In mice, vorinostat reverses brain changes after surgery

In a UVA Health laboratory, aged mice went through a simulation of anesthesia, surgery and intensive-care stress. Their brains changed at the molecular level, and the animals developed impaired memory, disrupted sleep and behaviors resembling postoperative delirium. The new study links those short-term effects to biological changes that may also help explain later cognitive decline.

Nadia Lunardi, UVA Health’s neuroanesthesia division chief, Hari Prasad Osuru and their colleagues found that the stress altered gene activity through two epigenetic mechanisms—processes that help control whether genes are switched on or off. The affected genes were involved in memory formation and the internal biological clock, which regulates healthy sleep patterns.

The team gave some mice vorinostat, an FDA-approved drug used to treat certain types of T-cell lymphoma, before the anesthesia, surgery and intensive-care-related stress. In those animals, the drug reversed many of the observed changes. Neuronal structure and cognitive performance improved, genes involved in memory and biological-clock regulation regained function, sleep patterns improved and delirium-like symptoms became less common.

The scale of the clinical problem is large: the American Delirium Society estimates that postoperative delirium affects 7 million hospitalized Americans each year and is associated with up to $152 billion in health care costs. The condition is especially common in older and frail patients, and it is a strong risk factor for subsequent cognitive decline and dementia, although the biological connection has been unclear.

So what changes in practice? Not yet a treatment for patients. The result identifies reversible pathways that could eventually be targeted to prevent postoperative delirium or reduce its long-term consequences, but these findings come from aged mice. UVA Health’s researchers are now using single-cell technologies and spatial transcriptomics to map the response of specific brain-cell populations before any human benefit can be claimed.