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

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.

RETRACTED: Dopamine protects cerebral autoregulation and prevents hippocampal necrosis after traumatic brain injury via block of ERK MAPK in juvenile pigs

“…We used a widely accepted clinical critical care pathway for treatment of TBI, elevation of MAP to limit cerebral hypoperfusion, to inform the study design of our basic science pig model of TBI. In our prior studies, we observed that Phe, NE, and EPI all prevented reductions in CBF associated with FPI and limited neuronal cell necrosis in hippocampal areas CA1 and CA3 as a function of age and sex (Armstead et al 2016a,b; Armstead et al 2017). While cognition depends on more than the hippocampus and cognitive testing was not performed in these studies, such results do suggest that vasoactive agent support may affect cognitive outcome after TBI.…”

“…For example, Phe and NE have been shown to worsen cerebral autoregulation and histopathology in male, but not female newborn piglets and male and female juvenile pigs after FPI (Armstead et al 2010 a,b, 2016 a,b; Curvello et al 2017). In contrast, EPI prevents impairment of cerebral autoregulation and histopathology in newborn male and female and juvenile female but not juvenile male pigs after FPI (Armstead et al 2017). The translational relevance, then, is that while our data suggest clinicians should use other vasoactive agents with caution dependent on age and sex, DA appears to equally improve outcome in both sexes and in younger and older children after TBI.…”

“…For example, Phe and NE has been shown to protect cerebral autoregulation and limit histopathology in newborn females, and juvenile male and female but not male newborn pigs after fluid percussion brain injury (FPI) (Armstead et al 2010b, 2016 a,b; Curvello et al 2017). In contrast, EPI prevents impairment of cerebral autoregulation and limits histopathology in newborn male and female and juvenile female but not juvenile male pigs after FPI (Armstead et al 2017). DA improves outcome in both male and female newborn pigs (Armstead et al 2013), but the effects of DA on outcome after TBI are unknown in juvenile male and female pigs.…”

tPA variant tPA‐A296–299 Prevents impairment of cerebral autoregulation and necrosis of hippocampal neurons after stroke by inhibiting upregulation of ET‐1

“…Another caveat relative to hemodynamics is that the method we used to test the intactness of autoregulation (hypotension via blood withdrawal), albeit well accepted in preclinical models, is not one that occurs commonly in the clinical setting. However, our conclusions are supported by the fact that comparable outcomes are seen when intactness of autoregulation is measured using the transient hyperemic response ratio, a technique used clinically (Girling, Cavill, & Mahajan, 1999), when applied to models of traumatic brain injury (TBI) in the piglet (Armstead et al, 2017).…”

KRSA: Network-based Prediction of Differential Kinase Activity from Kinome Array Data

“…Interest within the neuroscience community in defining sex differences in the brain has increased over the past several decades. Differences in kinase activity and signaling between males and females have been implicated in sex-related variations in neuronal cell survival, outcomes after brain injury, and fear extinction, among other research areas (Armstead et al, 2017;Matsuda et al, 2015;Zhang et al, 2003). While these studies increased our confidence that we would be able to identify sex-based differences in kinase activity through the KRSA algorithm, we expected that these differences in kinase activity would be small compared to previous experiments we performed in the areas of TBI and schizophrenia.…”