Paper Tools Add to my Library Share How would you like to share? Facebook Twitter LinkedIn Back to the Top Alzforum Recommends
This is a well-written and very exciting paper. Born and colleagues eloquently report on the intranasal administration in human subjects of three peptides, melanocortin (4-10), vasopressin and insulin, demonstrating direct access to the cerebrospinal fluid compartment, bypassing the bloodstream. Elucidation of the CNS function of many peptides is hampered after intravenous administration by both the presence of the blood-brain barrier, which prevents or limits access to brain receptors, as well as their rapid clearance.
More recently, intranasal administration has provided a route that circumvents the blood-brain barrier, the high metabolic enzyme concentrations in plasma, and eliminates the potent peripheral hormone-like side effects of circulating peptides in the blood. How well such peptides pass ultimately to more interior brain regions is not well documented. However, Chen and colleagues (1) report on the presence of human recombinant NGF in the amygdala following intranasal delivery in rodents.
Presumably, if large molecular weight peptides, such as NGF (118 amino acids), can pass through the intraparenchymal tissue to the amygdala, then smaller molecular weight peptides, such as insulin (51 amino acids), or glucagon-like peptide-1- (7-36)-amide (30 amino acids) will likely travel further into the brain parenchyma. However, diffusion distances in man are far greater than in rodents, and in comparing rodent and human data it is important to consider that the olfactory region of the rat covers a large part of the nasal mucosa whereas, in humans, the olfactory epithelium covers only a small area in the roof of the nasal cavity. Hence it is likely that the olfactory transport of drugs will be much more pronounced in rats than in humans.
As the authors demonstrate, intranasal administration can deliver neuropeptides to the brain without uptake into the circulation. This holds great promise for those of us involved in the development of peptides, such as GLP-1, for the treatment of CNS disorders. GLP-1 and its longer-acting analogue, exendin-4, produce powerful effects on blood glucose levels by stimulating insulin secretion. These effects therefore limit their systemic administration to amounts too small to have substantial biological effects in the brain. Their development currently relies on direct approach to the CNS, which sidesteps their rapid metabolism following oral or intravenous administration.
As nasal delivery systems for peptide administration move towards clinical trials for the treatment of brain diseases, peptide drug targets will undoubtedly increase in popularity.
Chen XQ, Fawcett JR, Rahman YE, Ala TA, Frey Ii WH. Delivery of Nerve Growth Factor to the Brain via the Olfactory Pathway. J Alzheimers Dis. 1998 Mar;1(1):35-44. PubMed.View all comments by TracyAnn Perry