Cortisol and Parkinson’s Disease

Research team from Daegu Gyeongbuk Institute Of Science And Technology (DGIST) has performed a high-throughput screening method to identify drug candidates that promote dopaminergic neuronal cell activation by inducing the expression of the parkin protein, the cell protection gene which can inhibit the death of dopaminergic neurons. The results of study are published in Scientific Reports.

Results of the study identified that cortisol induces the expression of the parkin protein and prevents dopaminergic neuronal death by eliminating the accumulation of cell death factors through ubiquitin proteasome system.

Hydrocortisone binds to glucocorticoid receptor which in turn leads to expression of CREB. CREB increases parkin expression via binding to CREB binding motifs of parkin promoter region. Hydrocortisone-stimulated parkin expression results in the downregulation of the toxic parkin substrate AIMP2, which is beneficial for dopaminergic neuronal survival.

In addition, the team has demonstrated the mechanism by which cortisol induces the expression of the parkin protein and CREB (cAMP response element-binding protein) transcriptional regulator through the hormone receptor regulates the expression of the parkin protein through the cell and animal model experiments.

Citation: Ham, Sangwoo, Yun-Il Lee, Minkyung Jo, Hyojung Kim, Hojin Kang, Areum Jo, Gum Hwa Lee, Yun Jeong Mo, Sang Chul Park, Yun Song Lee, Joo-Ho Shin, and Yunjong Lee. “Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson’s disease model.” Scientific Reports 7, no. 1 (2017).
doi:10.1038/s41598-017-00614-w.
Adapted from press release by Daegu Gyeongbuk Institute Of Science And Technology.

Peripheral vision reaction time assessment to diagnose mild traumatic brain injury patients

A new test using peripheral vision reaction time could lead to earlier diagnosis and more effective treatment of mild traumatic brain injury, often referred to as a concussion, according to Peter J. Bergold, PhD, professor of physiology and pharmacology at SUNY Downstate Medical Center and corresponding author of a study published by the Journal of Neurotrauma.

While most patients with mild traumatic brain injury or concussion fully recover, a significant number do not, and earlier diagnosis could lead to better management of patients at risk for developing persistent symptoms, according to Dr. Bergold and his co-authors. Lingering symptoms may include loss of concentration and/or memory, confusion, anxiety, headaches, irritability, noise and light sensitivity, dizziness, and fatigue.

“Mild traumatic brain injury is currently diagnosed with subjective clinical assessments,” says Dr. Bergold. “The potential utility of the peripheral vision reaction test is clear because it is an objective, inexpensive, and rapid test that identifies mild traumatic brain injury patients who have a more severe underlying injury.”

Reference: Womack, Kyle B., Christopher Paliotta, Jeremy F. Strain, Johnson S. Ho, Yosef Skolnick, William W. Lytton, L. Christine Turtzo, Roderick Mccoll, Ramon Diaz-Arrastia, and Peter J. Bergold. “Measurement of Peripheral Vision Reaction Time Identifies White Matter Disruption in Patients with Mild Traumatic Brain Injury.” Journal of Neurotrauma, 2017. doi:10.1089/neu.2016.4670.
Research funding: United States Army Medical Research and Materiel Command, Center for Neuroscience and Regenerative Medicine.
Adapted from press release by SUNY Downstate Medical Center.

New approach to Multiple Sclerosis treatment using immunosuppression and stem cells shows promise

New clinical trial results provide evidence that high-dose immunosuppressive therapy followed by transplantation of a person’s own blood-forming stem cells can induce sustained remission of relapsing-remitting multiple sclerosis (MS).

Five years after receiving the treatment, called high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), 69 percent of trial participants had survived without experiencing progression of disability, relapse of MS symptoms or new brain lesions. Notably, participants did not take any MS medications after receiving high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT). Other studies have indicated that currently available MS drugs have lower success rates.

The trial, called HALT-MS, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIAID-funded Immune Tolerance Network (ITN). The researchers published three-year results from the study in December 2014, and the final five-year results appear in Neurology, the medical journal of the American Academy of Neurology.

“These extended findings suggest that one-time treatment with high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging results support the development of a large, randomized trial to directly compare high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) to the standard of care for this often-debilitating disease.”

