The nasal pathway for drug delivery to the central nervous system: Studies with protein tracers and therapeutics

This thesis investigated the transport of protein tracers and therapeutics into the CNS following intranasal administration. We hypothesized that transport within or along olfactory sensory neurons or other neuronal elements located within the nasal passages would allow an effective circumvention of the blood-brain barrier.; The capacity for uptake and transport of select tracer proteins along olfactory sensory neurons was first determined in anesthetized rats following intranasal administration. The 62 kDa tracer wheat germ agglutinin-horseradish peroxidase was transported into the CNS where it concentrated in the olfactory nerve and glomerular layers of the olfactory bulb resulting in a mean olfactory bulb concentration of 140 ± 14 nM.; The CNS delivery of insulin-like growth factor-1 (IGF-1), a 7.65 kDa protein neurotrophic factor, was then demonstrated in anesthetized rats following intranasal administration. IGF-1 appeared to utilize two routes of rapid (<30 minutes) entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages and olfactory bulb/rostral brain regions (olfactory bulb, 5.0 ± 0.96 nM) and the other associated with the peripheral trigeminal system (trigeminal nerve, 170 ± 61 nM) connecting the nasal passages and brain stem/spinal cord regions (cervical spinal cord, 3.0 ± 1.2 nM). Enhanced tyrosine phosphorylation of IGF-1 signaling proteins was also demonstrated in IGF-1 treated animals as compared with controls, providing evidence that IGF-1 reached the CNS in a biologically active form.; Finally, the CNS delivery of interferon-β1b, a 20 kDa protein cytokine was demonstrated in anesthetized cynomolgus monkeys following intranasal administration. The distribution observed within the CNS was again consistent with two routes of rapid (<60 minutes) entry from the nasal passages, with highest levels observed in the olfactory bulbs (17 ± 2.1 nM) and the trigeminal nerves (16 ± 2.2 nM). Other CNS concentrations ranged from approximately 100–300 pM, with highest levels observed in components of the basal ganglia.; The results presented in this thesis demonstrate the existence of a rapid, extracellular pathway connecting the nasal passages with the CNS and suggest intranasal administration of protein drugs may offer a viable, noninvasive CNS drug delivery strategy.