NOSE-TO-BRAIN DIRECT

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A guest post from Dr Frederick Gay, School of Life Sciences at the University of Essex, Colchester.

“There- is- an- underground passage,”,said the Badger impressively,”that leads from the riverbank, quite near here, right up into the middle of Toad Hall.” O nonsence! said Toad rather airily, “You’ve been listening to some of the yarns they spin in the public houses about here.”

Kenneth Grahame. ‘The Wind in the Willows’.

Drug treatments delivered, nose to brain direct. 

Believe it or not, if you are on a DMT for MS you may have the option of becoming a ‘sniffer’ in a few years time. Let me relate what has been happening in the science of drug delivery to the brain. First of all, it will be useful to look at a little basic anatomy. 

Running behind your nostrils there are deep dark wet caves known as the maxillary, frontal, ethmoidal, and sphenoidal sinuses. (Each gets its name from the bone in which it is located).  The inner wall of each of the sinuses is lined with a thin mucous membrane which traps and sweeps out much of the general debris that we inhale from the environment.  

The sinus mucosa has also to cope with the viral and bacterial upper respiratory infections that we all regularly experience, especially in the colder months of the year. 

 The sinuses are the permanent home of a usually benign ‘flora’ of bacterial species which only overgrow and cause trouble when the mucosa is irritated. This can happen when for example,  the membrane is infected by viruses, or when it is exposed to smoke, volatile solvents, or even just excessively cold air. 

 Remarkably, the sinus mucous membrane is the only external structure of the body that is in direct contact with the brain.  

This provides us with smell through the ‘olfactory’ nerves that run directly from the mucous membrane up into the brain through small holes in the skull.  Any ‘substance sniffer’ can tell you that it only takes a few seconds to get a ‘high’! Access to the brain via the olfactory nerve is both fast and efficient.

 Many of the therapeutic drugs that we would like to get into the brain when given orally or by injection are kept out by the ‘blood-brain barrier’. 

You can now see from the anatomy of the nose what could be a simple and rather obvious solution to this problem. Place the drug on the mucous membrane and allow the olfactory nerves to deliver it directly to the brain.  

This may seem rather too simple to be true. 

However, in recent years researchers have discovered that a remarkable variety of molecules including drugs that are normally kept out by the blood-brain barrier, when deposited on the mucous membrane of the nose, do indeed go directly into the brain. 

The olfactory nerve is one direct route to the brain, but not the only one.  The fifth cranial nerve, (the ‘trigeminal’) which transmits sensations from all of the nasal structures to the brain, has been shown to carry substances back into the brain stem after they have been deposited in the maxillary sinus.

 A third route has now been recognized. This is located where the mucosa of the deep ethmoidal and sphenoidal sinuses lies on an exceptionally thin porous bone. Here the mucosa may lie so close to the coverings of the optic nerve tract, that leakage from one to the other would appear to be inevitable.

In the treatment of MS, you can easily imagine the advantages of accessing the brain by nose-to-brain routes.  Ease of administration, patient compliance, rapid and targeted safe delivery, to name but a few. And no injections.

But, does it work in clinical practice?  

Recent trials of nose-to-brain, with different medications and in a variety of conditions, including MS, have been promising. 

You can find a full and fascinating account of the current state of play in a 2018 review, which is referenced below. [1].

Another reference of special interest for MSers is an EU funded research project which started in January 2017, known appropriately as the “N2B-patch. [2]. This aims to develop a carrier biodegradable polymer, which can be conveniently placed strategically in the nose. This will deliver the desired slow-release pharmaceutical ingredient directly into the brain via the olfactory nerve channels.

 Direct Routes from nose to brain are available, but isn’t this dangerous?

Direct access to the centre of the brain from outside structures, that are notoriously susceptible to infections- shouldn’t we anticipate a problem?   

The microbes that live in the mucosal tissues and those that we pick up from time to time, secure their position by releasing cocktails of toxic molecules. These both confuse the immune system and ensure, by penetration, a bacterial foothold in the mucosa. Many are also damaging to cells, including those of the central nervous system. The bacterial nasal toxins can be released into the mucosa in biologically speaking, very large amounts, and especially when the mucosa is inflamed by the environmental irritations that I mentioned above.   