In HALT-MS, researchers tested the safety, efficacy and durability of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) in 24 volunteers aged 26 to 52 years with relapsing-remitting multiple sclerosis (MS) who, despite taking clinically available medications, experienced active inflammation, evidenced by frequent severe relapses, and worsened neurological disability.

The experimental treatment aims to suppress active disease and prevent further disability by removing disease-causing cells and resetting the immune system. During the procedure, doctors collect a participant’s blood-forming stem cells, give the participant high-dose chemotherapy to deplete the immune system, and return the participant’s own stem cells to rebuild the immune system. The treatment carries some risks, and many participants experienced the expected side effects of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), such as infections. Three participants died during the study; none of the deaths were related to the study treatment.

Five years after high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), most trial participants remained in remission, and their MS had stabilized. In addition, some participants showed improvements, such as recovery of mobility or other physical capabilities.

“Although further evaluation of the benefits and risks of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) is needed, these five-year results suggest the promise of this treatment for inducing long-term, sustained remissions of poor-prognosis relapsing-remitting MS,” said Richard Nash, M.D., of Colorado Blood Cancer Institute and Presbyterian-St. Luke’s Hospital. Dr. Nash served as principal investigator of the HALT-MS study.

If these findings are confirmed in larger studies, high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may become a potential therapeutic option for patients with active relapsing-remitting multiple sclerosis (MS), particularly those who do not respond to existing therapies,” said Daniel Rotrosen, M.D., director of NIAID’s Division of Allergy, Immunology and Transplantation.

Citation: Nash, Richard A., George J. Hutton, Michael K. Racke, Uday Popat, Steven M. Devine, Linda M. Griffith, Paolo A. Muraro et al. “High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report.” JAMA neurology 72, no. 2 (2015): 159-169.
DOI: 10.1212/WNL.0000000000003660
Research funding: NIH/National Institute of Allergy and Infectious Diseases.
Adapted from press release by NIH/National Institute of Allergy and Infectious Diseases.

Research shows positive outcome for early epilepsy surgery

There are important, long-term gains from hastening the processes around surgical interventions against epilepsy, before the disease has had too much negative impact on brain functions and patients’ lives. These are some of the findings of a thesis for which more than 500 patients were studied and followed up.

“Around one third of those undergoing surgery today are children and the percentage is growing, which is encouraging. But the average time until operation for adults is still 20 years, and that’s a very long time. There’s a major lack of knowledge among the treating neurologists about which patients may benefit from epilepsy surgery,” says Anna Edelvik, researcher at Sahlgrenska Academy and Senior Physician on the Sahlgrenska University Hospital epilepsy team.

Around 60,000 people have epilepsy in Sweden, making it our most common chronic neurological disease. Around one out of three patients do not become seizure free from medication and it is primarily here that surgery comes in. If the epilepsy is focal, which implies that seizure onset is clearly delimited in the brain, surgery may be possible.

“We try to locate the origin of the seizures as precisely as possible, and determine the proximity to areas of vital functional importance. It’s important to be able to give good information to the patients about possible risks and benefits before making a decision to operate or not,” says Anna Edelvik.

Her research shows that 58 percent of those who underwent surgery were seizure-free after five to ten years compared with 17 percent in the group of those who were not operated. The longer the individuals had had epilepsy, the fewer were seizure-free on the long term.

The importance of acting faster is also apparent from the study concerning how many of those who underwent epilepsy surgery who were gainfully employed at long-term.

“The highest number of persons in full-time employment at long-term was found among those who worked full-time before surgery, but even if they dropped out of the labor market before surgery, about one third of the persons who were seizure-free had full-time employment after ten to 15 years. It’s important to identify the patients as early as possible before the epilepsy has had too large of an impact,” says Anna Edelvik.

In another study, when non-surgical patients rated their health-related quality of life, it was considerably lower than among comparable individuals without epilepsy. The group who underwent surgery scored higher and was more like the age- and gender-matched reference group, but still had lower ratings for social function and mental health.  

“They want to have a job and a family like everyone else, but that doesn’t happen just by becoming seizure-free. Even if the whole lifestyle situation doesn’t change, many would in any case benefit from being examined or evaluated for epilepsy surgery earlier than today,” says Anna Edelvik.

