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Published on: December 9, 2013
K channel impairment determines sex and age differences in epinephrine-mediated outcomes after brain injury
William M Armstead1,2, John Riley1, Monica S Vavilala3
1Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia.
Insights
Epinephrine (EPI) protects young pigs from traumatic brain injury (TBI) by preserving K+ channel function, but this effect is age- and sex-dependent. This finding is crucial for understanding TBI outcomes in children.
Area of Science:
- Neuroscience
- Physiology
- Pediatric Injury
Background:
- Traumatic brain injury (TBI) is a major cause of death in children, with specific age and sex groups experiencing worse outcomes.
- Cerebral autoregulation, mediated by ATP- and calcium-sensitive potassium (KATP and KCa) channels, is impaired after TBI, worsening outcomes.
- Mitogen-activated protein kinase JNK (c-Jun-terminal kinase) is upregulated after central nervous system injury, impairing K+ channel function.
Purpose of the Study:
- To investigate the hypothesis that age- and sex-specific K+ channel impairment contributes to differential outcomes following TBI and epinephrine (EPI) treatment.
- To examine the role of K+ channels in TBI-induced cerebrovascular dysfunction and the protective effects of EPI.
Main Methods:
- Anesthetized pigs with a closed cranial window model were used.
- Pial artery dilation responses to KATP and KCa channel agonists (cromakalim and NS 1619) were measured after TBI.
- The effect of EPI on these responses and JNK modulation was assessed in different age and sex groups.
Main Results:
- TBI impaired pial artery dilation to KATP and KCa channel agonists.
- EPI prevented this impairment in newborn males and females, and in juvenile females, but not in juvenile males.
- These protective effects of EPI were linked to JNK pathway modulation.
Conclusions:
- EPI protects cerebral autoregulation and limits brain damage after TBI by preserving K+ channel function.
- This neuroprotective effect of EPI is dependent on the age and sex of the animal, mediated through JNK pathway blockade.
- Findings highlight critical age- and sex-dependent mechanisms in TBI pathophysiology and potential therapeutic targets.
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.
