The Blood Brain Barrier
The Blood-Brain Barrier
Considering the brain is like the central computer to our very existence, it is critical that the environment in which it works be kept purer than other parts of the body. This is possible by the presence of the blood-brain barrier (BBB).
Over 100 years ago, it was observed that dye injected into the bloodstream of a mouse did not infiltrate the brain, alluding to a barrier of some sort. Recent technology has allowed us to further understand the role and the structure of this barrier.
The BBB is considered part of the neurovascular unit (“neuro” referring to the brain and “vascular” referring to the blood vessel), and its role is to give special protection to the brain tissue by keeping out toxins and pathogens. By doing so the BBB assists in the maintenance of healthy neuron function.
The cells that makeup blood vessels are called endothelial cells, and it just so happens that in the brain, these endothelial cells are bound together EXTRA tightly! It’s no surprise to learn that these tightly wedged cell walls form what is called “tight junctions”. The tight junctions serve as a protective shield but in doing so, also make it difficult for many medications to cross into the brain, posing a problem for the effectiveness of some pharmaceuticals.
A healthy BBB will prevent unwanted molecules into the brain whilst still allowing certain important molecules through. You can guess what an unhealthy BBB does! But we’ll get to that later.
The BBB tight junctions physically separate the circulation of blood from the body and brain and will only allow the entry of gas (such as oxygen), water, and certain molecules smaller than 400 daltons! But the brain still needs certain larger molecules, such as glucose, and for these molecules, it acts as a selective transporter whereby it will actively transport the substance across the interface between the central nervous system (brain and spinal cord) and the periphery (parts outside of the brain and spinal cord). (1)
The structure of the BBB varies, depending on the region of the brain, and the requirements of the brain, such as fuel demands. But there is more to the BBB than endothelial cells, bound by tight junctions. There is also the presence of other cells, such as neurons, astrocytes, and pericytes! (See the diagram below, which illustrates a cross-section of a blood vessel within the brain tissue.)(1)
Each of these cells has a specific function but collectively they provide a connection between the brain environment and the blood vessels. Their key functions, among others, are to help regulate blood flow, water content, and permeability of the BBB and to provide the building blocks for maintenance and repair of the BBB structure. These cells are collectively in charge of monitoring and regulating what is coming through the permeable walls, into and out of the delicate brain environment.
So what happens when there is a head injury?
A head injury can create a list of effects on the state of the brain, including inflammation, oxidative stress, swelling, reduced blood flow to the brain, and disruption of the blood-brain barrier. Often these things are inter-related and simultaneous, and are at the root of long-term, perpetuating symptoms of concussion.
The integrity of tight junctions and the surrounding cells in the BBB is compromised after head injury and it is said that the BBB will break down within 2-7 minutes after a head impact.
But we should keep in mind that there are some good reasons for this breakdown, at least initially. The permeability in the vessel walls can allow immune cells such as macrophages and T-cells to enter the brain and begin cleaning up debris.
Microglia are also activated as part of the immune response. Microglia cells, in their normal state, are like street-sweepers in the brain, moving about and sweeping up plaque, debris, and dead neurons.
But after injury, some microglia can become “primed” and they begin to morph into an M1 or M2 state. The M1 state is pro-inflammatory and begins to destroy neurons and the M2 state is anti-inflammatory and aids in restoring a healthy environment. Both of these states are an important part of the injury healing process, however, as one can expect we would like the M1 pathway of inflammation and destruction, to eventually become calm. One of the objectives in healing the injured brain may be to help convert “primed” glial cells from the M1 to the M2 state. The person with “primed” microglia will generally feel WIPED OUT and end up wanting to STAY IN BED due to mildly stressful events, such as emotional stress, poor sleep, alcohol, over-exercising, or gut discomfort/reaction to food.
There a many influences on the state of the microglia, which will determine if they are in the M1 or M2 state. These influences, as mentioned above, can be optimized in a strategy to improve brain function. The diagram below shows the two states of the microglia cells. (2)
The primed microglia create a state of hypervigilance within the brain, and the opening of the BBB creates a vulnerable brain environment. Whilst the BBB is open, the brain environment can become easily contaminated and reactive to immune system changes in the outer region of the body, such as infections and toxins. It is therefore another objective to heal the “leaky” brain barrier when aiming to recover after brain injury.
