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Sex and age differences in phenylephrine mechanisms and outcomes after piglet brain injury
Victor Curvello1, Hugh Hekierski1, John Riley1
1Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Insights
Phenylephrine protects cerebral autoregulation and reduces brain tissue injury in juvenile pigs after traumatic brain injury. This effect is sex-dependent and age-dependent, impacting treatment strategies.
Area of Science:
- Neuroscience
- Pediatric Traumatology
- Pharmacology
Background:
- Traumatic brain injury (TBI) is a leading cause of death in children, with higher mortality in boys.
- Impaired cerebral autoregulation after TBI is linked to poor outcomes.
- Previous studies showed phenylephrine (Phe) protected autoregulation in female newborns but not males post-TBI.
Purpose of the Study:
- To investigate if phenylephrine (Phe) protects cerebral autoregulation and reduces tissue injury in juvenile pigs of both sexes following TBI.
- To determine the role of extracellular signal-related kinase (ERK) and endothelin pathways in Phe's protective effects.
Main Methods:
- Juvenile male and female pigs underwent moderate fluid percussion brain injury (FPI).
- Cerebral autoregulation, cerebrospinal fluid (CSF) ERK and endothelin levels, and histopathology were assessed after Phe administration.
- Comparison of outcomes between sexes and with previous newborn pig studies.
Main Results:
- Cerebral autoregulation was more impaired in male juvenile pigs compared to females.
- Phe administration protected cerebral autoregulation in both male and female juvenile pigs post-FPI.
- Phe blocked ERK and endothelin pathways and decreased neuronal necrosis in both sexes after FPI.
Conclusions:
- Phenylephrine (Phe) protects cerebral autoregulation and limits neuronal necrosis in juvenile pigs of both sexes after FPI, mediated by blocking ERK and endothelin.
- The sex- and age-dependency of Phe's protective effects suggests tailored therapeutic approaches for TBI are necessary.
Abstract:
BackgroundTraumatic brain injury (TBI) is the leading cause of injury-related death in children, with boys and children under 4 years of age having particularly poor outcomes. Cerebral autoregulation is often impaired after TBI, contributing to poor outcome. In prior studies on newborn pigs, phenylephrine (Phe) preferentially protected cerebral autoregulation in female but not in male subjects after TBI. We hypothesized that, in contrast to the newborn, Phe prevents impairment of autoregulation and tissue injury following TBI in both sexes of older pigs.MethodsCerebral autoregulation, cerebrospinal fluid (CSF) extracellular signal-related kinase (ERK) and endothelin, and histopathology were determined after moderate fluid percussion brain injury (FPI) in male and female juvenile pigs after Phe.ResultsAutoregulation was more impaired in male than in female subjects. Phe protects autoregulation in both sexes after FPI, blocks ERK and endothelin, and decreases the number of necrotic neurons in male and female subjects after FPI.ConclusionsThese data indicate that Phe protects autoregulation and limits neuronal necrosis via blockage of ERK and endothelin after FPI in male and female subjects. Together with prior observations in newborn pigs where Phe protected autoregulation in female but not in male subjects, these data suggest that use of Phe to improve outcomes after TBI is both sex- and age-dependent.
