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Blood-Brain Barrier – One Tough Fortress!

Blood-Brain Barrier – The blood-brain barrier is like the great wall of China for the brain and spinal cord and the rest of the body, only some things are allowed to pass through this barrier, few things make it out and it keeps the house pretty tidy on the inside for this reason. The blood-brain barrier acts as an interface between circulating peripheral blood and the central nervous system. The blood-brain barrier meshed so tightly in such a way that only some molecules and ions are allowed passage through the military cell front, while others are kept out. This makes it a streamlined process for the delivery of necessary nutrients and oxygen to be delivered for neuronal demand and for pathogens and toxins that are aren’t the right ‘fit’ to be denied access. Pretty genius right! [1]

Discovery of the Blood Barrier

The Discovery of the existence of the blood-brain barrier began in 1885 when German researcher Paul Ehrlich carried out experiments with the injection of Trypan Blue dye into the bloodstream of mice. What he discovered is that the dye did not leech into the brain or spinal cord but did with all other peripheral tissue. (Ehrlich 1885) [2]. Years later, on that back of this, Goldman [2][3] another researcher hypothesized that injecting the die into the brain should hypothetically show this leech or if it is retained. Sure enough, the blue dye saturated the brain but did not make it anywhere outside of that. From here onwards, the discovery of the blood-brain barrier has led to monumental discoveries in the health of the human central nervous system and neurodegenerative disease fronts. (Goldman 1909,1913) [3]

What is its Function?

So, now we know that it lets only select things in and select things out, what does this mean for our brain? Why can’t blood flow through this like the rest of us? Anatomically, the blood-brain barrier (BBB) is comprised of a very thin layer of Brain Endothelial Cells, these are tightly knitted together with ‘tight junctions’ which we will get into below in more detail.

Transportation of essential brain requirements like that of glucose and essential amino acids are allowed through with the aid of diffusions and transport carriers. This is because the brain requires glucose to function although can thrive on ketones if necessary, the brain uses for perspective; 20% of our total body energy and the remaining 75% of our energy is used for signaling (sending and processing electrical signals) across the brains ever interconnecting circuits! [4]. Thinking, moving, metabolic pathways, etc. are all very costly energy exchanges indeed! Getting glucose across the blood-brain barrier is so important and essential amino acids, why? Because the brain cannot synthesize these amino acids for use, this is also spoken in terms of neurotransmitter entry into the brain from their formation in the body too!

Not all Parts of the Brain are Protected!

There are in fact parts of the brain that are strategically not covered by the blood-brain barrier, this is because they require the entry of different molecules from blood circulation. These parts of the brain are located in what Is called the ‘Ventricular system’, they are located in the midline area of the brain. Tight junctions within this area are discontinuous – leaving the ventricular system organs open to indiscriminate molecules.

The Areas of the brain that are not covered by the blood-brain barrier include:
– Pineal Gland.
– Posterior Pituitary Gland.
– Area postrema (controls autonomic functions of the central nervous system, one being the action of vomiting)
– Preoptic recess (Responsible for thermoregulation receiving signals from the skin, mucous membrane and hypothalamus thermoreceptors)
– Parphysis.
– Endothelium of Choroid Plexus (production epicenter of cerebral spinal fluid as well as acting as a protective barrier of central nervous system tissue surrounds)
– Median Eminence of the Hypothalamus.

Areas listed above are not covered by the BBB because, for instance, hormones that are regulated by the hypothalamus and the pituitary gland collect in the region of the Median Eminence before being secreted directly into the bloodstream – when there are governing bodies like this and others like the pineal gland, these hormone secretion elements need to go straight into the bloodstream, and not filtered through first. [5]

Tight Junctions of the Blood-Brain Barrier

Above we mentioned Tight Junctions briefly – The endothelial cells of the BBB that give it its mesh-like wall function are reliant on what are termed tight junctions. [6] Tight junctions act like the middleman holding onto two opposing objects with all his strength to create a wall-like structure. They allow only specific elements through to the brain, essentially the crucial gatekeepers with an intimate relationship with the BEC’s (Brain Endothelial Cells). See image for perspective on how they work in the system of protective barrier and targeted drugs for passing the blood-brain barrier. [6]

How are Nutrients given the all-clear for Transport?

