Perivascular and perineural pathways involved in brain delivery and distribution of drugs after intranasal administration

One of the most challenging aspects of treating disorders of the central nervous system (CNS) is the efficient delivery of drugs to their targets within the brain. Only a small fraction of drugs is able to cross the blood–brain barrier (BBB) under physiological conditions, and this observation has prompted investigation into the routes of administration that may potentially bypass the BBB and deliver drugs directly to the CNS. One such route is the intranasal (IN) route. Increasing evidence has suggested that intranasally-administered drugs are able to bypass the BBB and access the brain through anatomical pathways connecting the nasal cavity to the CNS. Though the exact mechanisms regulating the delivery of therapeutics following IN administration are not fully understood, current evidence suggests that the perineural and perivascular spaces of the olfactory and trigeminal nerves are involved in brain delivery and cerebral perivascular spaces are involved in widespread brain distribution. Here, we review evidence for these delivery and distribution pathways, and we address questions that should be resolved in order to optimize the IN route of administration as a viable strategy to treat CNS disease states.