Research Overview
Researchers at the University of Illinois Urbana-Champaign have conducted two studies in mice, exploring pharmaceutical interventions to address memory impairment and cognitive recovery after surgery in older brains. Uwe Rudolph, professor and head of comparative biosciences at the U. of I., stated that these studies provide a blueprint for further preclinical research.
Post-Surgical Cognitive Impairment Study
The first study, published in PNAS Nexus, focused on postoperative cognitive impairment, a condition affecting approximately 10% of adults over 60 three months after surgery, according to Rudolph.
The researchers investigated propofol, a common anesthetic. Previous mouse studies had indicated propofol's potential in Alzheimer’s disease models, although high doses may have adverse effects. The Illinois team performed surgery on older mice to differentiate between effects of anesthesia and surgical trauma, an approach highlighted by postdoctoral researcher Rajasekar Nagarajan, first author of both studies.
Intermittent administration of propofol, initiated before surgery, resulted in increased mouse performance on various cognitive tasks post-surgery. These effects persisted for five days, despite propofol's short clearance time from the body. Analysis of mouse brains revealed that propofol administration led to a sustained increase in gamma-aminobutyric acid (GABA) receptor subtypes on neurons in the hippocampus, a brain region critical for learning and memory. Markers for inflammation and cell death were also observed to decrease in these mice.
Nagarajan noted the observation that a general anesthetic like propofol could improve cognitive function after surgery in aged individuals. Ongoing experiments involve a compound designed to specifically increase the activity of the identified GABA receptor subtype, with potential clinical applications for preventing postoperative cognitive deficits.
Age-Related Memory Impairment Study
The second study, published in Pharmacology Research and Perspectives, examined age-related memory impairment. The research team explored the potential of intranasal insulin, following findings from other studies suggesting its role in improving memory in Alzheimer's disease models.
Using a developed "pseudo-aged" mouse model, researchers administered intranasal insulin daily for nine days. Pseudo-aged mice treated with intranasal insulin showed improved performance in tasks related to working memory, recognition memory, and associative memory. No significant changes were observed in the control group.
Molecular analysis indicated that intranasal insulin treatment reversed an increase in two markers regulating neural inflammation in pseudo-aged mice, thereby reducing inflammation. The authors concluded that intranasal insulin may offer a noninvasive therapeutic approach for mitigating age-related cognitive decline by modulating neuroinflammatory mechanisms.
Rudolph indicated that intranasal insulin might exhibit effects similar to propofol for post-surgical cognition. Future research aims to investigate the involvement of alpha-5 GABA-A receptors in intranasal insulin's action and to identify the specific neuron subtypes in the hippocampus responsible for these effects.
This work received support from the U.S. National Institutes of Health.