Our brain has a number of defences to protect itself from physical damage. Our skulls are 7mm thick and our brains are surrounded by cerebrospinal fluid and a membrane called the meninges for protection. However, the brain also has a defence to protect pathogens and toxins that may be in our blood from entering the brain, where they could cause catastrophic damage. The blood-brain barrier (BBB) is a barrier between the brain’s blood vessels and the brain tissue, and is formed by tightly packed endothelial cells. Endothelial cells line all of the blood vessels in the body, but in blood vessels leading to the brain they are crammed close together, making an almost impermeable barrier between the blood in our body and our brain tissue. This tight gap allows only small and fat-soluble molecules to pass into the brain.
Nobel Prize winning German physician Paul Ehrlich discovered the BBB in the early 19thcentury when he injected dye into the bloodstream of a mouse, and watched as it permeated into all tissue except the brain and spinal cord. In a later follow-up experiment, Ehrlich injected the same dye into the brains of mice, and this time the dye permeated only the brains of the mice but no other tissue. However, due to microscopes at this time not being powerful enough, it wasn’t until the 1960’s that scientists could see the detailed anatomy of the blood-brain barrier.
So what happens if the blood-brain barrier is damaged?
A common way the blood-brain barrier can be damaged is through a bacterial infection, such as bacterial meningitis. Meningococcal bacteria can bind to the endothelial cells, causing the blood-brain barrier to open. When this occurs, bacteria and toxins can invade the brain tissue, causing damage, inflammation, or even death.
Some research has also suggested damage to the blood-brain barrier may precede or cause neurodegenerative disorders. For example, studies have suggested that patients with multiple sclerosis (a neurodegenerative disease in which the myelin, the insulating cover of nerve cells in the brain and spinal cord, becomes damaged over time) have a leaky blood-brain barrier. This allows too many white blood cells to enter the brain, which damage the myelin, causing symptoms such as muscle weakness, blindness and pain.
What if we need to get through the blood-brain barrier?
Although the blood-brain barrier is a line of defence against damage, a disadvantage is that drug treatments also cannot pass this barrier. Approximately 98 percent of potential drug treatments for neurological disorders are unable to pass through the BBB, meaning there are limited treatment options for patients with neurological illnesses. Because of this, researchers are developing ways to temporarily open the blood-brain barrier in order to allow drugs to reach the brain.
One way to do this is to “trick” the blood-brain barrier into allowing a drug to permeate into the brain. In this “Trojan horse” method, a drug is fused to a molecule that can pass through the barrier. In research by Boado et al. (2010), erythropoietin (a hormone that can be used in the development of drugs for brain disorders), which alone cannot pass through the blood-brain barrier, was fused to an antibody of the human insulin receptor. This fusion of the proteins could pass through the blood-brain barrier as insulin is transported across the barrier through a saturable transport system, allowing the erythropoietin to also pass into the brain. Using this “trojan horse” method, new drugs to treat brain disorders could be developed through further research.
Further research has shown there is another way to make it easier for drug treatments to permeate through the blood-brain barrier. Nisbet et al. (2017) used ultrasound technology to open the blood-brain barrier and allow therapeutic antibodies to access the brains of patients with Alzheimer’s Disease. Once in the brain, these antibodies can begin to destroy the protein deposits that contribute to Alzheimer’s symptoms, causing an improvement in cognitive function.
Although the blood-brain barrier creates a challenge for scientists developing drug treatments for brain disorders, it’s one of the many ways our brains protect themselves from damage. Without the blood-brain barrier, pathogens and bacteria that enter our blood would spread to the brain where they could cause life-threatening damage. By researching into how we can open the blood-brain barrier, scientists can develop new treatments for patients with brain disorders.
References:
Boado, R.J., Hui, E.K., Lu, J.Z., Pardridge, W.M. (2010). Drug targeting of erythropoietin across the primate blood-brain barrier with an IgG molecular Trojan horse. Journal of Pharmacology and Experimental Therapeutics, 333(3),961-969.
Hawkins, B.T., Davis, T.P. (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews, 57,173-185.
Nisbet, R. M., van der Jeugd, A., Leinenga, G., Evans, H. T., Janowicz, P. W., & Götz, J. (2017). Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain: A Journal of Neurology, 140(5), 1220–1230.
Zlokovic, B.V. (2008). The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron, 57, 178-201.
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