Transportation of nutrients across the blood-brain barrier happens via six core pathways. [7] Through methods of substance diffusion. Diffusion is the movement of a substance from high compacted concentration to low dispersed concentration. Think of it like when salt is added to water, in the beginning, it’s all clustered in one area at the bottom and then as it dissolves it dissipates in the water – the amount of sodium is the same, it is now, however, more evenly dispersed throughout the solution. This is what happens when transporting a substance through the BBB. [7]

What Micronutrients get passed through the Blood-Brain Barrier?

Ideally what we want are essential things to be passing through like water, oxygen, carbon dioxide, glucose and micronutrients, and advanced pharmaceutical drugs like that of benefit such as an anesthetic for surgery, etc.
All while excluding the nasty stuff like bacteria, viruses, poisons, and such – anything compromising the brain’s environment is dangerous for the entire system so its health is of A1 importance. [8]

There are specific nutrients that are required to maintain the health of the BBB and these are [8]:

– Magnesium.
– B-Vitamins.
– N-Acetyl Cysteine.
– Glutathione.
– EPA and DHA.
The brain also requires access to essential amino acids[8]:
– Phenylalanine.
– Leucine.
– Tyrosine.
– Valine.
– Tryptophan.
– Methionine.
– Histidine.

Other elements from the conversion of amino Acids Tyrosine/phenylalanine – L-Dopa the precursor to dopamine as well as glucose are readily passed through the barrier membrane. Other small more neutral amino acids like that of alanine, glycine, proline, and GABA more readily restricted in the hierarchy of acceptance through the barrier and are more likely to be fed back out than fed in as they can be produced by the brain instead of the essential amino’s, which need to be fed in. This brings us to the next element in a Newton’s law type way – for elements that go through, some must come out right!? Otherwise, we just get a clog up of metabolized junk accumulated in the brain. Enter the Glymphatic System! [8]

Blood-Brain Barrier and the Glymphatic system

What goes in, must come out… albeit not in the same form. The glymphatic system is an interesting one and relatively recent in its discovery. The glymphatic system in essence is the fluctuating exchange of fluids between that of the cerebral spinal fluid and the interstitial fluid occupying the space of the brain and skull. The glymphatic system works similarly to our lymphatic system in that it helps to move the waste from areas of the body, in this case, its moving waste solutes from the use of the nutrients listed above out through the blood-brain barrier.

Dysfunction of the glymphatic system and the overlapping requirements from the BBB to clear waste can lead to accumulative disruption like that of accumulative proteins that have been linked in with neurodegenerative disorders as seen in Alzheimer’s with the accumulation of B-amyloid plaque. Future endeavors to assess imaging of glymphatic flow and movement disruption can lead to much earlier identification of these disorders such as Alzheimer’s. [9]

How does the Glymphatic System move Solutes out of the Brain?

The Cerebral spinal fluid is moved first through an exchange with Interstitial fluid and then this ISF is processed by our then lymphatic system initially in the neck and cascades down to be processed by circulatory systems and effectively removed by the body. The differentiating factor between this glymphatic system and the lymphatic system we know is small but important. The Glymphatic system is a merging of the words lymphatic and Glial by Danish neuroscientist Maiken Nedergaard because the rate-limiting step between the two is via Glial cells. [9]

Glial cells are non-neuronal cells intimately involved in the central nervous system function – They aid in the Myelin protective sheaths of connections, CNS homeostasis, and support the health of neurons. They are abundant in the CNS equating to the same number of neurons in an almost 1:1 ratio estimated to be around 85 billion. [9]
Interestingly, most clearance happens while we are asleep – this is because the extracellular space increased by 60% during sleep, allowing a far more effective capacity of exchange between the cerebral spinal fluid and ISF, standing hard on the hypothesis of sleep for recovery and brain function. [10]

Role in the Central Nervous System

Adequate signaling is essential for the health of our central nervous system – we have established that now, and if we are letting through aspects that are dangerous to the brain and thus the function of these signals then we can be in a world of trouble, hence the need for the BBB. But, what is so important about the central nervous system, what does is it actually do?

The central nervous system is comprised of two parts protected in a membrane called the Meninges:

– Spinal cord.
– Brain.

