In my research as a student of medical writing, I often come across many new promising treatments for debilitating neurological diseases. Unfortunately, it seems that illnesses such as Alzheimer’s disease (AD), multiple sclerosis (MS), epilepsy, rabies and all the other diseases that affect the brain are especially difficult to treat. I never knew exactly why. It turns out that all of these scary diseases share one common trait that makes treating them with modern-day medicine virtually impossible: the blood-brain barrier (BBB).
I’ve always found neurological diseases fascinating, probably because modern scientists and bioengineers, with their cumulative knowledge of disease pathology and with all their ingenious, state-of-the-art medical equipment, really have no idea how to treat the vast majority of them. Well, I shouldn’t say they have no idea how to treat these diseases. In the past 50 years or so, scientists have made some pretty astonishing breakthroughs in the treatment of neurological diseases, but most of these treatments aim to relieve symptoms rather than attack the root cause of disease.
What exactly is the blood-brain barrier?
Over 100 years ago, a bacteriologist with extensive knowledge of staining, Paul Ehrlich, injected dyes into animals and discovered something interesting: the stains would travel throughout the body, but would not enter the brain system. Some 20 years later, students of Ehrlich injected dyes into the brains of animals and found that these injected dyes would travel throughout the brain but would not enter the body system. Clearly, there seemed to be some sort of compartmentalization existing between the body and brain systems. This compartmentalization continues to baffle scientists today as there are only limited experimental models of how this specialized barrier works, and therefore, very little is understood about how this barrier functions.
The blood-brain barrier is a semi-permeable system of tightly-joined cells that acts as a gatekeeper for the brain, preventing harmful substances from entering the brain tissue
but still letting in necessary nutrients. The BBB is necessary to keep the brain and nervous system healthy. However, it also causes problems in medication delivery because it treats medications as the enemy, preventing the therapeutic agents from doing their job.
In most parts of the body, the smallest blood vessels, known as capillaries, are lined with endothelial cells. Endothelial tissue has small spaces between each individual cell so substances can move readily between the inside and the outside of the vessel. However, in the brain, the endothelial cells fit tightly together and substances cannot pass out of the bloodstream. Some molecules, such as glucose, can be transported out of the blood by special methods.
What are some diseases of the blood-brain barrier?
Alzheimer’s disease (AD) – Alzheimer’s disease (AD) is also known as “old-timer’s disease” as the symptoms of AD aren’t typically seen in patients until they have reached the age of 60. AD is a progressive brain disease that slowly destroys memory and thinking skills, which ultimately leads to dementia in most patients. Although AD is the most common cause of dementia in older patients, the beginning process, cause, and cure for the disease is completely unknown. As the disease progresses, the neurons in the brain become entangled and fill with plaques, which causes the brain to shrink and ultimately leads to death. Although the exact cause of AD continues to elude scientists, some hypothesize that AD may be caused or aggravated by a breakdown in the BBB.
Multiple Sclerosis (MS) – Multiple sclerosis (MS) is a neurodegenerative disorder in which the immune system attacks the central nervous system causing a myriad of physical and cognitive impairments from muscle weakness and paralysis to coordination and motor skill problems. During an MS “attack,” or period of worsening symptoms, neuroimaging has shown the BBB to break down in the brain or spinal cord allowing white blood cells to move freely between the brain and body and “fight” vital organs. Recent studies suggest the impairment of protein production in the brain is the cause of a weakened BBB, and new treatments have been studied that may help stabilize it.
Epilepsy – Epilepsy is a common neurological disease characterized by continuing and untreatable seizures. Studies suggest that these recurring seizures are potentially caused by an inflammatory response of the BBB, although the exact mechanism of action of epilepsy is unknown. Despite current pharmacological treatment of epilepsy to manage and control seizures, a cure producing the complete eradication of repeated seizures continues to elude scientists.
Rabies – Rabies is a viral infection that causes acute inflammation of the brain in mammals. Rabies is transmitted between animals by bite, and once the symptoms of rabies are present in humans, there is no reversing the progression of the disease, which ultimately leads to death by respiratory insufficiency. During rabies infection, the BBB does not permit anti-viral immune cells to enter the brain and cease viral replication. Currently, there is no known cure for rabies in animals once symptoms are present, but increasing the permeability of the BBB may permit anti-viral drugs to enter the brain and destroy the disease, although no such efforts have been made to explore this treatment.
What research is being done?
The BBB makes certain exceptions for allowing passage of large molecules and water-soluble molecules. Identifying these exceptions is paramount in developing new classes of drugs.
For example, one binding and transport system in the BBB permits water-soluble glucose into the brain and another mediates the bidirectional movement of large molecule peptides. Formulating new drugs to follow these binding and transport systems may present promising new drug delivery systems.
Drug delivery to the brain is extremely complex. However, scientists know that certain factors can increase permeability and “open” the BBB. Using this knowledge, scientists hope to create pharmacologic agents that use these factors to cross into the BBB and treat disease. The following factors increase permeability in the BBB:
Hypertension (high blood pressure
Development
Hyperosmolitity
Microwaves
Radiation
Infection
Trauma, Ischemia, Inflammation, Pressure
There are areas of the brain where the BBB is weaker, which may allow for safe passage of certain molecules. These areas are known as circumventricular organs. The circumventricular organs include:
Pineal body: Secretes melatonin and neuroactive peptides
Neurohypophysis (posterior pituitary): Releases neurohormones like oxytocin and vasopressin into the blood.
Area postrema: "Vomiting center": when a toxic substance enters the bloodstream it will get to the area postrema and may cause the animal to throw up. In this way, the animal protects itself by eliminating the toxic substance from its stomach before more harm can be done.
Subfornical organ: Important for the regulation of body fluids.
Vascular organ of the lamina terminalis: A chemosensory area that detects peptides and other molecules.
Median eminence: Regulates anterior pituitary through release of neurohormones.
Implications for future research, or lack thereof
Surprisingly, research for developing drugs that successfully cross the BBB and treat neurological disease remains largely undervalued. Creating a drug delivery research program specifically for the blood-brain barrier could introduce many promising drug classes and neuropathic agents that may advance treatments in neurological disease.
This quote from an unknown academic sums up the state of BBB pharmaceutical research:
"Despite the importance of the BBB to neuropathic agents, this area is underdeveloped in the neurosciences. To my knowledge, no pharmaceutical company in the world has a BBB drug delivery program! It is not unusual for an entire conference to be convened on a given neurologic disorder (eg, brain tumors), with no discussion of targeting drugs through the BBB."
Breaching the Blood-Brain Barrier: Finding May Permit Drug Delivery to the Brain for Alzheimer's, Multiple Sclerosis and Brain Cancers. Science Daily Website. http://www.sciencedaily.com/releases/2011/09/110913172631.htm. Published September 13, 2011. Accessed November 8, 2011.
