Simple pharmaceutical interventions could help older brains cope with memory impairment and recovery after surgery, new studies in mice suggest.
In two studies, researchers at the University of Illinois Urbana-Champaign investigated different aspects of cognitive impairment: postoperative impairment - a relatively common phenomenon among older adults - and age-related memory decline, as well as noninvasive methods of restoring function.
"These studies provide a blueprint for further basic science studies that can identify compounds in preclinical tests that may eventually also be testable in humans," said research leader Uwe Rudolph, professor and head of comparative biosciences at the U. of I.
The first paper, published in the journal PNAS Nexus, examined the problem of post-surgical cognitive impairment. Immediately after surgery, cognitive impairment is common, but studies have found that 10% of adults over the age of 60 still have deficits to learning, memory and executive function three months after surgery, Rudolph said. "If you then multiply that by the number of surgeries that are done on people 60 years and over, the number is very significant," he said.
Propofol is a common anesthetic agent that has shown promise in other mouse studies for improving cognition in Alzheimer's disease models, though in high doses it may harm the brain, Rudolph said. To study whether propofol could help with cognition after surgery, the researchers performed surgery on older mice - an approach not as common as it may seem.
"Other studies have been done on younger mice, or they used older mice and put them under anesthesia but did not perform surgery. That makes it hard to separate what is attributable to the anesthesia and what is due to the trauma of the surgery itself," said Illinois postdoctoral researcher Rajasekar Nagarajan, the first author of both studies.
The Illinois team found that intermittent administration of propofol, beginning before surgery, increased mouse performance on a wide variety of cognitive tasks after the surgery. And the results lasted five days after a dose, even though propofol is thought to be cleared from the body in a matter of hours.
Looking closely at what was happening in the mouse brains, the researchers found that mice who were administered propofol had a long-lasting increase of certain receptors for the neurotransmitter GABA, a key regulator of learning and memory, on the surface of neurons in the hippocampus region of the brain and decreased markers for inflammation and cell death. Mice who were not administered propofol did not have these molecular changes.
"It is well known that general anesthesia and surgery may result in cognitive impairments, especially in older individuals. It is surprising and interesting that a general anesthetic like propofol actually can improve cognitive function after surgery in aged individuals," Nagarajan said. "We are currently doing experiments with a compound that specifically increases the activity of the GABA receptor subtype that is increased after a single administration of propofol. Such a compound may help prevent postoperative cognitive deficits and potentially could be useful clinically."
In the second paper, published in the journal Pharmacology Research and Perspectives, the researchers investigated age-related memory impairment. Other studies have found potential for insulin nasal spray in improving memory in Alzheimer's disease models, so the Illinois team wondered whether it also affected general age-related memory impairment.
The researchers used a mouse model they developed to mimic aging in the hippocampus, called pseudo-aged mice. They administered the insulin to the nose every day for nine days to both the pseudo-aged mice and a control group of mice.
While no significant changes were seen in the control group, the pseudo-aged mice treated with intranasal insulin improved their performance in tasks related to working memory, recognition memory and associative memory.
Again delving into the molecular changes in the brain, the researchers found that pseudo-aged mice had an increase in two markers that regulate neural inflammation, and intranasal insulin reversed that increase, reducing inflammation.
"Together, the results suggest that intranasal insulin may provide a noninvasive therapeutic approach for mitigating age-related cognitive decline by modulating neuroinflammatory mechanisms," the authors wrote.
"There are some indications that intranasal insulin has similar effects as propofol for cognition after surgery as well," Rudolph said, "Next, we want to study whether alpha-5 GABA-A receptors, which propofol increased on the neural surface, are involved in the action of intranasal insulin. We also want to identify the exact neuron subtype in the hippocampus that is responsible for these effects."
This work was supported by the National Institute of General Medical Sciences of the U.S. National Institutes of Health under award numbers R01GM128183 and R35GM153232.
