The Blood Brain Barrier (BBB) is a main focus of Multiple Sclerosis research.  There are currently two main directions for that research:

  • Control of the entry into  the brain of the immune system T-cell crossing through the impaired BBB

  • Sending drugs into the brain directly by overriding the BBB

An article in the Neurology Research Journal [1] is exploring the first approach: Reinstating the BBB  integrity:

In Relapsing Remitting MS (RRMS),  T-cells attack neurons in the brain and spinal cord causing lesions visible using Magnetic Resonance Imaging  (MRI) Techniques.

Blocking the passage of  T-Cells from the blood capillaries to the brain neurons is a research avenue discussed in an article published in Neurological Research [1].   The article proposes to block the attack not by killing or disabling the  rogue T-Cells, but keeping them at bay. Tall order!

But why do the immune system’s T-cells  attack the brain’neurons connectors (axons), and where are they  coming from?

MS attacks involve an inflammation of the brain’s blood vessels [1]. The brain’s blood is irrigated by a complex network of capillaries branching off the larger arteries as shown in the sketches of Fig.(1).  But  brain capillaries that are branching off the main arteries have a wall structure that filters cells and  nutrients coming  into the brain. That wall structure, as mentioned, is called the Blood Brain Barrier (BBB).

More precisely, in the words of Wikipedia:

“Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria) while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones).  Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.”

Fig. (2) shows a  brain capillary cross section sketch from Carnegie Mellon Univ. and Thomas P. Davis, U. of Az.

Fig (1-a) The Brain and its Carotid Arteries (ADAM, Medline)

Fig (1-b) Brain Carotid Arteries Front (Adam, Medline)

Capillary in Within Brain (Thomas P. Davis, U. Arizona)

So, what happens during an MS attack?

During an MS inflammation attack, white blood cells called T-lymphocytes cross over to the brain or spinal cord, because of a breakdown of the BBB.  The T-lymphocytes then attack the myelin sheath  of the axons connecting the neurons. Look at Figs (3) and (4) to visualize the neuron systems.

Fig (3) Neuron-Axon-Myelin                             Wikipedia Commons Sketch

Fig (4) Neuron-Axon Photo by Scholarpedia by E. M. Izhikevich

Note that MS can cause lesions in the spinal cord too. There is also a Blood Spinal Cord Barrier. According to [2],  the Blood Spinal Cord Barrier (BSCB) has similarities and differences with the BBB.

This is the inflammatory, many say auto-immune, aspect of the disease, most apparent for the Relapsing Remitting phase of MS (RRMS). We will discuss later the relevancy, if any, of this research to people suffering from the Progressive type of MS who are much less subject to attacks, if at all.

If such a cross over of the rogue T-cells could be controlled and contained, that could be a path to a new class of RRMS  treatments.

That is precisely what is discussed in the study published in the  Neurological Research article.  Granted, this approach seems to be at this time little more than a concept, but we are  trying to understand the processes. Actually the idea was already suggested by Jeanne Wallace [3] in 2000!  So the approach still investigates the fundamentals of MS and has not yet produced a therapy to our knowledge.

A  recent activity on this research angle was performed at the Washington U.  [4] and focused on the role played by certain proteins (chemokines)  in the regulation of the passages of the T-Cell leukocytes through the BBB. Such chemokines are located at endothelium thin layer lining the blood vessel inner surface, from wich they direct T-Cell traffic, both during inflammatory or benign homeostatic states.

[Chemokines are signaling proteins molecules that can induce the movement of cells in certain directions. More specifically they can induce the leakage of T-Cell leukocytes through the capillaries at the brain (extravasation)]

An  intriguing part of this approch is that inflammation of the endothelium,  is also present in other illnesses, namely atherosclerosis.

Atherosclerosis is  a disease of the blood vessels of the body as a whole, not just the brain capillaries.  Actually  Jeanne Wallace [3] mentions that high levels of an amino acid called homocysteine in MS , which is usually present in cardiovascular diseases. This connection has been confirmed by other studies [5]. On top of it atherosclerosis can affect blood vessels of large to medium size anywhere in the body, and has  impact on capillaries. But we have not heard that the comparison of these two types of vessel inflammations probably  goes much further.

Another connection between the BBB capillaries inflammation and the large to small whole body blood vessel  inflammation is oxidative stress, which  is thought to have a presence  presence in both types.

Quoting [6] oxidative stress is linked to:

“… atherosclerosis, cancer, diabetics, rheumatoid arthritis, post-ischemic perfusion injury, myocardial infarction, cardiovascular diseases, chronic inflammation, stroke and septic shock, aging and other degenerative diseases in human..”

However, this is not much of a lead, since so many , particularly inflammatory, have oxidation as a part of the disease process

Note that one of the author of [5] is Paolo Zamboni, the guru of  the Chronic Cerebrospinal Venous Insufficiency (CCSVI) MS theory.  In this approach,  MS is caused by poor blood circulation causing iron deposits  in the brain, with subsequent inflammation. This theory is vigorously disputed by many  in the MS neurologist community.

Nevertheless, Dr. Zamboni thinks he has found the source for the brain vessels inflammation and subsequent BBB breakdown. Finding the source of the inflammation should be one of main  goal of MS research.

