“We’ve shown that intranasal deferoxamine protects dopamine brain cells and improves movement in animals with Parkinson’s disease… We’ve shown that just a few nose drops of deferoxamine given before or after a stroke reduce brain damage in rats by 55%. We’ve shown that even in normal mice, it improves memory when given intranasally. And it also improves or reduces memory loss in Alzheimer transgenic mice.”
Alzheimer’s Disease
Fludeoxyglucose (18F) PET scans reveal adequate uptake and utilization of glucose, the main energy source for brain cells, in the brains of healthy elderly controls. But the brains of patients with Alzheimer’s disease do not take up glucose normally, and their brain cells consequently have less energy. “A number of areas of the brain require insulin to take up glucose, and the hippocampus is one of those areas,” Dr. Frey explained. “Insulin signaling is reduced in the brains of patients with Alzheimer’s disease, causing what some have called type 3 diabetes, or diabetes of the brain, which leaves these brain cells starved for energy and not able to function normally.”
Dr. Frey obtained several patents on the direct intranasal delivery of therapeutics, including insulin, to the brain, and various clinical trials have been conducted. “Four trials in patients with Alzheimer’s disease and five trials in normal, healthy adults have demonstrated improved memory following intranasal insulin treatment, with no change in the blood levels of insulin or glucose,” Dr. Frey reported.
In one of the first trials, a single intranasal insulin treatment improved verbal memory for individuals with Alzheimer’s disease within 15 minutes. In a three-week trial, intranasal insulin enhanced memory, compared with placebo, and significantly improved attention and functional status in patients with Alzheimer’s disease. However, patients who carried the APOE ε4 gene allele were not improved with intranasal regular insulin. “Only long-acting insulin detemir, given intranasally, has been shown to improve memory in patients who have the APOE ε4 gene allele,”Dr. Frey said.
The longest completed trial lasted for four months and showed improved memory and function in patients who were given insulin twice per day in a nasal spray. It also showed that the treatment reduced the loss of glucose uptake and utilization in key brain regions, as seen in PET scans. A new six-month treatment trial is now underway at the HealthPartners Center for Memory & Aging in St. Paul.
Mechanism of Action
One open question is whether intranasal insulin only provides symptomatic treatment (ie, improved memory and functioning in patients with Alzheimer’s disease) or also has the potential to change the underlying disease process. “We know it can provide energy to prevent brain cells from degenerating and allow the cells to produce materials to replace worn-out parts,” said Dr. Frey. “That result has been shown in humans using P-31 MRI. After administration of intranasal insulin, levels of brain cell adenosine triphosphate (ATP) and brain cell phosphocreatine increase significantly. We know that insulin, after it causes signaling, and glucose uptake occurs, causes the production of insulin-degrading enzyme to reduce the insulin signal so that the next time the signal comes in, it can be easily detected. That turns out to be the enzyme that degrades beta amyloid, which accumulates abnormally in the brains of individuals with Alzheimer disease. So, if you don’t have insulin signaling, you don’t make insulin-degrading enzyme, and you accumulate beta amyloid. Insulin also inhibits glycogen synthase kinase 3 beta that phosphorylates tau to form Alzheimer neurofibrillary tangles. Insulin is also needed to maintain synaptic density, so it is possible that if humans were given intranasal insulin at the first sign of an insulin-signaling deficiency or a decrease in glucose uptake in the brain, it might be possible to delay, or maybe even prevent, the onset of this disease,” Dr. Frey said.
Stem Cells
Dr. Frey and research collaborators in Germany, including Lusine Danielyan MD, discovered and patented that intranasal stem cells bypass the blood–brain barrier to reach the brain and treat Parkinson’s disease in rats. Adult bone marrow–derived stem cells have anti-inflammatory and neurotrophic properties. “After cell treatment, the proinflammatory cytokines in this inflammatory brain disease go down to normal levels. Our study showed highly significant improvement, compared with placebo, in motor function or movement,” Dr. Frey said.
Researchers in the Netherlands demonstrated that intranasal adult stem cells treat neonatal ischemia and neonatal brain damage. Other researchers at Emory University reported treatment of stroke with adult stem cells from bone marrow. Swedish researchers reported that intranasal Treg cells treat multiple sclerosis (MS). “These studies are all in animals,” Dr. Frey noted. Other researchers reported that neuronal stem cells induce recovery and remyelination in an animal model of MS. Brain tumors have also been treated in animals with intranasal stem cells. Recently, intranasal stem cell therapy was also reported to improve motor function and reduce lesion size in spinal cord injury in animals. “Noninvasive intranasal delivery can target therapeutics to the brain while reducing systemic exposure to facilitate the treatment of brain disorders,” said Dr. Frey.