Inhibiting IL-6 May Reduce Delirium Damage
Suppressing the activity of a protein called IL-6 may protect brain cells from damage typically found in delirium, a syndrome common in hospitalized patients that impairs thinking, memory and understanding, according to a new Cedars-Sinai-led study.
An MRI of the human brain by Getty Images.
The study, which was conducted in mice and published in the American Journal of Respiratory Cell and Molecular Biology, showed how IL-6, which normally helps regulate the body's reaction to infection or injury, could in certain circumstances promote delirium-related brain damage. IL-6 is the same protein involved in the so-called cytokine storm of inflammation that has gravely sickened many COVID-19 patients during the pandemic.
The findings, if confirmed in studies in humans, may have implications for reducing the risk of delirium-related brain damage in those most at risk: severely ill patients and those relying on mechanical ventilators to breathe.
As a critical care neurologist, the study's lead investigator Shouri Lahiri, MD, assistant professor of Neurology and director of Neurocritical Care at Cedars-Sinai, said he has witnessed the impact of delirium on patients. "Patients who suffer from delirium are hospitalized longer and are at greater risk of disability and death," he explained. "Delirium during an acute illness can foretell long-term cognitive impairment."
Shouri Lahiri, MD
One previous study found that more than 30% of patients in the intensive care unit experienced delirium during their stay, with patients on mechanical ventilation at highest risk. Patients with delirium typically developed damage to the frontal cortex and hippocampal regions of the brain, which are responsible for memory, planning and critical thinking.
Heightened IL-6 activity has been associated with delirium and lung injury caused by mechanical ventilation, said Lahiri. The investigators hypothesized that suppressing IL-6 activity would protect the brain from injury.
To investigate this hypothesis, the team studied differences between normal-breathing, healthy mice and two groups of mechanically ventilated mice: those that developed lung injury after being on a mechanical ventilation device for two hours and those that did not. Some of the ventilated mice initially received an IL-6-suppressing injection, and others received an inert saline injection.
Analysis of brain tissue from the frontal cortex and hippocampus of all ventilated animals showed elevated levels of proteins associated with brain injury. Brain tissue from animals without lung injury did not show signs of damage. Ventilated animals that had lung injury and also received the IL-6 suppression treatment had lower levels of brain injury markers than did the animals that received the placebo saline treatment.
The study confirmed that lung injury caused by mechanical ventilation induced damage and inflammation in the frontal cortex and hippocampus of the mice, and that significantly, this damage was mitigated with IL-6 inhibition, said Lahiri.
The findings suggest that IL-6 inhibition could have a protective role on brain tissues from delirium-type damage. This is important because understanding the processes and mechanisms behind the onset of delirium is critical to help severely ill patients recover with mental function intact, Lahiri explained.
Research associate Nicklaus Sparrow, PhD, was first author of the study.
Funding: Research reported in this publication was supported by the National Institutes of Health under award number R03AG064106 and the American Academy of Neurology Institute.