The blood-brain barrier is one of the human body's most complex and intricate parts. Given the body's vast vascular network, you would think everything in the blood gets transported everywhere. That is not the case with the BBB, so what can cross the blood-brain barrier?
Only selected substances can cross the blood-brain barrier without intervention, such as water, small ions, lipophilic molecules, essential polar molecules, CBD and THC in cannabis, alcohol, caffeine, barbiturates, anesthetics, insulin, glucose, Melphalan, H2O2s, and ethanol.
The blood-brain barrier was discovered over 100 years ago when a blue dye was used to see the contrast in the bodies of animals. The scientists discovered that only the spinal cord and brain remained untainted when the dye entered the animal's bloodstream. They named this phenomenon the blood-brain barrier to describe what they witnessed.
What Substances Can Cross The Blood Brain Barrier?
When the blood-brain barrier was discovered, it was clear that the dye was somehow prohibited from entering and coloring the brain and spinal cord blue.
Only in recent years was more in-depth information exposed on the fascinating way the blood-brain barrier protects the brain and spinal cord from malicious and harmful substances.
In simple terms, the blood-brain barrier acts like an anti-virus program on a desktop or laptop computer. It is programmed to detect and identify malware, spyware, worms, and Trojan horses that want to enter the mainframe and destroy it.
The anti-virus program stops these harmful programs from entering and destroying them. The blood-brain barrier works on the same principle as the anti-malware or anti-virus program that protects the brain from destruction.
There are only selected substances that are allowed to cross the blood-brain barrier naturally and without external interference, and they are –
Through the channels as a transporter –
- Small Ions such as Na+ / K+ / Cl and
- Water/ H2O
Through the membrane as a transporter
- Small lipophilic molecules such as – CO2 and O2
- Nicotine
- Barbiturates
- Anesthetic
- Caffeine
- Cannabis
- Ethanol
Through solute carriers or carrier-mediated transport
- Creatine
- Monocarboxylates, pyruvate, and lactate
- Glucose
Through receptor-mediated transport
- Leptin
- Insulin
- Transferrin
- IgG
Through active efflux transporters
- MRP 1,2,4,5
- P-glycoprotein
- BRCP
The Anatomy Of The Blood-Brain Barrier
The blood-brain barrier is tightly packed with endothelial cells. These tiny cells are found in all capillaries, making up the smallest parts of the body's blood vessel system. These cells have small gaps in between that allow certain substances to pass in and out.
Because the blood-brain barrier is semi-permeable, it only allows selected substances to cross into the brain. The endothelial cells found in the brain are so tightly packed together that there are no gaps to allow any substances to pass from the bloodstream into the brain.
Astrocytes are important in the formation and development of the blood-brain barrier. These glial cells are layered around the blood vessels in the brain and are thought to be responsible for the transportation of ions from the brain.
Four cell types make up the blood-brain barrier as a compound structure in the anatomy of the blood-brain barrier. The four cell types that follow the vasculature of the brain are –
Endothelial Cells - The endothelial cells are found inside capillaries and packed so closely together through junctions that they form the blood-brain barrier. These junctions maintain the permeability and integrity of the microvessels in the brain. The cellular junctions regulate the blood-brain barrier passage of all substances.
Pericytes – Pericytes in the brain act like immune cells that seek and destroy blood-derived organisms they deem harmful. Pericytes associate closely with the endothelial cells of the blood-brain barrier because they are embedded into the microvessels of the basement membrane.
Pericytes influence the growth and permeability of the membrane and lend structural integrity to the microvessels.
Astrocytes - These star-shaped cells lend structural integrity and strength to the blood-brain barrier. Astrocytes recruit peripheral cells ( like white blood cells) into the central nervous system through the blood-brain barrier.
Microglia – Microglia cells are the immune cells of the central nervous system and sit just outside the blood-brain barrier. Even though they do not form a part of the blood-brain barrier, they scan the central nervous system for harmful organisms they destroy. Microglial cells form part of the immune defense that prevents harmful substances from crossing the blood-brain barrier.
What Are The Functions Of The Blood Brain Barrier?
The blood-brain barrier has many critical functions, such as maintaining a homeostatic environment for the brain, protecting the brain from harmful organisms and foreign substances, and protecting the brain from neurotransmitters and hormones from the rest of the body.
