University of Minnesota
Researcher William Frey has pioneered the intranasal administration of therapies for brain diseases.
Photo: Erika Gratz
Sniffing out brain diseases
Therapies delivered up the nose may work against brain maladies
By Deane Morrison
The best route to deliver therapies for brain diseases may be through the nose.
Not only can "snorted" drugs and even stem cells reach the brain, they can exert therapeutic effects, University of Minnesota researcher William Frey and his colleagues have shown.
Over more than 20 years, Frey has developed and patented non-invasive means of delivering drugs, including insulin, and other therapeutic substances to the brain by the intranasal (IN) route. In his latest study, published in the journal Rejuvenation Research, he and his colleagues at the University Hospital of Tübingen (Germany), including first author Lusine Danielvan, describe how snorted stem cells led to a highly significant improvement in rat models of Parkinson's disease.
And if that seems revolutionary, consider this: Using his methods, he and other researchers around the world have found that insulin given IN can reach the brain and improve memory, attention, and cognition in persons with Alzheimer's disease, who have trouble metabolizing glucose.
The intranasal route gets around the blood-brain barrier, an anatomical network that keeps many therapeutic substances from diffusing out of cranial capillaries and into the fluid that bathes the brain.
"Non-invasive intranasal delivery bypasses the blood-brain barrier to target therapeutics directly to the brain," says Frey, an adjunct professor of pharmaceutics. "It also reduces systemic exposure [to therapies] and unwanted side effects."
The Parkinson's work
Parkinson's disease results from a loss of neurons that produce and use the messenger molecule dopamine. In the latest study, Frey and his colleagues treated either the right or the left brain hemisphere of rats with a chemical that destroys dopamine neurons. They thus created brains that mimicked Parkinson's disease in one hemisphere while leaving the other as a control.
They then divided the rats into two groups: one that snorted stem cells from bone marrow of other rats and a control group that snorted buffered saline. Over the next three months, the researchers tested the animals' ability to step with the forepaw controlled by the hemisphere with Parkinson's compared to the other paw.
Starting about 34 days after treatment, the rats given stem cells showed significant improvement—up to about 68 percent of normal function—while those given saline alone showed no improvement or worsened.
Also, in rats that received stem cells, dopamine levels were the same in both the Parkinson's hemisphere and the healthy hemisphere. But in the control animals, which had been treated only with buffered saline, the Parkinson's hemisphere had significantly lower dopamine levels. The stem cell-treated rats also showed a dramatic reduction in the brain inflammation associated with Parkinson's disease.
"Intranasal administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of [cell] transplantation," says Frey. "And unlike the surgical application of cells to the brain, IN delivery can be performed multiple times."
Alzheimer's disease = type III diabetes?
It has been known for many years that patients with Alzheimer's disease (AD) have an impaired ability to remove glucose from the blood and metabolize it in the brain.
This hits the brain especially hard, because unlike other organs, the brain normally gets its energy solely from glucose, rather than from protein or fat.
Several studies have shown that the brains of AD patients have a deficiency in both insulin and the ability of insulin to signal brain cells to metabolize glucose. In fact, says Frey, his colleague Suzanne de la Monte of Rhode Island calls AD "type III diabetes."
Insulin delivered via Frey's intranasal method improves memory, attention, and functioning in AD patients, according to work published by Frey and colleagues--notably Suzanne Craft of the University of Washington. And it does so without altering blood levels of insulin or glucose.
Researchers around the world have adopted Frey's IN method. For example, Craft led a study in which adults with AD received twice daily IN insulin treatments over 21 days. Compared to controls, the insulin-treated adults showed significantly improved memory of details in a story read to them, along with improvements in attention and brain function. Clinical trials in Germany have shown that the IN insulin treatment Frey developed also improves memory in normal adults.
"Intranasal insulin is far more than simply a treatment for AD symptoms," adds Frey. When it reaches the brain, "it stimulates the formation of [an enzyme that] is capable of degrading beta amyloid, one of the principal abnormal proteins known to accumulate in the brains of AD patients."
Published in 2011