What is there to prevent these undesirables from sneaking into the brain by the nose to brain routes?   Are they simply dispersed without consequence?   

If they do access the brain directly by these routes could they be implicated in the degenerative and inflammatory processes which are found in the brain in multiple sclerosis?

Is MS caused by bacterial toxins from the nasal mucosa?

I first asked myself this question thirty years ago. I was at that time continuing my laboratory microbiological and pathological career.  I decided to leave the laboratory and completely change direction. I should explain.

 During my early career in microbiology, Polio, which was a major interest in my training laboratories, had been defeated. 

In the lab from time to time, we now turned our imaginations to the problem of MS, ‘the next paralyzing disease of young adults to be defeated’. 

MS was one of the first medical conditions to be distinctly identified as a specific recognizable disease.  Over more than 150 years of research, there had accumulated so much fascinating data with which to work. Surely it would be possible with some informed imagination to guess the likely cause.

The strange geographical distribution, the increased incidence associated with higher latitudes, the distinctive age range, the increased incidence in families, the patterns of relapse, remission and progression, the oligoclonal bands in CSF, the strange perivascular ‘plaques’ in the brain etc, etc. 

We knew that nearly all of these could be matched by other diseases, but taken together they formed a unique pattern.  

A unique pattern must surely have a unique cause.  

However, the ‘natural history’ of tigers may only be discovered by studies in the jungle and certainly not in the Zoo. MS does not develop and progress in our laboratories and neurology clinics. It occurs out in the real world of human families and communities. 

So I left the laboratories and became a general practitioner.

What I and a few colleagues found using a study of the NHS records of our MS patients, was published in the Lancet in 1987 [2]. 

Our MS patients lifetime records showed that sinusitis had been recorded significantly more frequently than their matched controls. What was even more interesting was that their sinus infections closely and significantly resembled MS. They occurred at the same age, they peaked at the same season, and both MS and sinusitis were activated by various environmental insults including viral infections, smoking, solvent inhalation and wind-chill cold. 

Despite some serious and well-meaning skepticism from general practitioners, ENT specialists, epidemiologists and neurological aficionados, I could not ignore what seemed to be an important clue to the enigma of MS.  

What was particularly interesting was that nearly all of these observations had been made before. They had individually been published in the literature, but they had escaped serious notice.  

I now argued that if bacterial toxins were responsible for the link between MS and sinus infections, these bacterial products should be detectible in the brain at the ‘scene of the crime’, and most likely in the very early stages of the disease. 

This is not the place to relate how I managed to get back into the laboratories and to obtain early MS brain tissues for study. Suffice it to say that it took years and the help of generous colleagues. Some of these appear with me on the publications that resulted from these studies. I have listed these below, for they tell their own story.

‘Bacterial toxins and multiple sclerosis’ [3] relates the numerous observations and insights linking nasal infections to optic neuritis and MS. Remarkably the link was first recorded 1000 years ago by the Persian ophthalmologist Ali ibn Issa. 

I first realized the potential pathological significance of the work of the clinical pharmacologists in discovering and exploiting nose to brain routes in a 2012 paper, ‘Nose to Brain. Is the trigeminal nerve a conduit for CNS disease? [4]. 

The Identification of the earliest signs of damage in MS tissues, in clinically early cases [5,6] revealed that damaging events were afoot even before the breakdown of the blood-brain barrier and the invasion of inflammatory and immune cells from the blood. What were the scavenger cells of the brain reacting to at this early stage?  Some toxic insult had accessed the brain by a route other than the blood, and now Barnett and Prineas in Australia, [7] were asking the same question after their explorations into similar early cases.

 The identification in these early lesions of a specific bacterial toxin [8] with the potential to initiate both inflammatory and neurotoxic degeneration and to deviate the immune response from a location deep within the brain, completed the picture.