Molecules with a high electrical charge are slowed when passing through the blood-brain barrier, and other large molecules have difficulty passing through the blood-brain barrier. Molecules with a low-lipid count don’t penetrate the brain in contrast to barbiturates that are lipid-soluble and penetrate the brain rapidly.
How Does The Blood-Brain Barrier Get Accessed?
A healthy blood-brain barrier protects the central nervous system effectively but not completely. Peripheral cells and other microorganisms can enter and access the central nervous system, potentially due to its permeability, causing doubt about its immunity.
To get a better idea of the weaknesses of the blood-brain barrier, its important to know what can cause it to break down and become weak, therefore opening a door –
- In Utero Development – While the fetus is forming, the present blood-brain barrier is not yet fully formed and vulnerable.
- Hyperosmolarity – An excessive amount of glucose or sodium in the blood can force the blood-brain barrier to open.
- Infection – Microorganisms, bacteria, or viruses can cause the blood-brain barrier to open.
- High Blood Pressure – Hypertension is a major cause of the blood-brain barrier opening.
- Head trauma – any incident such as an accident, fall, or other injuries that cause ischemia, pressure, or inflammation of the brain can cause the blood-brain barrier to open.
- Radiation – Radiation exposure of between 10 to 15 Gy (Grey) severely compromised the integrity of the blood-brain barrier.
- Microwaves – Excessive microwave exposure can affect the blood-brain barrier and compromise its integrity.
Weakness In Circumventricular Organs
Circumventricular organs in the brain are areas where the brain’s defense system or the blood-brain barrier is weaker than elsewhere, allowing prohibited organisms or substances to enter.
The function of these circumventricular organs is to assist the brain in assessing the blood makeup in the body and make decisions based on their findings.
The circumventricular organs are made up of the following –
- The Vascular Organ Of The Lamia Terminalis – This area identifies different molecules and peptides.
- The Area Postrema – This area is known as the vomiting center of the body. When you eat or drink something toxic, and it enters the bloodstream, the area postrema will make the body throw up to try and eliminate the substance from the gut.
- The Subfornical Organ – Responsible for regulating fluids in the body.
- The Neurohypophysis – The posterior pituitary gland is responsible for releasing the neurohormones vasopressin and oxytocin into the bloodstream.
- The Median Eminence – Releases neurohormones and regulates the anterior pituitary gland.
- The Pineal Gland – This endocrine gland is responsible for secreting neuroactive peptides and melatonin and helps regulate the circadian rhythm.
How Can Therapeutics Cross The Blood-Brain Barrier?
Some of the most prolific mortality causes in the world are microorganisms that have the capability to enter the blood-brain barrier. Among them are HIV/AIDS, West Nile Virus, Meningitis, Syphilis, and Escherichia coli K1.
These infections bacteria and viruses manage to enter the blood-brain barrier via a compromised central nervous system, but the blood-brain barrier sometimes blocks the therapeutics to treat these diseases.
In these cases, three applicable mechanisms can be used to treat these types of diseases – Invasive or non-invasive methods.
- The Trojan Horse Route – Using an infected phagocyte
- The Transcellular Route – Passing through lipid structures
- The Paracellular Route – Passing through the space between epithelial cells
Invasive Techniques Used To Cross The Blood-Brain Barrier
The following techniques are considered invasive methods to cross the blood-brain barrier -
Transient Disruption
This invasive method requires the use of ultrasounds, hyperosmotic solutions, or noxious agents such as –
- X-Irradiation
- Metals
- Ethanol
- Dimethyl Sulphoxide
- Glycerol
- Mannitol
- Polysorbate-80
These methods break down the junctions in the blood-brain barrier by shrinking the tightly packed epithelial cells and opening sufficient space in between to allow molecules to pass through.
Since this method forces the epithelial cells to open and let something through that would normally be blocked, it is considered harmful and compromises the integrity of the blood-brain barrier and central nervous system, causing injury.
One main concern is that it may allow an accumulation of neurotoxic agents, xenobiotics, and unwanted components in the blood. This can severely harm the central nervous system.
Intrathecal And Intra Cerebrovascular Infusions
These invasive methods allow the therapeutics to be delivered to the brain via enzymes resulting in the minimal use of drugs. This is done by directly injecting it and infusing the proteins into the cerebrospinal fluid.