The brain itself contains an estimated 86 BILLION neurons [11] with thousands of consecutive connections in between each. It’s the most intricate circuit we will ever come across and, it governs the following parts of our body:

– Thoughts.
– Movements.
– Emotions.
– Desires.
– Breathing.
– Heart rate.
– Regulation of hormonal release (some not all).
– Body temperature regulation.

Among some of the main aspects.. but the list is endless. In essence, it is the determining factor of quality of life. So yeah, protection at all costs from compromise is important. As we can see in the intricacy of its protective barrier between what goes in and what really goes in.

Function in Energy Maintenance and Metabolism

The brain as we mentioned uses around 20% of total energy, however, it does not hold energy as we do with glycogen stores in the body elsewhere, which makes this energy demand constant. The brain is the most metabolically demanding organ in our body, and for good reason. So, this being said, the continuous supply of exogenous (external) substrates via the bloodstream, filtered by the BBB are required. Glucose is a prime example of the aforementioned exogenous substrate. It is delivered via glucose transporters (GLUT-1) after carbohydrates have been broken down from the digestive process into glucose and entered the bloodstream. [12]

What Diseases are associated with the BBB?

Disease states of the blood-brain barrier may affect the barrier itself but as a result, affect the central nervous system as a whole. It’s like leaking a dam wall, over time it might be a small leak, but the more that compromise in structure erodes, the more that gets through and you are all of a sudden finding yourself in ‘deep water’ literally and metaphorically. Having a look at neurodegenerative disease states linked with a compromise in the BBB is as such [13]:

  • Acute Cerebral Ischemia/hypoxia.
  • Multiple Sclerosis – Autoimmune, infection, traumatic initiation.
  • Meningitis. – Bacterial and Viral Compromise.
  • Encephalitis – Herpes, HIV/etc.
  • Brain injury leading to hemorrhaging and edema.
  • Small Vessel Disease – Hypertension, diabetes, hyperlipidemia.
  • B-Amyloid accumulation – Alzheimer’s.

Reversal of BBB compromise is extremely difficult, so looking after the health of it at all costs as a preventative measure for what you can measure, obviously there will be variables that you cannot account for like accidents and genetic predisposition to a permanent degree.

Long Term Outlook on the Blood-Brain Barrier and Aging

We are born to age – it’s a strange concept, cells replicating all the time from the moment of conception, over time damage occurs, oxidation, and those cells still replicate. Its minute, but accumulative. That’s the very simplified view of aging, so don’t hang everything on one hook with that brief.

Some age better than others based on their life choices, environment, and genetics. When we look at the mind, the brain and consciousness as a whole – we want to have our sound mind with us for as long as possible, to outwork the creaking joints and stiff back, to be present, recall memories, and think for ourselves, right? Well, the poor health of the mind/brain is not something that starts when we see the symptoms, it starts long before that. Prevention is the best method here!

I want to care for my BBB, what do I do?

The key aspect to take home here is that the body is extremely adaptive, don’t panic that you are at a loss before you begin, that’s not what we are saying – but altering some key focus points into your routine can make a world of difference now in your everyday mental performance. They are simple!

  • Sleep, we have established the importance of sleep for the removal of waste products and recovery. Retention of learning done in the day is also imprinted during sleep!
    – Take note of your micros – are you getting your full spectrum of essential amino acids in your diet!
  • Your other micros too! Vitamin B, Magnesium, N-Acetyl Cysteine, Glutathione, and your essential fatty acids are all so important for this infrastructure! These can be found in foods we consume in our diet.
  • Water – sounds odd, but the brain is around 75% water and is a circuit board of 100 billion neurons remember, all with a demand on energy production to communicate and signal, not only that, the solute that comes in and out of the BBB requires water. So drink up!

Easy dietary and lifestyle changes that likely won’t cost too much to implement but maybe the best effort for longevity!