So where have we got to and what does it all mean? The latest review [9] makes the case for serious further investigations, and in suggesting what these might involve, concludes,

‘If these direct nose to brain findings are confirmed it would undoubtedly open up an almost entirely new range of investigations and approaches to the diagnosis, treatment, and prevention of MS. 

‘A consummation devoutly to be wished’

[1] . Bourganis.  V, Kammona O, Alexopoulos A, Kiparissides C. Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics. European Journal of Pharmaceutics and Biopharmaceutics. Volume 128, July 2018, 337-362 

[2]. Gay D, Dick G, Upton G. Multiple sclerosis associated with sinusitis: case controlled study in general practice. Lancet 1986;1:815-9

[3]. Gay F. Bacterial toxins and multiple sclerosis. Journal of the neurological sciences 2007;262:105-12.

[4]. Gay F. Nose to Brain. Is the trigeminal nerve a conduit for CNS disease?  Multiple Sclerosis and Related Disorders. 2012;4:154-5.

[5]. Gay F, Drye T, Dick G, Esiri M. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 1997;120:1461-83. 

[6]. Gay F. Early cellular events in multiple sclerosis. Intimations of an extrinsic myelinolytic antigen. Clinical Neurology and Neurosurgery 2006;108:324-40.

[7] Barnett J, Prineas J. Relapsing and remitting multiple sclerosis pathology of the newly forming lesion. Annals of Neurology 2004;55:458-68.

 [8] Gay F. Staphylococcal immune complexes and myelinolytic toxin in early acute multiple sclerosis lesions. An immunohistological study supported by multifactorial cluster analysis and antigen-imprint isoelectric focusing. Multiple Sclerosis and related Disorders 2013;2:213-232.

[9] Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose to brain direct. Rev Neurologique (Paris). 2019. Oct 16.

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9 comments

    • Most of the evidence points to vitamin d/ sunlight/latitude avoiding MS not curing it. This is probably because it prevents some triggering event. Vitamin d shortage affects/modifies the behavior of the whole immune system so it is as applicable here as any other theory involving the immune system.

      I think it is likely that as vitamin d levels drop some uses by the immune system turn off so as to conserve vitamin d through the winter. This is because incorrectly controlled blood calcium levels (rickets in children) will kill faster than an immune problem. For those who evolved away from the equator this is an evolutionary advantage, like pale skin. If this is true it means that what counts as a sufficient vitamin d level will vary from person to person. Also some people may have higher blood vitamin d levels, 25(OH)D, not because of greater intake but because they are less able to use it for anything but calcium control. So comparing blood 25(OH)D levels against outcomes may not work.

  • MD2 has experience of this nose to the brain route. The question is once up the nose then where. Can enough be delivered this way?

    • Exactly: nose, mouth, vein…. then what? More of the same thing. The real cause of ms needs to be found. Otherwise more time waste.

    • Exactly MD, as usual you hit the nail on the head. The pharma people who are developing nose to brain delivery systems are working to deliver the best molecule, in an appropriate quantity, with slow release at a key anatomical location, and are making progress with this. pathologically, i believe the localised sub mucosal location of particular bacterial strains notorious for high output when stimulated by local factors, may achieve nose to brain in a ‘pathological way. Staph aureus strains warrant particular attention in this regard. An animal model might well interest you? (!!!).

  • If ms is cause by Ebv how could nasal mucosa be infected by Ebv (thought that ebv infect tonsils)

    And all the great efficacy drug (Alemtuzumab,ocrelizumab,etc) how do you dilliver them thru the nose

    Obrigado

  • Fascinating
    Thank you for your interest in MS and for your years of work

    Still, all this makes things even more confusing, because the number of hypothetical causes keeps increasing

    Could it be that MS as a condition can have different causes in different people?
    And that once MS starts, it follows its own process? Perhaps the original trigger is no longer irrelevant

    The propensity for MS must be genetic, along with a propensity for autoimmune diseases in general, as these diseases seem to run in families. At the individual level it may be a matter of luck or environment – what hits you, what disease you develop, what environment you live in, …

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