Inhaled Nitric Oxide Protects Cerebral Autoregulation and Reduces Hippocampal Necrosis After Traumatic Brain Injury Through Inhibition of ET-1, ERK MAPK and IL-6 Upregulation in Pigs.

Abstract

OBJECTIVE:

Traumatic brain injury (TBI) is an important contributor to morbidity and mortality. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) and ET-1 are upregulated and contribute to impairment of cerebral autoregulation and histopathology after porcine fluid percussion brain injury (FPI). Recent studies show that inhaled nitric oxide (iNO) prevents impairment of cerebral autoregulation and histopathology after FPI in pigs. Unrelated studies indicated an association between ERK and increased IL-6 after FPI. However, the role of IL-6 in central nervous system (CNS) pathology is not well understood. We investigated whether iNO protects autoregulation and limits histopathology after FPI in pigs due to modulation of brain injury associated upregulation of ET-1, ERK MAPK, and IL-6.

METHODS:

Lateral FPI was produced in anesthetized pigs equipped with a closed cranial window and iNO administered at 30 min or 2 h post injury.

RESULTS:

CSF ET-1, ERK MAPK, and IL-6 were increased by FPI, but release was blocked by iNO administered at 30 min or 2 h after TBI. The IL-6 antagonist LMT-28 prevented impairment of cerebral autoregulation and hippocampal CA1 and CA3 neuronal necrosis after FPI. Papaverine induced dilation was unchanged by FPI and LMT-28. Protection lasted for at least 2 h after iNO administration was stopped.

CONCLUSIONS:

These data indicate that iNO protects cerebral autoregulation and reduces hippocampal necrosis after traumatic brain injury through inhibition of ET-1, ERK MAPK, and IL-6 upregulation in pigs.

• Authors: Victor Curvello, Philip Pastor, Hugh Hekierski, William M Armstead
• Journal: Neurocritical care (Neurocrit Care) Vol. 30 Issue 2 Pg. 467-477 (04 2019) ISSN: 1556-0961 [Electronic] United States
• PMID: 30386963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Endothelin-1
• Interleukin-6
• LMT-28
• Oxazolidinones
• Protein Synthesis Inhibitors
• Vasodilator Agents
• Nitric Oxide
• Papaverine
• Extracellular Signal-Regulated MAP Kinases

Topics

• Administration, Inhalation
• Animals
• Animals, Newborn
• Brain Injuries, Traumatic (cerebrospinal fluid, drug therapy, pathology)
• Disease Models, Animal
• Endothelin-1 (cerebrospinal fluid, drug effects)
• Extracellular Signal-Regulated MAP Kinases (cerebrospinal fluid, drug effects)
• Female
• Hippocampus (drug effects, pathology)
• Homeostasis (drug effects)
• Interleukin-6 (antagonists & inhibitors, cerebrospinal fluid)
• Male
• Necrosis (pathology, prevention & control)
• Nitric Oxide (administration & dosage, pharmacology)
• Oxazolidinones (pharmacology)
• Papaverine (pharmacology)
• Protein Synthesis Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Swine
• Up-Regulation (drug effects)
• Vasodilator Agents (administration & dosage, pharmacology)