Citation: Edelvik, Anna. “Long-term outcomes of epilepsy surgery-prospective studies regarding seizures, employment and quality of life.” (2016).University of Gothenburg, Sahlgrenska Academy Doctoral thesis.
Link: hdl.handle.net/2077/48660
Adapted from press release by University of Gothenburg.

Chronic headache and Vitamin D deficiency

Vitamin D deficiency may increase the risk of a chronic headache, according to a new study from the University of Eastern Finland. The findings were published in Scientific Reports.

The Kuopio Ischaemic Heart Disease Risk Factor Study, KIHD, analyzed the serum vitamin D levels and occurrence of a headache in approximately 2,600 men aged between 42 and 60 years in 1984-1989. In 68% of these men, the serum vitamin D level was below 50 nmol/l, which is generally considered the threshold for vitamin D deficiency. A chronic headache occurring at least on a weekly basis was reported by 250 men, and men reporting chronic headache had lower serum vitamin D levels than others.

When the study population was divided into four groups based on their serum vitamin D levels, the group with the lowest levels had over a twofold risk of a chronic headache in comparison to the group with the highest levels. A chronic headache was also more frequently reported by men who were examined outside the summer months of June through September. Thanks to UVB radiation from the sun, the average serum vitamin D levels are higher during the summer months.

The study adds to the accumulating body of evidence linking a low intake of vitamin D to an increased risk of chronic diseases. Low vitamin D levels have been associated with the risk of a headache also by some earlier, mainly considerably smaller studies.

In Finland and in other countries far from the Equator, UVB radiation from the sun is a sufficient source of vitamin D during the summer months, but outside the summer season, people need to make sure that they get sufficient vitamin D from food or from vitamin D supplements.

No scientific evidence relating to the benefits and possible adverse effects of long-term use in higher doses yet exists. The Finnish Vitamin D Trial, FIND, currently ongoing at the University of Eastern Finland will shed light on the question, as the five-year trial analyses the effects of high daily doses of vitamin D on the risk factors and development of diseases. The trial participants are taking a vitamin D supplement of 40 or 80 micrograms per day. The trial also investigates the effects of vitamin D supplementation on various pain conditions.

Citation: Virtanen, Jyrki K.,  Rashid Giniatullin, Pekka Mäntyselkä, Sari Voutilainen, Tarja Nurmi, Jaakko Mursu, Jussi Kauhanen & Tomi-Pekka Tuomainen. “Low serum 25-hydroxyvitamin D is associated with higher risk of frequent headache in middle-aged and older men.” Scientific Reports 2017 vol: 7 pp: 39697.
DOI: 10.1038/srep39697
Adapted from press release by the University of Eastern Finland.

Deep brain magnetic stimulation provides precise and reliable activation of target neurons

Massachusetts General Hospital (MGH) researchers have developed what appears to be a significant improvement in the technology behind brain implants used to activate neural circuits responsible for vision, hearing or movement. The investigators, who are also affiliated with the Boston VA Healthcare System, describe their development of tiny magnetic coils capable of selectively activating target neurons in journal Science Advances.

“Neural stimulation systems based on electrodes are currently being used to restore senses such as vision and hearing; to treat neurological disorders such as Parkinson’s disease, and for brain-computer interfaces that can give paralyzed patients the ability to communicate or move objects,” explains lead author Seung Woo Lee, PhD, of the MGH Department of Neurosurgery. “But electrode-based neural stimulation devices, especially those that target the cortex, have several significant limitations. The environment within the brain can erode a metal electrode over time, and the brain’s natural foreign-body response can lead to scarring, which can impede passage of electrical fields.”

The use of magnetic rather than electrical fields to stimulate neurons presents several advantages, including the ability to penetrate scar tissue. Since the magnetic signal can pass through the biocompatible insulating material, direct contact between neural tissue and the metal coil is eliminated, further reducing the potential for damage to the coil. But it had been believed that magnetic coils strong enough to activate neurons would be too large to be implanted within the brain’s cortex. The device developed by Lee and senior author Shelley Fried, Ph.D., of MGH Neurosurgery — in collaboration with scientists at the Palo Alto Research Center – takes advantage of the fact that the passage of electric current through a bent wire will induce a magnetic field. The novel coil they designed, while similar to the size of electrodes used for brain stimulation, was able to generate magnetic fields in excess of the thresholds required to activate neurons.

