Researchers at the University of Rochester Medical Center (URMC) have discovered a new way to potentially get medicine to the brain. The research, which appeared last month in the journal JCI Insight, could significantly change how we treat Alzheimer’s, Parkinson’s, ALS and brain cancer.
“Improving the delivery of drugs to the central nervous system (CNS) is a considerable clinical challenge,” said Maiken Nedergaard M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and lead author of the JCI Insight article. “The findings of this study demonstrate that the brain’s waste removal system could be harnessed to transport drugs quickly and efficiently into the brain.”
Nedergaard should know. She discovered the Glymphatic System-the brain's unique process for removing waste-in 2012.
According to Nedergaard, many promising therapies for diseases of the central nervous system have failed in clinical trials because of the difficulty in getting enough of the drugs into the brain to be effective. “This is because the brain maintains its own closed environment that is protected by a complex system of molecular gateways – called the blood-brain barrier – that tightly control what can enter and exit the brain,”
Scientists have discovered these limitations in their efforts to use antibodies to treat the buildup of amyloid beta plaques that accumulate in the brains of people with Alzheimer’s, Nedergaard said. Researchers at URMC believe that because antibodies are typically administered intravenously, the entry of these large proteins into the brain is stopped by the blood-brain barrier. As a result, they say, it is estimated that only two percent of therapies actually enter the organ.
“The brain is precious, and evolution has gone to great lengths to protect it from damage. The most obvious is our 7mm thick skull, but the brain is also surrounded by protective fluid (cerebrospinal – of the brain and spine) and a protective membrane called the meninges. Both provide further defense against physical injury,” writes Jürgen Götz, director of Clem Jones Centre for Ageing Dementia Research at The University of Queensland. “Another protective element is the blood–brain barrier. As the name suggests, this is a barrier between the brain’s blood vessels (capillaries) and the cells and other components that make up brain tissue. Whereas the skull, meninges and cerebrospinal fluid protect against physical damage, the blood–brain barrier provides a defense against disease-causing pathogens and toxins that may be present in our blood.”
The German physician Paul Ehrlich discovered the blood-brain barrier when he injected a dye into the bloodstream of a mouse in the late 19th century. The dye infiltrated all tissues except the brain and spinal cord showing that a barrier did indeed exist between brain and blood. But it wasn’t until the 1960s that researchers could use microscopes powerful enough to see the physical layer of the blood–brain barrier.
Scientists now know that the purpose of the blood–brain barrier is to protect against circulating toxins or pathogens that could cause brain infections, while at the same time allowing vital nutrients to reach the brain and maintaining levels of hormones, nutrients and water in the brain.
If the blood–brain barrier is damaged or somehow compromised, Götz writes, through bacterial infection like meningococcal disease for example, it can become more porous, allowing bacteria and other toxins to infect the brain tissue, which can lead to inflammation and even death. And the blood–brain barrier’s function can decrease in other conditions like multiple sclerosis, wherein a defective blood–brain barrier allows white blood cells to infiltrate the brain and attack the functions that send messages from one brain cell (neuron) to another.
Still, sometimes we need to get through the blood–brain barrier, Götz said. The vast majority of potential drug treatments do not readily cross the barrier, posing a huge obstacle to treating mental and neurological disorders.
“One possible way around the problem is to “trick” the blood–brain barrier into allowing passage of the drug. This is the so-called Trojan horse approach, in which the drug is fused to a molecule that can pass the blood–brain barrier via a transporter protein,” he writes. “A different approach is to temporarily open the blood–brain barrier using ultrasound.”
In 2015, Götz and his colleagues showed that using ultrasound to open the blood–brain barrier can improve cognition and decrease the amount of toxic plaque that accumulates in the brain.
In a 2017 study, Götz's researchers declared that ultrasound is a promising tool for temporarily opening the blood–brain barrier. They contend that ultrasound allows more of a therapeutic antibody into the brain, improving Alzheimer’s-like pathology and cognition more than when using ultrasound or the antibody drug in isolation.
Nedergaard’s and URMC’s new research taps into the power of the glymphatic system, first discovered by Nedergaard in 2012. The brain’s unique process of removing waste, the glymphatic system consists of a type of plumbing system that seems to expand on the work of the brain’s blood vessels—functioning in the brain much like the lymph system does in the rest of the body—by pumping cerebral spinal fluid (CSF) through the brain’s tissue and flushing away waste products. Nedergaard’s lab has also reported that his so-called glymphatic system works primarily while we sleep, is disrupted after traumatic brain injury and could be a key player in diseases like Alzheimer’s.
“Waste clearance is of central importance to every organ, and there have been long-standing questions about how the brain gets rid of its waste,” Nedergaard said at the time. “This work shows that the brain is cleansing itself in a more organized way and on a much larger scale than has been realized previously.
Nedergaard’s team dubbed the system “the glymphatic system,” since it acts much like the lymphatic system but is managed by brain cells known as glial cells. Scientists already knew that CSF plays an important role cleansing brain tissue, carrying away waste products and carrying nutrients to brain tissue through a process known as diffusion. Nedergaard’s team showed that the glymphatic system circulates CSF to every corner of the brain much more efficiently, through what scientists call bulk flow or convection.
“It’s as if the brain has two garbage haulers – a slow one that we’ve known about, and a fast one that we’ve just met,” Nedergaard said.
Researchers said this system eluded the notice of scientists till now because it functions only when it’s intact and operating in the living brain, making it very difficult to study for earlier scientists who could not see CSF flow in a live animal, but rather had to study sections of nonliving brain tissue. Scientists can now use a two-photon microscope to study the living, whole brain allowing them to look at the flow of blood, CSF and other substances in the brain of a living animal.
In the new study, researchers used the mechanics of the glymphatic system to deliver drugs deep into the brain of mice, administering antibodies directly into CSF. They then injected the mice with hypertonic saline, a treatment used to reduce intracranial pressure on patients with traumatic brain injury.
Researchers reported the saline triggers an ion imbalance which pulls CSF out of the brain. “When this occurs, new CSF delivered by the glymphatic system flows in to take its place, carrying the antibodies with it into brain tissue.” The researchers developed a new imaging system to non-invasively observe the increase of the antibodies into the brains of the animals.
According to Nedergaard, the researchers believe that this method could be used to not only deliver large proteins such as antibodies into the brain, but also small molecule drugs and viruses used for gene therapies.
Co-authors on the study include Benjamin Plog, Humberto Mestre, Genaro Olveda, Amanda Sweeney, H. Mark Kenney, Alexander Cove, Kosha Dholakia, Jeffrey Tithof, Thomas Nevins, Iben Lundgaard, Ting Du and Douglas Kelley with the University of Rochester. The research was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Office of the Assistant Secretary of Defense for Health Affairs under the Peer Reviewed Alzheimer’s Research Program.