Intranasal treatment of central nervous system dysfunction in humans

Abstract

One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.

Fig. 1

A scheme illustrating the mechanism of nose-to-brain delivery. Unlike the olfactory nerve which terminates in the olfactory bulb, the trigeminal nerve enters the brain through both the pons and the cribriform plate, which allows for drug delivery to both the anterior and posterior regions of the brain (9,12). Transport of substances along the olfactory and trigeminal nerve pathways can happen through both intracellular and extracellular mechanisms (9). However, intracellular transport is a slow process, requiring at best several hours and at worst several days (17,20). Extracellular transport, on the other hand, is rapid and likely accounts for much of the rapid delivery and onset of action observed with intranasal CNS therapeutics (8,21). Abbreviations: ECS, extracellular space.