Issues Related to Intranasal Delivery of Neuropeptides to Temporal Lobe Targets

The nasal cavity is the first line of defense from airborne pathogens yet it has been known since antiquity that the nose and its mucosal lining serves as a locus for drug delivery to the systemic circulation and brain. The intranasal application of tobacco snuff, cocaine, and various hallucinogens and psychotropic agents are well known examples (Doty, 1995). Intranasal delivery of peptides to blood is a more recent accomplishment (Pontiroli, 1998). Delivery of neuropeptides directly to specific CNS loci is just beginning to emerge and timely reviews on this approach have appeared. Advantages of this means of crossing the blood brain barrier include: ease of use, long-term compliance, uninterrupted delivery, ease of dosing and treatment schedules (Baker, 1995; Mathison et al.,1998; Agarwal and Mishra, 1999; Thome et al.,1995; Ilium, 2000). However, several transolfactory barriers exist. Solutes entering the nasal cavity are destined for three regions: 1) vestibular; 2) respiratory and 3) olfactory. The olfactory region is the most functionally important site for direct access to the brain. Three major barriers to neuropeptide bioavailability exist in this region: 1) presence of tight junctions between sensory and supporting cells, preventing epithelial transport to the submucous space; 2) a mucous layer containing protective proteolytic/hydrolytic enzymes that impart an enzymatic barrier to nasally administered drugs and peptides and; 3) mucous layer clearance that influences time-dependent neuropeptide absorptive (uptake) availability. Following olfactory neuronal uptake, neuropeptides are susceptible to further degradation as they are carried by axonal transport and following synapses of the olfactory tract to primary CNS targets; namely amygdala, hippocampus, piriform, and entorhinal cortices. Sufficient sustained neuropeptide release at these targets is necessary for a pharmacological effect. We reported previously that site-specific delivery of the neuropeptide Thyrotropin-releasing hormone fabricated as polyanhydride microdisks can attenuate kindled epileptogenesis indicating that it is likely carried to sites in the brain where it affects local excitability (Kubek et al.,1998). We suggest that intranasal application of surfaceeroding TRH-polyanhydride microstructures would enhance: 1) olfactory nerve uptake; 2) transneuronal transport and transfer; and 3) site-specific release of TRH in temporal lobe targets for the treatment of certain neurodegenerative disorders. In addition to its clinical importance, TRH is the smallest neuropeptide to date, and would serve as a prototype peptide in further understanding this delivery pathway.