These considerations about BBB Inflammatory breakdown brought [1] to envision an MS treatment

Quoting them:

“…The manipulation of the endothelial biology aiming to block trans-endothelial migration of activated immune cells into the CNS is a potent form of treatment for MS achieving significant reductions in disease activity and new lesion formation….”

Note that research [13] has shown that statin drugs, help reduce the BBB’s permeability

Fig (5) : Your White Blood Cell (Leukocyte) in the Bloodstream                                                              Electron Microscope Photograph by Bruce Wetzel and Harry Schaefer , NCI

While we are discussing  possible MS treatment application of T-Cell flow control at the BBB, it is important to understand  that  MS presents aspects  that are not just inflammatory, but also neurodegenerative.

The following is based on References (7-11)

A word about the so-called Primary Progressive (PPMS) and Secondary Progressive (SPMS) forms. People with the PPMS might never have been aware of an “attack”, people with SPMS had some initial attacks, but hardly or not at all anymore.

The individual differences have to do with the two known mechanisms of MS:

  • Inflammatory auto-immune disease, where rogue T-Cells attack “innocent cells”, here of the myelin

  • Neuro-Degenerative disease, where the Neuron-Axon-Myelin system loses function and structure.

The inflammatory process is most prevalent in RRMS. However, during the progressive phases, attacks are either not felt or, the role of inflammation decreases and the neuro-degenerative aspect becomes dominant.

However, the more recent studies tend to see inflammation and neurodegeneration working hand in hand, at least in MS. Ref. (8,9,10)

In the conventional approach, the axons connecting the neurons have been damaged by the RRMS inflammation activity, and are now subject to neurodegeneration. In the latter phase, heavily damaged neurons essentially cease to function.

In another approach, inflammation and neurodegeneration are not necessarily back to back, but coexist in the disease [ 4,5]. So theoretically anti-inflammatory medications should work throughout progressive MS too, but the efficacy of RRMS drugs against Progressive MS is limited at best. [6]

So the clamping down on the BBB permeability, as suggested by  [1], could be more applicable to slowing down the RRMS inflammatory attacks than the latter progressive phase.

Actually, current MS drug research has often taken an opposite approach: Delivering drugs across the BBB!

In Refs (14-16), Researchers want to cross the BBB to deliver MS drugs right at the lesion level. We have discussed in [15] the nanotechnology approach to drug delivery across the BBB. Nano particles are extremely small and have a better chance to cross the barrier. This also should mean that viral brain infection should be more common than the bacterial ones. Not always so: the Meningitis bacteria “recruits” or subverts complex electrical polarity at the BBB, to create an opening and pass through…

Be it as it may, nanotechnology has been mostly focused at delivering cancer drugs to brain tumors. MS research seems to lag cancer research here. Except for intranasal delivery of nanoparticle mists. from [15]:

“…Additional ways to bypass the BBB for MS treatments include Intranasal Delivery [9]: “…intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system…” Sounds like going through the backdoor of the brain to me, as opposed to breaking through…Keep in mind that nasal delivery is not as simple as it seems. The OptiNose Company has an interesting video describing a nasal delivery system…

In Summary:   Blood Brain Barrier based treatments mastery is still elusive, and much research needs to be done. A delight for researchers, not so for patients

Sources:

  1. Neurological Research ; “Emerging Roles of Endothelial Cells in Multiple Sclerosis Pathophysiology and Therapy.”; July 2001

  2. Annals of Neurology : “The blood-spinal cord barrier: morphology and clinical implications.” ; 2011

  3. Brewster Science Library;  ”Multiple Sclerosis & the Blood Brain Barrier: A Novel Approach in Integrative Care, Jeanne M. Wallace ; 2010 (reprinted from the Winter 2000/Spring 2001 New Horizons)”

  4. Biochemica et Biophisica Acta ; “The blood-brain barrier, chemokines and multiple sclerosis.” ; 2011

  5. Journal of Neurology, Neurosurgery and Psychiatry; “Plasma homocysteine levels in multiple sclerosis.” ; 2006

  6. Current Pharmacology ; “Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options” ; 2009

  7. Annual Reviews ; “Multiple Sclerosis: An Immune or Neurodegenerative Disorder” ; 2008

  8. Journal of Neuroimmunology ; “The interplay between inflammation and neurodegeneration in CNS disease” ; 2006

  9. John Hopkins Advanced Studies in Medicine ; Bruce Trapp ; “NEURODEGENERATION: THE PATHOLOGIC EVIDENCE” ; 2009

  10. Trends in Immunology   ; “Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression ” ; 2008

  11. Cleveland Clinic ; “”Secondary Progressive Multiple Sclerosis” ; 2009

  12. Wikipedia/Blood Brain barrier

  13. Annals of Neurology ; “Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis.” ; 2006

  14. Autoimmunity ; “”The blood-brain-barrier in multiple sclerosis: functional roles and therapeutic targeting.” ; 2007

  15. medinewsdigest ; “Multiple sclerosis: Research Progress on Drug Delivery Across the Blood Brain Barrier” ; 2011

  16. BMC Neurology ; “”Characteristics of compounds that cross the blood-brain barrier” ; 2009

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