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. 2017 Apr 15;34(8):1666-1675.
doi: 10.1089/neu.2016.4770. Epub 2017 Jan 13.

Sex and Age Differences in Epinephrine Mechanisms and Outcomes after Brain Injury

William M Armstead  1   2 , John Riley  1 , Monica S Vavilala  3
Affiliations

Sex and Age Differences in Epinephrine Mechanisms and Outcomes after Brain Injury

William M Armstead et al. J Neurotrauma. .

Retraction in

Abstract

Traumatic brain injury (TBI) is the leading cause of injury-related death in children, with boys and children <4 years of age having particularly poor outcomes. Cerebral autoregulation is often impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure can be normalized by use of vasoactive agents. The c-Jun-terminal kinase (JNK) isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after TBI, but less is known about its role in histopathology. We investigated whether epinephrine (EPI), age, and sex dependently protected cerebral autoregulation and limited histopathology after TBI, and sought to determine the role of JNK in that outcome. Lateral fluid percussion injury (FPI) was produced in anesthetized pigs. Pial artery reactivity was measured via a closed cranial window. Phosphorylated JNK MAPK was quantified by enzyme-linked immunosorbent assay (ELISA). Results show that EPI preserves autoregulation, prevents histopathology, and blocks phosphorylated JNK upregulation in newborn males and females and juvenile females but not juvenile males after TBI. These data indicate that EPI preserves cerebral autoregulation and limits histopathology after TBI through blockade of JNK in an age- and sex-dependent manner.

Keywords: age; brain injury; cerebral autoregulation; histopathology; sex; signal transduction; vasopressor.

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Conflict of interest statement

No competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
Transient hyperemic response ratio (THRR) during unilateral and bilateral carotid artery compression in (A) newborn male and female pigs and in (B) juvenile male and female pigs before (sham), after fluid percussion injury (FPI), and after FPI treated with epinephrine (EPI), n = 5. *p < 0.05 compared with corresponding sham value, +p < 0.05 compared with corresponding FPI alone value, #p < 0.05 compared with corresponding female value.
<b>FIG. 2.</b>
FIG. 2.
Influence of fluid percussion injury (FPI) on pial artery diameter during hypotension (moderate, severe) in (A) newborn male and female pigs and in (B) juvenile male and female pigs before (sham), after FPI, and after FPI treated with epinephrine (EPI), n = 5. *p < 0.05 compared with corresponding sham value, +p < 0.05 compared with corresponding FPI alone value, #p < 0.05 compared with corresponding female value.
<b>FIG. 3.</b>
FIG. 3.
Influence of papaverine (10−8, 10−6 M) on pial artery diameter in (A) newborn male and female pigs and in (B) juvenile male and female pigs before (sham), after fluid percussion injury (FPI), and after FPI treated with ephinephrine (EPI), n = 5.
<b>FIG. 4.</b>
FIG. 4.
Cerebral blood flow (CBF) (mL/min 100 g) before (0 time) and after fluid percussion injury (FPI) in (A) newborn male and female pigs and in (B) juvenile male and female pigs before (sham), after FPI, and after FPI treated with epinephrine (EPI), n = 5. *p < 0.05 compared with corresponding 0 time value, +p < 0.05 compared with corresponding FPI alone value, #p < 0.05 compared with corresponding female value.
<b>FIG. 5.</b>
FIG. 5.
Phosphorylated c-Jun-terminal kinase (JNK) mitogen activated protein kinase (MAPK) (pg/mL) before (0 time) and 4 h after fluid percussion injury (FPI) in (A) newborn male and female pigs and in (B) juvenile male and female pigs before (sham), after FPI, and after FPI treated with epinephrine (EPI), n = 5. *p < 0.05 compared with corresponding 0 time value, +p < 0.05 compared with corresponding FPI alone value, #p < 0.05 compared with corresponding female value.
<b>FIG. 6.</b>
FIG. 6.
Influence of fluid percussion injury (FPI) and FPI + epinephrine (EPI) on histopathology as a function of sex in newborn pigs. (A) Male sham control (40 × ) showing CA1 (#1) and CA3 (#2) hippocampal regions. (B) Male sham CA3 (100 × ). (C) Male FPI CA3 (100 × ). (D) Female FPI CA3 (100 × ). (E) FPI + EPI male CA3 (100 × ). (F) FPI + EPI female CA3 (100 × ). (G) Sham control male neuron (600 × ) #3, with intact cytoplasm and darkly stained nucleus and (H) Male necrotic neurons (600 × ) showing # 4 pyknotic nucleus of small neuron, accompanied by neuronal cytoplasm shrinkage (#5) and granulated eosinophilic characteristics (“red dead” neuron) (#6) associated with cell death. Summary data for necrotic neurons (I) in CA1 and CA3 before (sham), after FPI, and after FPI treated with EPI, n = 5. *p < 0.05 compared with corresponding sham control value, +p < 0.05 compared with corresponding FPI alone value, #p < 0.05 compared with corresponding female value.
<b>FIG. 7.</b>
FIG. 7.
Influence of fluid percussion injury (FPI) and FPI + epinephrine (EPI) on histopathology as a function of sex in juvenile pigs. (A) Male sham control (40 × ) showing CA1 (#1) and CA3 (#2) hippocampal regions. (B) Male sham control CA3 (100 × ). (C) Male FPI CA3 (100 × ). (D) Female FPI CA3 (100 × ). (E) FPI + EPI male CA3 (100 × ). (F) FPI + EPI female CA3 (100 × ). (G) Summary data for necrotic neurons in CA1 and CA3 before (sham), after FPI, and after FPI treated with EPI, n = 5. *p < 0.05 compared with corresponding sham control value, +p < 0.05 compared with corresponding FPI alone value, #p < 0.05 compared with corresponding female value.
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Comment in

  • Findings of Research Misconduct.
    [No authors listed] [No authors listed] Fed Regist. 2023 Jul 7;88(129):43363-43364. Fed Regist. 2023. PMID: 37434991 Free PMC article. No abstract available.

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