It is understandable that this article does not mention direct intranasal delivery of therapies to the CNS, since it would, by comparison, make invasive delivery look somewhat less appealing. There is an entire literature about the use of noninvasive direct delivery of therapeutics from the nose to the brain (see, e.g., Lochhead et al., 2011, and Dhuria et al., 2010).

In 2012, the NIH selected intranasal insulin as a promising treatment for Alzheimer's disease and committed millions in funding to further test it nationally in additional Phase 2 clinical trials. I first developed (and patented) the non-invasive intranasal method for bypassing the blood-brain barrier to target therapeutics (including insulin) to the brain to treat neurodegenerative disorders such as Alzheimer's disease and stroke, and later expanded the specific use of intranasal insulin to target the brain to treat Alzheimer's disease and other CNS disorders. Even though these patents have now expired, interest in the intranasal insulin treatment continues to grow.

In 2004, Benedict et al. demonstrated...  Read more

It is understandable that this article does not mention direct intranasal delivery of therapies to the CNS, since it would, by comparison, make invasive delivery look somewhat less appealing. There is an entire literature about the use of noninvasive direct delivery of therapeutics from the nose to the brain (see, e.g., Lochhead et al., 2011, and Dhuria et al., 2010).

In 2012, the NIH selected intranasal insulin as a promising treatment for Alzheimer's disease and committed millions in funding to further test it nationally in additional Phase 2 clinical trials. I first developed (and patented) the non-invasive intranasal method for bypassing the blood-brain barrier to target therapeutics (including insulin) to the brain to treat neurodegenerative disorders such as Alzheimer's disease and stroke, and later expanded the specific use of intranasal insulin to target the brain to treat Alzheimer's disease and other CNS disorders. Even though these patents have now expired, interest in the intranasal insulin treatment continues to grow.

In 2004, Benedict et al. demonstrated that this intranasal insulin treatment improves memory in healthy adults in Germany with no change in the blood levels of insulin or glucose. Over the next several years, researchers in Germany conducted multiple human clinical trials showing that intranasal insulin treatment improves memory in normal healthy adults.

Some years ago, I approached Dr. Suzanne Craft at the University of Washington and Veterans Affairs Medical Center in Seattle about my intranasal insulin treatment, and encouraged her to conduct a clinical trial in Alzheimer's patients. In 2006, Craft and colleagues (of which I was one) reported that intranasal insulin improved memory only 20 minutes after a single intranasal insulin treatment in patients with Alzheimer's disease. In 2008, Craft and colleagues showed that intranasal insulin (b.i.d.) improved memory, attention, and functioning in Alzheimer's disease (AD) patients over a 21-day period, and in September of 2011, Craft and coworkers reported improved memory and general cognition, and brain fluorodeoxyglucose uptake in patients with AD or amnestic mild cognitive impairment treated in a four-month clinical trial. The patients had no change in blood levels of insulin or glucose.

It is not surprising that intranasal insulin is an effective treatment for AD, since it has been known for many years that glucose uptake and utilization is dramatically decreased in patients with AD, based in part on the early work of Mony de Leon at New York University. Glucose is the only source of energy normally used by brain cells, except under unusual conditions such as starvation, and the brain cells of AD patients are starved for energy. Eric Steen, Suzanne de la Monte, and colleagues reported in 2005 that Alzheimer's disease involves insulin and IGF-I deficiency and insulin/IGF-I signaling deficits in the brain. Siegfried Hoyer first suggested that Alzheimer’s was a brain type of diabetes, and de la Monte has more recently referred to Alzheimer's as a type 3 diabetes. We also know that type 2 diabetes is a major risk factor for developing Alzheimer's disease. Intranasal insulin may potentially reduce the risk of individuals with diabetes from developing Alzheimer's disease and help prevent or delay the onset of the disease.

Intranasal insulin is far more than simply a treatment for AD symptoms. When intranasal insulin reaches the brain, it stimulates the formation of insulin degrading enzyme (IDE), which is capable of degrading β amyloid, one of the principal abnormal proteins known to accumulate in the brains of AD patients. Further, the activity of glycogen-synthase kinase-3β, the enzyme that phosphorylates tau to create AD neurofibrillary tangles, has been reported to be downregulated in response to insulin. Finally, insulin receptor signaling increases synaptic density, and loss of synapses is key to the neuropathology of AD. Research shows that insulin signaling deficit precedes Aβ42 accumulation in a transgenic mouse model. Along with Benedict and colleagues, I have reviewed intranasal insulin as a therapeutic option in the treatment of cognitive impairment.

References:
Lochhead JJ, Thorne RG. Intranasal Delivery of Biologics to the Central Nervous System. Adv Drug Deliv Rev. 2011 Nov 15. Abstract

Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal Delivery to the Central Nervous System: Mechanisms and Experimental Considerations. J Pharm Sci. April 2010; Volume 99(4):1654-73. Abstract

Schiöth HB, Craft S, Brooks SJ, Frey WH, Benedict C. Brain insulin signaling and Alzheimer's disease: current evidence and future directions. Mol Neurobiol. 2012 Aug;46(1):4-10. Abstract

Jogani V, Jinturkar K, Vyas T, Misra A (2008) Recent patents review on intranasal administration for CNS drug delivery. Recent Pat Drug Deliv Formul 2(1):25-40. Abstract

Danielyan L, Schäfer R, von Ameln-Mayerhofer A, Bernhard F, Verleysdonk S, Buadze M, Lourhmati A, Klopfer T, Schaumann F, Schmid B, Koehle C, Proksch B, Weissert R, Reichardt HM, van den Brandt J, Buniatian GH, Schwab M, Gleiter CH, Frey WH. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res. 2011 Feb;14(1):3-16. Abstract

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