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K channel impairment determines sex and age differences in epinephrine-mediated outcomes after brain injury

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  • SIGNIFICANCE Traumatic brain injury (TBI) is the leading cause of injury-related death in children, with boys and children under 4 years having particularly poor outcomes. Low cerebral perfusion pressure (CPP) after TBI is associated with poor outcomes. Vasoactive agents such as epinephrine are used to normalize CPP after TBI. Yet, the cerebral effects of this commonly used vasoactive agent are not known. Mechanistically driven questions that cannot be investigated in humans for ethical reasons can be conducted in pigs, which ultimately will inform and lead to improvements in the clinical care of pediatric patients with TBI.

  • Sources of Funding: This study was supported by RO1 NS090998 from the National Institutes of Health.

Abstract

Traumatic brain injury (TBI) is the leading cause of injury-related death in children, with boys and children under 4 years having particularly poor outcomes. Activation of ATP- and calcium-sensitive (KATP and KCa) channels produces cerebrovasodilation and contributes to autoregulation, both of which are impaired after TBI, contributing to poor outcomes. Upregulation of the c-Jun-terminal kinase (JNK) isoform of mitogen-activated protein kinase produces K channel function impairment after CNS injury. Vasoactive agents can be used to normalize cerebral perfusion pressure. Epinephrine (EPI) prevents impairment of cerebral autoregulation and hippocampal neuronal cell necrosis after TBI in female and male newborn and female juvenile but not male juvenile pigs via differential modulation of JNK. The present study used anesthetized pigs equipped with a closed cranial window to address the hypothesis that differential K channel impairment contributes to age and sex differences in EPI-mediated outcomes after brain injury. Results show that pial artery dilation in response to the KATP and KCa channel agonists cromakalim and NS 1619 was impaired after TBI and that such impairment was prevented by EPI in female and male newborn and female juvenile but not male juvenile pigs. Using vasodilation as an index of function, these data indicate that EPI protects cerebral autoregulation and limits histopathology after TBI through protection of K channel function via blockade of JNK in an age- and sex-dependent manner. © 2017 Wiley Periodicals, Inc.

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