Accessing the Brain: The Nose may Know the Way

It was with great interest we read the recent review titled ‘Drug transport across the blood-brain-barrier’ . ¹ In this paper, Pardridge describes the challenge of bypassing the blood–brain barrier (BBB) to allow therapeutic molecules to access the central nervous system (CNS), a challenge long recognized as one of the major issues in developing new treatments for brain disorders. The paper focused on how molecules can be reengineered for BBB transport via carrier-mediated transport and molecular ‘Trojan horse’ delivery to access receptor-mediated transfer systems within the BBB, an interesting and exciting approach to this problem.

Although discussed only briefly in the review, the potential for transnasal delivery of drugs into the CNS is also an interesting, and in some instances possibly a quicker and easier approach to implement and overcome this development challenge. We believe the research supporting transnasal delivery into the CNS and thereby bypassing the BBB requires further discussion and clarification of the points raised in the review.

The review article refers to a paper from 1971 stating that the close connection between the olfactory bulb and the cerebrospinal fluid (CSF) offers a potential route for nasally delivered drugs to the CSF, provided the drug is able to cross the nasal epithelium and the arachnoid membrane. ² While nose-to-CSF transport has been shown in animals and even in humans, this is not the only and certainly not the most important or promising, transport route into the CNS via the nose.^3–5 A recent research paper and two review papers on the method of transport and the animal studies conducted conclude that both small and large molecules can pass rapidly from the nose into the brain along olfactory nerves and into the brain and brain stem along branches of the first and second trigeminal nerve structures, without primarily passing via the CSF.^3–5

In animals, transport along the olfactory and trigeminal nerves has been shown to occur within minutes through channels created by ensheathing cells, rather than simply by slow axonal transport or diffusion.^3,4 Recent data showed that peptides administered intranasally were directly transported and distributed within the brain parenchyma fairly rapidly (within 5 minutes). As pointed out by the authors, simple diffusion within the brain parenchyma would be too slow to explain the broad distribution to all brain regions observed. ⁵ One interesting hypothetical mechanism for the observed speed with which a broad distribution within the brain is achieved, is bulk flow in the interstitial fluid ‘powered’ by the ‘perivascular pump’ mechanism naturally produced by arterial pulsation and blood pressure.^5,6

It was suggested in the review that local injury to the nasal epithelial barriers was required for large molecules or water soluble molecules to penetrate into the CSF. It was further suggested that such injury is induced by instillation of volumes larger than 100 μL per nares in humans and refers to a paper from 2003. ⁷ However, the reference in question does not describe mucosal injury, but states that the ‘nasal passage cannot accommodate more than 100 μL’ . Larger volumes, in and of themselves, do not pose a risk of injury, though they are inconvenient and suboptimal for drug delivery. Large volumes do, however, contribute to loss of a significant portion of the liquid simply due to dripping out of the nose (or to being swallowed) as a result of the limited volume of the nasal cavity. In fact, a key challenge surrounding use of standard nasal sprays for ‘nose to brain’ applications relates to poor distribution deep into the nasal cavity, including excessive anterior deposition, after delivery. ⁸ Provided that the formulation itself does not cause irritation, the nose can safely tolerate large volumes. In fact, nasal irrigation with deciliters of saline with or without drugs is recommended as treatment for local inflammatory conditions and injured mucosal membranes in the nose, and has been shown to have positive treatment effects. ⁹

The difference between humans and animals with regard to the relative extent of the olfactory region is an important factor when attempting to translate the effects observed in experiments with animals to what can be anticipated in humans. It is clear that the relative size of the olfactory region in humans is considerably smaller than in animals. However, recent anatomic studies show that the olfactory region in humans extends 1 to 2 cm more anterior and inferior than the 8 to 10 millimeters cited in most text books, suggesting that surface area available to transport drugs along the olfactory nerve is larger than previously thought. ¹⁰ Furthermore, it is a common misconception that nose to brain transport can only occur along the olfactory nerve. As described above, evidence suggests that transport can also occur along the trigeminal nerves innervating much of the nasal respiratory mucosa in the anatomic regions beyond the nasal valve.^3–5,8

Although direct evidence for nose to brain delivery in humans is still an emerging area of investigation, due in part to ethical and methodological challenges, several studies assessing nasal delivery with neuropeptides such as insulin and oxytocin strongly suggest the existence of an active pathway in humans.^3,4 Due to inadequate delivery of formulation to deep target sites beyond the nasal valve with traditional nasal delivery devices such as nasal sprays, the full potential of direct nose to brain delivery has probably not yet been realized, and may be a simple solution that has an important and complimentary role alongside efforts to engineer molecules for carrier-mediated transport or ‘Trojan horse’ delivery. ⁸