Testing these microcoils in brain tissue samples from mice revealed not only that they were capable of activating neurons but also that they did so more selectively than would be possible with metal electrodes. Electric fields most effectively activate neurons when they are oriented along the length of nerve cells, but most implantable electrodes generate fields that spread uniformly in all directions. In contrast, magnetic fields extend in specific directions, allowing selective targeting of neurons with the same orientation while simultaneously avoiding the activation of other neurons. The ability to avoid activation of passing nerve fibers prevents the spread of activation that typically occurs with electrodes, which can lead, for example, to the blurring of a visual image generated in response to stimulation of the visual cortex.

The MGH team proceeded to show that these microcoils could safely be implanted into the brains of anesthetized mice. Stimulation of coils inserted into the portion of the motor cortex that controls the animals’ whiskers resulted in whisker motion, with the direction depending on the frequency of the signal. Stimulating coils placed in the whisker sensory cortex caused whisker retraction. These experiments proved that implanted coils can be used to drive responses associated with the targeted neurons.

“Our next steps will be to continue improving coil design to reduce power and enhance selectivity, to confirm that the enhanced effectiveness of these coils will persist over time, and to determine whether stimulation of the visual cortex does elicit a visual signal,” says Fried, who is an associate professor of Neurosurgery at Harvard Medical School. “More stable long-term performance of these microcoils and the high-resolution signals produced by ever greater selectivity in neuron activation would significantly improve currently available neural prostheses and open up many new applications.”

Citation: Lee, Seung Woo,  Florian Fallegger, Bernard D. F. Casse and Shelley I. Fried. “Implantable microcoils for intracortical magnetic stimulation.” Science Advances 2016 vol: 2 (12).
DOI: 10.1126/sciadv.1600889
Research funding: Veterans Administration-Rehabilitation Research and Development Service, NIH/National Eye Institute, NIH/National Institute for Neurological Disease and Stroke, Rappaport Foundation.
Adapted from press release by Massachusetts General Hospital.

MESO-BRAIN stem cell research project to develop 3D nanoprinting techniques to replicate neural networks

Aston University heading up major €3.3m stem cell research project to develop 3D nanoprinting techniques that could replicate brain’s neural networks.

Aston University has launched MESO-BRAIN, a major stem cell research project which it hopes will develop three-dimensional (3D) nanoprinting techniques that can be used to replicate the brain’s neural networks.

The cornerstone of the MESO-BRAIN project will be its use of pluripotent stem cells generated from adult human cells that have been turned into brain cells, which will form neural networks with specific biological architectures. Advanced imaging and detection technologies developed in the project will be used to report on the activity of these networks in real time.

Credit: Ashton University
Such technology would mark a new era of medical and neuroscience research which would see screening and testing conducted using physiologically relevant 3D living human neural networks. In the future, this could potentially be used to generate networks capable of replacing damaged areas in the brains of those suffering from Parkinson’s disease, dementia or other brain trauma.
The MESO-BRAIN initiative, which will span three years, received €3.3million of funding from the European Commission as part of its prestigious Future and Emerging Technology (FET) scheme. Aston University is leading the project, with partners from industry and higher education across Europe: Axol Bioscience Ltd, Laser Zentrum Hannover, The Institute of Photonic Sciences, University of Barcelona and Kite Innovations. This unique partnership brings together stem cell biologists, neuroscientists, photonics experts and physicists.

Head of the MESO-BRAIN project, Professor Edik Rafailov, said: “What we’re hoping to achieve with this project has, until recently, been the stuff of science-fiction.

“If we can use 3D nanoprinting to improve the connection of neurons in an area of the brain which has been damaged, we will be in a position to develop much more effective ways to treat those with dementia or brain injuries.

“To date, attempts to replicate and reproduce cells in this way have only ever delivered 2D tissues or poorly defined 3D tissues that do not resemble structures found within the human body. The new form of printing we are aiming to develop promises to change this. The MESO-BRAIN project could improve hundreds of thousands of lives.”

Dr Eric Hill, Programme Director for MSc Stem cells and Regenerative Medicine at Aston University, commented: “This research carries the potential to enable us to recreate brain structures in a dish. This will allow us to understand how brain networks form during development and provide tools that will help us understand how these networks are affected in diseases such as Alzheimer’s disease.”

Adapted from press release by Ashton University.