References:

1. The Blood-Brain Barrier doi: 10.1101/cshperspect.a020412Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved. Richard Daneman1 and Alexandre Prat2

2. Fluids and Barriers of the CNS: a historical viewpoint. Shane A Liddelow Fluids Barriers CNS. 2011; 8: 2.Published online 2011 Jan 18. doi: 10.1186/2045-8118-8-

3. The rights and wrongs of blood-brain barrier permeability studies: a walkthrough 100 years of history. Norman R. Saunders,1,* Jean-Jacques Dreifuss,2 Katarzyna M. Dziegielewska. Front Neurosci. 2014; 8: 404. Published online 2014 Dec 16. doi: 10.3389/fnins.2014.00404

4. Sugar for the brain: the role of glucose in physiological and pathological brain function. Philipp Mergenthaler,1 Ute Lindauer, Trends Neurosci. Author manuscript; available in PMC 2014 Oct 1. Published in final edited form as Trends Neurosci. 2013 Oct; 36(10): 587–597. Published online 2013 Aug 20. doi: 10.1016/j.tins.2013.07.001

5. The cerebral Circulation: Cipolla MJ. San Rafael (CA): Morgan & Claypool Life Sciences; 2009.

6. Tight junctions at the blood-brain barrier: physiological architecture and disease-associated dysregulation. Anny-Claude Luissint,1,2,3 Cédric Artus,1,2,3 Fabienne Glacial, Fluids Barriers CNS. 2012; 9: 23. Published online 2012 Nov 9. doi: 10.1186/2045-8118-9-23

7. Campos-Bedolla, P., Walter, F. R., Veszelka, S., & Deli, M. A. (2014). Role of the Blood-Brain Barrier in the Nutrition of the Central Nervous System. Archives of Medical Research, 45(8), 610–638. doi:10.1016/j.arcmed.2014.11.018

8. Campos-Bedolla, Patricia & Walter, Fruzsina & Veszelka, Szilvia & Deli, Mária. (2014). Role of the Blood–Brain Barrier in the Nutrition of the Central Nervous System. Archives of medical research. 45. 10.1016/j.arcmed.2014.11.018.

9. Verheggen, I.C.M. & Boxtel, Martin & Verhey, Frans & Jansen, Jacobus & Backes, W.H.. (2018). Interaction between the blood-brain barrier and glymphatic system in solute clearance. Neuroscience & Biobehavioral Reviews. 90. 10.1016/j.neubiorev.2018.03.028.

10. Sleep Drives Metabolite Clearance from the Adult Brain. Lulu Xie,1,* Hongyi Kang,1,* Qiwu Xu,1 Michael J. Chen, Science. Author manuscript; available in PMC 2014 Oct 18. Published in final edited form as Science. 2013 Oct 18; 342(6156): 10.1126/science.1241224. doi: 10.1126/science.1241224

11. The Human Brain in Numbers: A Linearly Scaled-up Primate Brain Suzana Herculano-Houzel1, Front Hum Neurosci. 2009; 3: 31. Published online 2009 Nov 9. Pre-published online 2009 Aug 5. doi: 10.3389/neuro.09.031.2009

12. Roberts E.L. (2007) 2.1 The Support of Energy Metabolism in the Central Nervous System with Substrates Other than Glucose. In: Lajtha A., Gibson G.E., Dienel G.A. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA

13. Neurological diseases in relation to the blood-brain barrier. Gary A Rosenberg1 J Cereb Blood Flow Metab. 2012 Jul; 32(7): 1139–1151. Published online 2012 Jan 18. doi: 10.1038/jcbfm.2011.197

14. Fluids and Barriers of the CNS: a historical viewpoint. Shane A Liddelow. Fluids Barriers CNS. 2011; 8: 2. Published online 2011 Jan 18. doi: 10.1186/2045-8118-8-2

15. Obermeier, B., Daneman, R. & Ransohoff, R. Development, maintenance, and disruption of the blood-brain barrier. Nat Med 19, 1584–1596 (2013). https://doi.org/10.1038/nm.3407

16. Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance. 1Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States Division of Gerontology and Geriatric Medicine, Department of Medicine, University Washington, Seattle, WA, United States. Elizabeth M. Rhea1,2* and William A. Banks1,2 Front. Neurosci., 04 June 2019 | https://doi.org/10.3389/fnins.2019.00521

17. The development of the paraphysis cerebri in man with comments on its relationship to the inter‐columnar tubercle and its significance for the origin of cystic tumors in the third ventricle First published: April 1955 https://doi.org/10.1002/cne.901020205