Researchers find why ICU ventilation can cause brain damage

Patients who have been mechanically ventilated in intensive care units have long been known to suffer some form of mental impairment as a result. Now, researchers have uncovered a molecular mechanism that may explain why this happens.

The study, published in the American Journal of Respiratory and Critical Care Medicine, was conducted by researchers from the University of Oviedo in Spain, St. Michael's Hospital in Canada, and the Perelman School of Medicine at the University of Pennsylvania.

The researchers say that a minimum of 30% of patients in intensive care units (ICU) suffer some form of mental dysfunction, such as anxiety, depression, and most commonly, delirium. They note that the incidence of delirium in patients who are mechanically ventilated is around 80%.

They hypothesized that this may be partly a result of damage in the hippocampus, but how ventilation causes this damage has been unclear.

Dopamine a cause of apoptosis





Researchers have discovered a molecular mechanism that may explain why some patients who are mechanically ventilated in ICUs suffer mental impairments.

For their study, the research team analyzed the harvested brains of mice who had been connected to low or high-pressure ventilation for 90 minutes, alongside the brains of control mice who had not been on ventilation.

In comparison with the control mice, the mice on ventilation showed evidence of neuronal cell death in the hippocampus as a result of apoptosis - the process of programmed cell death (PCD). 

The research team discovered that the apoptosis process was caused by dopamine-induced suppression of Akt - a molecule that usually prevents neuronal apoptosis.

They note that in the ventilated mice, Akt suppression was clearly evident in the hippocampus and was linked with increased levels of dopamine (hyperdopaminergic) in that area of the brain. The ventilated mice also showed increased gene expression of tyrosine hydroxylase - an enzyme critical in synthesizing dopamine.

The resulting rise in dopamine, the researchers say, increases the strength of activation of the dopamine receptor in the hippocampus.

To confirm these findings, the researchers injected type 2 dopamine (D2) receptor blockers into the brain ventricles of a group of mice. This significantly reduced ventilation-induced apoptosis in the hippocampus.

Dysbindin-1 'protects against apoptosis'

The researchers then looked to analyze the consequences of ventilation and elevated dopamine in the hippocampus on dysbindin-1 - a protein that affects levels of cell surface D2 receptors, cognition, and potentially, risk of psychosis.

Results showed that mice who experienced high-pressure ventilation showed increased gene expression of dysbindin-1C. Later on in the process, the ventilated mice also showed increased gene expression in protein levels of dysbindin-1C.

Dopamine alone showed similar effects on dysbindin-1C when analyzing hippocampus slice preparations, the researchers say, and these effects were inhibited by D2 receptors.

The researchers say that since dysbindin-1 is able to reduce cell-surface D2 receptors, as well as protect against apoptosis, it is possible that increasing dysbindin-1 expression in ventilated mice could trigger "compensatory responses" to ventilation-induced hippocampal apoptosis.

They note that this could potentially apply to ICU patients, given that an additional study finding showed that total dysbindin-1 was increased in the hippocampal neurons of ventilated humans who passed away, but not in non-ventilated humans.

Potential for new and improved drugs

The researchers say these findings may lead to new uses for already established drugs, as well as potential development of new drugs that are able to trigger certain molecular pathways able to resolve adverse effects on brain function as a result of ICU ventilation.

Dr. Konrad Talbot, assistant research professor in Neurobiology in the Department of Psychiatry at Penn Medicine, says:

"The study indicates the need to reevaluate use of D2 receptor antagonists in minimizing the negative cognitive effects of mechanical ventilation in ICU patients and to evaluate the novel possibility that elevation in dysbindin-1C expression can also reduce those effects."

Written by Honor Whiteman

Source: Medical News Today




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