The BBB also regulates the transport of insulin into the brain and therefore regulates levels of insulin within the brain. Insulin is important as it allows cells to transport glucose internally, to produce energy. Inflammation can have detrimental effects on the insulin transport at the BBB, and therefore can add to the problems with energy production in the injured brain. (2)
The effect on insulin can also decrease the ability of the BBB to transport certain unwanted debris out of the brain, leading to a build of plaque within the brain and therefore leading to early neurodegenerative changes, such as that with Alzheimer’s disease (AD) and Chronic traumatic encephalopathy (CTE). It is no surprise that people with diabetes may be more at risk of insulin-related complications with the BBB, post-concussion.
“BBB breakdown, due to disruption of the tight junctions, altered transport of molecules between blood and brain and brain and blood, aberrant angiogenesis, vessel regression, brain hypoperfusion, and inflammatory responses, may initiate and/or contribute to a “vicious circle” of the disease process, resulting in progressive synaptic and neuronal dysfunction and loss in disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and others.” (3)
How do we know if your BBB is disrupted?
An interesting development in the area of injury detection is around the protein S100B. The protein S100B is released into the bloodstream in the event of brain injury, even with a mild case. The majority of S100B is thought to come from dead or dying brain tissue, and it is thought that the S100B protein could be released through spaces in the broken barrier. However, there is also some thought that it is actively transported through the barrier, regardless of BBB integrity. For this reason, perhaps S100B will be more of an indicator of mTBI, rather than BBB permeability… watch this space! (4)
S100B has a short half-life, and so it is generally used to identify recent head injury, in the vicinity of 3-48 hours (see diagram above) (5). For this reason, there is some potential for S100B to be used in emergency / first-aid situations, to help identify a concussion, and to help make decisions about the need for MRI or CT images of the head/brain. Blood serum tests can be done to investigate the presence of S100B, and even more useful is that they can also be used to identify the absence of intracranial bleeding. Salivary S100B is now being researched and tested as a reliable, cost-effective, and user-friendly way of testing for concussions. (5)
Another way to test the BBB permeability is by testing for antibodies. The antibodies form in response to the BBB proteins and tight junctions and are in the form of IgG, IgM, or IgA. The presence of these antibodies may indicate an alteration of the protective BBB and are more stable than the acute release of S100B, so are perhaps a more helpful indicator of some more chronic BBB issues. Continued opening of the BBB, such as with repeated head trauma and chronic disease, is linked to early cognitive decline.
Healing the blood-brain barrier
The tight junctions in the brain are similar in the gut, and for similar reasons; to keep out unwanted pathogens and toxins. The mechanisms which break down the tight junctions in the gut are also likely to influence the brain. It is likely that if there is permeability in the gut, there is also permeability in the brain. Testing for “leaky gut” can be done via a test for zonulin and one can be sure that the factors influencing gut permeability also influence the tight junctions in the BBB.
As with many things, it may be necessary to begin the healing process for the blood-brain barrier, via dietary modifications or supplements administered via the gut. Certain supplements can help improve the blood vessel protective barriers and restore function to the astrocytes which help maintain and support the barrier.
Furthermore, the brain must be given the right opportunity to heal. This may mean removing the brain from potential damage. For athletes, this may mean ceasing sport.
Another contributing factor to brain health is stress. Stress is actually healthy in some shapes and forms! For example, exercise is stress and this sort of stress is actually a good stress. However, high stress or chronic stress tends to be inflammatory to the brain and may impair the ability of the brain to repair. Removing stress from your life should be targeted at chronic, ongoing stress, as opposed to a single stressful event. Stress can also come in the form of over-training, reactions to food, infections, or emotional stress, and although some of these things are in our control, some are not.
In summary, the BBB is an interesting part of the complex presentation of brain injury. Although it may only be part of the puzzle, it is worth considering when aiming to optimize brain function, because if it is disrupted, it is unlikely that the brain will improve.
References
- https://www.frontiersin.org/articles/10.3389/fnins.2019.00521/full
- https://www.researchgate.net/publication/317558915_Role_of_Atypical_Chemokine_Receptors_in_Microglial_Activation_and_Polarization
- https://pubmed.ncbi.nlm.nih.gov/32209037/
- https://pubmed.ncbi.nlm.nih.gov/18215617/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241347/
- https://www.frontiersin.org/articles/10.3389/fneur.2020.00528/full
