate receptor activation produces Ca2+ overload that causes oxidative stress-induced apoptosis and leads to cell detachment;4) Investigate, in vivo, the causal relationships among BCECs, oxidative stress, and the severity of seizure-related loss of endothelial-dependent vasodilator functions in the neonatal cerebral circulation. These experiments are novel both by combining in vivo and in vitro approaches to study the mechanisms of seizure-induced loss of cerebral blood flow regulation and by investigating, for the first time, brain-derived circulating endothelial cells as well as their association with neonatal cerebral vascular injury. Seizures in the neonatal period cause life-long neurological disabilities. Cerebral vascular dysfunction may contribute to seizure-induced neurological sequilae. Understanding mechanisms of seizure-related loss of cerebral blood flow regulation and finding correlations between cerebrovascular insult and systemic parameters is essential in improving the long-term neurological outcome of human newborns.

Public Health Relevance

Seizures are the most frequent neurological event in the neonatal period that can cause morbidity and mortality in newborns and life-long neurological disabilities in survivors, and cerebral vascular dysfunction may contribute to neurological sequilae. Brain- derived circulating endothelial cells in peripheral blood are of potential importance as non-invasive markers of cerebrovascular insults. Understanding mechanisms of seizure-related loss of cerebral blood flow regulation and finding correlations between cerebrovascular insult and systemic parameters is essential in improving the long-term neurological outcome of human newborns.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063936-02
Application #
8019991
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Fureman, Brandy E
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
2
Fiscal Year
2011
Total Cost
$317,275
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Harsono, Mimily; Pourcyrous, Massroor; Jolly, Elliott J et al. (2016) Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity. Am J Physiol Heart Circ Physiol 311:H1202-H1213
Liu, Jianxiong; Fedinec, Alexander L; Leffler, Charles W et al. (2015) Enteral supplements of a carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by neonatal seizures. J Cereb Blood Flow Metab 35:193-9
Pourcyrous, Massroor; Basuroy, Shyamali; Tcheranova, Dilyara et al. (2015) Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury. Physiol Rep 3:
Basuroy, Shyamali; Leffler, Charles W; Parfenova, Helena (2013) CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis. Am J Physiol Cell Physiol 304:C1105-15
Parfenova, Helena; Leffler, Charles W; Basuroy, Shyamali et al. (2012) Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures. J Cereb Blood Flow Metab 32:1024-34
Parfenova, Helena; Tcheranova, Dilyara; Basuroy, Shyamali et al. (2012) Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate. Am J Physiol Heart Circ Physiol 302:H2257-66
Xi, Qi; Tcheranova, Dilyara; Basuroy, Shyamali et al. (2011) Glutamate-induced calcium signals stimulate CO production in piglet astrocytes. Am J Physiol Heart Circ Physiol 301:H428-33
Basuroy, Shyamali; Tcheranova, Dilyara; Bhattacharya, Sujoy et al. (2011) Nox4 NADPH oxidase-derived reactive oxygen species, via endogenous carbon monoxide, promote survival of brain endothelial cells during TNF-?-induced apoptosis. Am J Physiol Cell Physiol 300:C256-65
Leffler, Charles W; Parfenova, Helena; Jaggar, Jonathan H (2011) Carbon monoxide as an endogenous vascular modulator. Am J Physiol Heart Circ Physiol 301:H1-H11
Leffler, Charles W; Parfenova, Helena; Basuroy, Shyamali et al. (2011) Hydrogen sulfide and cerebral microvascular tone in newborn pigs. Am J Physiol Heart Circ Physiol 300:H440-7

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