Intrathecal infusions are done via a lumber puncture or an IDDD – (intrathecal drug delivery device).
Non-Invasive Techniques Used To Cross The Blood-Brain Barrier
Non-invasive techniques make it clear that no methods are used that forcefully alter the blood-brain barrier or require anything surgery related.
The main method is using drugs that make crossing the blood-brain barrier easy and effective. The best methods are –
Lipid Soluble Enhancement Through Drug Modification
This method is made possible by changing water-soluble molecules into becoming lipid-soluble molecules. These lipid-soluble molecules can cross the blood-brain barrier without issues.
Hiding On A Carrier Or Transport System
By the chemical modification of a small molecule drug, it can be made to mimic the structure of an endogenous molecule such as –
- Large neutral amino acids
- Purine bases
- Monosaccharides
- Acidic amino acids
- Monocarboxylic acids
- Nucleotides
- Hormones
- Amines
Efflux Transporter Inhibitors
This method prevents or inhibits efflux transporters expressed by the cerebrovascular endothelium. This prevents the brain from taking up the drug via the blood. There are a few types of transporters commonly inhibited, namely –
- Breast cancer resistance proteins
- Multidrug-resistant proteins
- P-glycoprotein
The Trojan Horse Method
This method is designed to ferry drugs, non-viral gene medicines, and proteins over the blood-brain barrier via a molecular Trojan horse. By using monoclonal antibodies or endogenous ligands and binding exofacial epitopes on the blood-brain barrier receptor-mediated transporting system, it triggers the attached drug to internalize the receptor.
Once the drug receptor has internalized, these two breaks away from one another and follow their distinctive paths. The receptor will travel back to the membrane, and the drug that used it as a Trojan horse will be able to do its work in the brain.
The Chimeric Peptide Method
This method is formulated through a disulfide bond by making a covalent coupling of a non-transportable drug to a blood-brain barrier transportable peptide transmitter. Examples of this would be –
- Transferrin
- Insulin
- Catatonized albumin
The chimeric peptide is transported to the brain via the capillary endothelial cells through receptor-mediated transcytosis. The therapeutic peptide that is now pharmacologically active is cleaved from the peptide vector because of the brain’s disulfide reductase.
The peptide receptor system of the blood-brain barrier includes receptors for transferrin, leptin, and insulin-like growth factor, including the disulfide reductase for the rapid joining of the chimeric peptides.
The Pro-Agent Bioconversion Method
The development of therapeutically inactive agents or drugs that can effectively cross the blood-brain barrier is an effective non-invasive method to deliver compounds to the brain parenchyma.
These agents undergo a chemical or enzymatic conversion or transformation and structurally modify themselves to achieve a form that is biologically active. This biologically active form can then deliver the desired therapeutic action.
The Nanoparticle Method
Using nanoscale drug delivery through nanosized technology, certain drugs can be released directly into the brain through different platforms such as polymer-based nanoparticles or lipid-based nanoparticles.
The nanoparticles ensure a controlled drug release and protect the drug from being metabolized. Nanoparticles are highly effective drug carriers and get to the delivery site through minimal interference or invasive alternatives.
Nanoscale drug delivery, especially where the blood-brain barrier is concerned, might well be the future of non-invasive therapies.
Foods And Supplements That Keep The Blood-Brain Barrier Healthy
The blood-brain barrier can become hyper-permeable and leak, especially after a traumatic accident or injury that caused brain trauma. It is possible to take certain supplements like magnesium and eat certain foods that have a high magnesium level to prevent further damage, such as –
- Spinach
- Pumpkin seeds
- Avocado
- Bananas
- Dark chocolate
- Chard
- Chicken liver
- Beef liver
- Almonds
- Ostrich meat
- Broccoli
- Brussel sprouts
Conclusion
The blood-brain barrier remains one of the more mysterious parts of the human anatomy, particularly the brain. This highly effective security network protects the brain and spinal cord from harm.
A healthy blood-brain barrier will ensure the brain stays in homeostasis, ensuring the body is managed optimally. To keep your blood-brain barrier happy, eat that dark chocolate and enjoy it!
Resources
https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-9-S1-S3
https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-020-00230-3
https://www.frontiersin.org/articles/10.3389/fnins.2017.00224/full
https://asm.org/Articles/2020/April/How-Pathogens-Penetrate-the-Blood-Brain-Barrier
