Retracted:Norepinephrine Protects Cerebral Autoregulation and Reduces Hippocampal Necrosis after Traumatic Brain Injury via Blockade of ERK MAPK and IL-6 in Juvenile Pigs

Abstract

Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of 1-to 5-day-old newborn piglets, we observed that norepinephrine (NE) preferentially protected cerebral autoregulation and prevented hippocampal necrosis in females but not males after fluid percussion injury (FPI). The ERK isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after FPI, but less is known about the role of the cytokine interleukin-6 (IL-6). We investigated whether NE protects autoregulation and limits histopathology after FPI in older juvenile (4-week-old) pigs and the role of ERK and IL-6 in that outcome by sex. Results show that NE significantly protects autoregulation and prevents reduction in cerebral blood flow (CBF) in both male and female juvenile pigs after FPI; co-administration of the ERK antagonist U 0126 with NE fully protects both indices of outcome. Papaverine induced dilation was unchanged by FPI and NE. NE blunted ERK MAPK and IL-6 upregulation in both males and females after FPI. NE attenuated loss of neurons in CA1 and CA3 hippocampus of males and females after FPI. These data indicate that NE protects autoregulation and limits hippocampal neuronal cell necrosis via blockade of ERK and IL-6 after FPI in both male and female juvenile pigs. These data suggest that use of NE to improve outcome after TBI is both sex and age dependent.

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.…”

“…Our other recent studies using different vasoactive agents have observed the opposite, building the argument for use of a precision medicine approach in treatment of pediatric 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).…”

“…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).…”

Cerebral Blood Flow Autoregulation and Dysautoregulation

“…67 In contrast, in the second study using older pigs, NE blunted ERK MAPK and IL-6 upregulation in both males and females after FPI. 68 Co-administration of the ERK MAPK antagonist U 0126 preserved autoregulation and maintained CBF after FPI in newborns, regardless of sex. 67 U 0126 also prevented hippocampal neuronal cell necrosis associated with FPI.…”

“…67 However, NE had no protective effect on cerebral autoregulation and potentiated neuronal cell necrosis in male newborn pigs, despite achievement of a similar CPP. 67 In the second study, NE protected cerebral autoregulation and limited hippocampal neuronal cell necrosis after FPI in both male and female juvenile pigs, 68 indicating that the same vasoactive drug elicits both age and sex dependent differences in outcome under equivalent injury intensity conditions.…”