Preferential Protection of Cerebral Autoregulation and Reduction of Hippocampal Necrosis With Norepinephrine After Traumatic Brain Injury in Female Piglets*

Abstract

Objective 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 vasopressors to increase MAP. In prior studies, we observed that phenylephrine prevented in female but exacerbated impairment of autoregulation in male piglets after fluid percussion injury (FPI). In contrast, dopamine prevented impairment of autoregulation in both sexes after FPI, suggesting that pressor choice impacts outcome. The ERK isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after FPI, but the role of the cytokine IL-6 is unknown. We investigated whether norepinephrine (NE) sex dependently protects autoregulation and limits histopathology after FPI and the role of ERK and IL-6 in that outcome. Design Prospective, randomized animal study. Setting University laboratory. Subjects Newborn (1–5 day old) pigs. Interventions CPP, CBF, and pial artery diameter were determined before and after FPI in piglets equipped with a closed cranial window and post treated with NE. CSF ERK MAPK was determined by ELISA. Measurements and Main Results NE does not protect autoregulation or prevent reduction in CBF in male but fully protects autoregulation in female piglets after FPI. Papaverine induced dilation was unchanged by FPI and NE. NE increased ERK MAPK upregulation in male but blocked such upregulation in female piglets after FPI. NE aggravated IL-6 upregulation in males in an ERK MAPK dependent mechanism but blocked IL-6 upregulation in females after FPI. NE augments loss of neurons in CA1 and CA3 hippocampus of male piglets after FPI in an ERK MAPK and IL-6 dependent manner, but prevents loss of neurons in females after FPI. Conclusions NE protects autoregulation and limits hippocampal neuronal cell necrosis via modulation of ERK MAPK and IL-6 after FPI in a sex dependent manner.

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

“…In contrast, NE augmented ERK MAPK upregulation in newborn males but similarly blocked it in newborn females after TBI. 19 The magnitude of increase in CSF ERK MAPK was greater in newborn 19 compared with juvenile pigs (present study) after equivalent FPI. The ERK MAPK antagonist U 0126 permitted full restoration of hypotension induced pial artery dilation and THRR during carotid artery compression and maintained CBF after FPI similarly in male newborn 19 and juvenile pigs (present study).…”

“…In a recent prior study, it was observed that NE protected cerebral autoregulation and prevented hippocampal cell necrosis in newborn female but not newborn male piglets after TBI. 19 Taken together, the present study is the first to demonstrate that not only are there sex differences in outcome, but that there are age related differences in outcome when NE is used as part of the same critical care pathway for treatment of TBI. Because newborn and juvenile pigs may approximate the human neonate (6 months to 2 years old) and child (8 to 10 years old), respectively, 7 these data support the consideration of individualized medical approaches for younger and older children, in addition to that of boys compared with girls.…”

“…6 Histopathological data in the present study are the first to demonstrate that severe injury (as judged by hippocampal cell necrosis) results from a moderate FPI insult (2 atm) in the older pig, albeit less than after comparable FPI insult (2 atm) in the newborn pig. 19 This study is also the first to show that the well-accepted clinical intervention of systemic vasoactive agent support in treatment of TBI not only improves cerebral hemodynamics and protects autoregulation, but it also limits hippocampal cell damage post-FPI in the older pig. The generalizability of the neurovascular unit concept can be found in a recent prior study from our group wherein normalization of CBF and prevention of autoregulatory impairment by tPA-S481A, a drug that limited N-methyl-D-aspartate (NMDA) receptor toxicity, similarly resulted in preservation of hippocampal neuronal cell integrity in the newborn pig.…”

“…18 More recently, we have observed that NE preferentially protected cerebral autoregulation and prevented neuronal cell necrosis in hippocampal areas CA1 and CA3 in female newborn piglets after FPI. 19 However, NE had no protective effect on cerebral autoregulation and potentiated neuronal cell necrosis in male newborn pigs, despite achievement of a similar CPP. 19 These data indicate that, like Phe, NE improves outcome after TBI in female newborn piglets.…”

“…19 However, NE had no protective effect on cerebral autoregulation and potentiated neuronal cell necrosis in male newborn pigs, despite achievement of a similar CPP. 19 These data indicate that, like Phe, NE improves outcome after TBI in female newborn piglets.…”