Magnetoencephalography and computational analysis to accurately diagnose concussions

Simon Fraser University researchers have found that high-resolution brain scans, coupled with computational analysis, could play a critical role in helping to detect concussions that conventional scans might miss.

In a study published in PLOS Computational Biology, Vasily Vakorin and Sam Doesburg show how magnetoencephalography (MEG), which maps interactions between regions of the brain, could detect greater levels of neural changes than typical clinical imaging tools such as MRI or CAT scans.
Qualified clinicians typically use those tools, along with other self-reporting measures such as headache or fatigue, to diagnose concussion. They also note that related conditions such as mild traumatic brain injury, often associated with football player collisions, don’t appear on conventional scans.

“Changes in communication between brain areas, as detected by MEG, allowed us to detect concussion from individual scans, in situations where MRI or CT failed,” says Vakorin. The researchers are scientists with the Behavioral and Cognitive Neuroscience Institute based at SFU, and SFU’s ImageTech Lab, a new facility at Surrey Memorial Hospital. Its research-dedicated magnetoencephalography (MEG) and MRI scanners make the lab unique in western Canada.

The researchers took magnetoencephalography (MEG) scans of 41 men between 20-44 years of age. Half had been diagnosed with concussions within the past three months.

They found that concussions were associated with alterations in the interactions between different brain areas–in other words, there were observable changes in how areas of the brain communicate with one another.

The researchers say magnetoencephalography (MEG) offers an unprecedented combination of “excellent temporal and spatial resolution” for reading brain activity to better diagnose concussion where other methods fail.

Relationships between symptom severity and magnetoencephalography (MEG) based classification also show that these methods may provide important measurements of changes in the brain during concussion recovery.

The researchers hope to refine their understanding of specific neural changes associated with concussions to further improve detection, treatment and recovery processes.

Citation:  “Detecting Mild Traumatic Brain Injury Using Resting State Magnetoencephalographic Connectivity.” Vakorin, Vasily A., Sam M. Doesburg, Leodante da Costa, Rakesh Jetly, Elizabeth W. Pang, and Margot J. Taylor. PLOS Computational Biology 12, no. 12 (2016): e1004914.
DOI: 10.1371/journal.pcbi.1004914
Research funding: Defense Research and Development Canada.
Adapted from press release by Simon Fraser University.

New biomarker based on expression of SHOX2 gene for predicting survival in Gliomas

Researchers at UT Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment. The findings are published in EBiomedicine.

Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate-grade gliomas.  “As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations,” said Dr. Adi Gazdar, Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center.

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According to the National Cancer Institute, cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent.
Knowing the probable survival status of an individual patient may help physicians choose the best treatment. In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis.

“Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined,” said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

Citation: “SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas”. Yu-An Zhang1, Yunyun Zhou1, Xin Luo, Kai Song, Xiaotu Ma, Adwait Sathe, Luc Girard, Guanghua Xiao and Adi F Gazdar. EBioMedicine 2016 vol: 13 pp: 80-89.
DOI: 10.1016/j.ebiom.2016.10.040
Research funding: NIH
Adapted from press release by UT Southwestern Medical Center.

NeuroVascular Unit on a chip created to mimic functions of Blood-brain barrier

The blood-brain barrier is a network of specialized cells that surrounds the arteries and veins within the brain. It forms a unique gateway that both provides brain cells with the nutrients they require and protects them from potentially harmful compounds.

This is an illustration of the neurovascular unit on a chip.
Credit: Dominic Doyle, Vanderbilt University

An interdisciplinary team of researchers from the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) headed by Gordon A. Cain University Professor John Wikswo report that they have developed a microfluidic device that overcomes the limitations of previous models of this key system and have used it to study brain inflammation, dubbed the “silent killer” because it doesn’t cause pain but contributes to neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. Recent research also suggests that it may underlie a wider range of problems from impaired cognition to depression and even schizophrenia.

The project is part of a $70 million “Tissue Chip for Drug Testing Program” funded by the National Institutes of Health’s National Center for Advancing Translational Sciences. Its purpose is to develop human organ-on-a-chip technology in order to assess the safety and efficacy of new drugs in a faster, cheaper, more effective and more reliable fashion.

