Mechanism of intranasal drug delivery directly to the brain

Neurological diseases are becoming increasingly prominent worldwide due to rapidly aging populations, which greatly contributes to increasing healthcare costs. The development of neuroprotective drugs has so far proven exceptionally difficult due to the blood-brain barrier. One novel approach to address this challenge is to administer drugs intranasally to noninvasively bypass the blood-brain barrier. The intranasal route can thus transport drugs directly to the brain from the nasal cavity along the olfactory and trigeminal nerves. The purpose of this review is to describe the details of this mechanism to better direct future research. The intranasal route is composed of two pathways, one being intracellular while the other being extracellular. The intracellular pathway begins with endocytosis by olfactory sensory cells, followed by axonal transport to their synaptic clefts in the olfactory bulb where the drug is exocytosed. This transynaptic process is repeated by olfactory neurons, thereby distributing the drug to other brain regions. In the extracellular mechanism, drugs are transported directly into the cerebral spinal fluid by first passing through the paracellular space across the nasal epithelium, then through the perineural space to the subarachnoid space of the brain. With a growing body of evidence and trials in both rodent and human models, this is an exciting area for research as therapeutics come to market.