The importance of understanding how the blood-brain barrier works have increased in recent years as medical researchers have found that this critical structure is implicated in a widening range of brain disorders, extending from stroke to Alzheimer’s and Parkinson’s disease to blunt force trauma and brain inflammation.

Despite its importance, scientists have had considerable difficulty creating faithful laboratory models of the complex biological system that protects the brain. Previous models have either been static and so have not reproduced critical blood flow effects or they have not supported all the cell types found in human blood-brain barriers.

The new device, which the researchers call a NeuroVascular Unit (NVU) on a chip, overcomes these problems. It consists of a small cavity that is one-fifth of an inch long, one-tenth of an inch wide and three-hundredths of an inch thick – giving it a total volume of about one-millionth of a human brain. The cavity is divided by a thin, porous membrane into an upper chamber that acts as the brain side of the barrier and a lower chamber that acts as the blood or vascular side. Both chambers are connected to separate microchannels hooked to micropumps that allow them to be independently perfused and sampled.

To create an artificial blood-brain barrier, the researchers first flip the device over so the vascular chamber is on top and inject specialized human endothelial cells. They found that if they maintain a steady fluid flow through the chamber during this period, the endothelial cells, which left to themselves form shapeless blobs, consistently orient themselves parallel to the direction of flow. This orientation, which is a characteristic of the endothelial cells in human blood-brain barrier, has been lacking in many previous models.

After a day or two, when the endothelial cells have attached themselves to the membrane, the researchers flip the device and inject the two other human cell types that form the barrier — star-shaped astrocytes and pericytes that wrap around endothelial cells — as well as excitatory neurons that may regulate the barrier. These all go into the brain chamber that is now on top. The porous membrane allows the new cells to make physical and chemical contact with the endothelial cells just as they do in the brain.

The researchers were able to purchase the human endothelial cells, astrocytes and pericytes that they need from commercial sources. For the excitatory neurons required, they turned to Vanderbilt University Medical Center collaborators M. Diana Neely, research associate professor of pediatrics, and Aaron Bowman, associate professor of pediatrics, neurology and biochemistry. Starting with human induced pluripotent stem cells that are generated directly from adult cells they were able to produce the specialized neurons that the project needed.

“This is one of the most exciting projects I’m involved with,” said Neely. “Although it’s still in its infancy, it has tremendous potential.” According to Bowman, one potential application is to develop tissue chips that contain cells from individual patients, making it possible to predict their personal reactions to different drugs.

“Once we had successfully created the artificial barrier, we subjected it to a series of basic tests and it passed them all with flying colors. This gives us the confidence to state that we have developed a fully functional model of the human blood-brain barrier,” said VIIBRE staff scientist Jacquelyn Brown, who is first author of the paper “Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor” that described this achievement in the journal Biomicrofluidics.

“The NeuroVascular Unit (NVU) on a chip has reached the point where we can begin using it to test different drugs and compounds,” observed team member Donna Webb, associate professor of biological sciences who is interested in studying how different substances affect synapses — the junctions between neurons. “There is an urgent need for us to understand how various substances affect cognitive processes. When we do, we will be in for a number of surprises!

Already, the VIBRE team has used the NeuroVascular Unit (NVU) on a chip to overcome a basic limitation of existing studies of brain inflammation, which have only produced snapshots of the process at various stages. Because the NeuroVascular Unit (NVU) on a chip can be continuously monitored, it has provided the first dynamic view of how the brain and blood-brain barrier respond to systemic inflammation.

These results are summarized in a paper titled “Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit” accepted for publication in the Journal of Neuroinflammation.

The scientists exposed the NeuroVascular Unit (NVU) on a chip to two different compounds known to induce brain inflammation: a large molecule found on the surface of certain bacteria called lipopolysaccharide and a “cocktail” of small proteins called cytokines that play an important role in immune response to inflammation.

“One of our biggest surprises was the discovery that a critical component in the blood-brain barrier’s response to these compounds was to begin increasing protein synthesis,” said Brown. “Next will be to find out which proteins it is making and what they do.”

The researchers also found that the blood vessels in the barrier respond to inflammation by pumping up their metabolic rate while the metabolism of the brain cells slows down. According to Brown, “It might be that the vasculature is trying to respond while the brain is trying to protect itself.”

Citation: “Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit” accepted in Journal of Neuroinflammation.
Research funding: NIH

Adapted from press release by Vanderbilt University.