The key factor leading to epileptic seizures in rats has been identified by Russian scientists who investigated the complex interaction of neural signals.
The scientists studied the complex changes in the temporal lobe cortex of a rat brain during prolonged epileptic seizes to identify the key factor leading to the seizures. The work has been published in Frontiers in Cellular Neuroscience.
Epistatus is the condition where a person subject to epilepsy experiences seizures which follow each other after a short time. The condition is considered to be particularly dangerous. Although scientists know that this is caused by an excessive excitation of neurons in the brain, the reason for such neuron activity is unclear.
The difficulty of analysing individual neuron signals
Anton Chizhov is a doctor of physical and mathematical sciences, senior researcher at the Ioffe Institute of RAS, and Leading Researcher at Sechenov Institute of Evolutionary Physiology and Biochemistry. Chizhov explained:”Neurons send each other signals that can be excitatory or inhibitory, depending on the type of target receptor on the cell membrane. For example, the first are those that react to glutamate and its analogues, the second are sensitive to gamma-aminobutyric acid or GABA. Yet GABA receptors of those suffering with the epilepsy also become exciting. There lies the main research difficulty: when several signals act on the neuron at once it is very difficult to assess their individual contribution.”
The key mechanism causing epileptic seizures
The researchers investigated the signalling processes in the cortex of the temporal lobe before and after the rat epileptic seizures. They examined the effect of amino acids on receptors of all major types. They found that each of the components of the signal after epileptic electrical discharges becomes stronger and longer.
In order to find out what happened as a result of affecting only one amplified signal on the remaining paths, the team created a mathematical model of interacting nerve cells system.
The results showed that only the conductivity of the AMPA receptors in the network of neurons significantly changes. This leads to stronger excitation of all neurons and stronger synaptic signals recorded on one nerve cell. Chizhov added: “Further studies showed that this is the mechanism of synaptic plasticity with the incorporation of new calcium-permeable AMPA receptors into the cell membranes. Under normal conditions, such a process in the brain is associated with memory and learning, but under pathological conditions it leads to an excitability increase up to tens of minutes. Therefore, the risk of a new convulsive discharge rises, which may lead to pathology fixation.”
Chizhov concluded: “Knowing that embedding calcium-permeable AMPA receptors leads to the consolidation of seizure activity, we can develop new antiepileptic drugs.”
SOURCE: SCITECH Europa
For people with severe epilepsy, no medication is effective – but a radical approach of implanting stem cells into the brain could stop seizures at their source.
The technique, which has so far shown promise in rats, would involve taking some of a patient’s own skin cells and turning them into embryonic-like stem cells in the lab. These can then be directed to become a kind of brain cell that damps down seizures.
Epilepsy arises when there is an imbalance between two different kinds of nerve cell in the brain; excitatory ones, which cause other cells to fire, and inhibitory ones, which block firing. Seizures result when excitation swamps inhibition.
For some people with epilepsy, the surge of excitation starts in one part of the brain, called the hippocampus, before spreading elsewhere. So Ashok Shetty at Texas A&M University and his colleagues tried boosting inhibition at that site to see what would happen.
First, Shetty’s team injected 38 rats with a chemical that triggers a long seizure. The resulting brain damage causes the animals to have spontaneous seizures, starting from the hippocampus, over the next few months.
A week after the initial damage, the team implanted inhibitory brain cells in the hippocampi of about half the rats. Five months later, those given implanted cells had 70 per cent fewer seizures than those without implants.
To check it was really the inhibitory cells working, five implanted animals were given cells that were genetically modified to stop firing when the animal was dosed with a drug. When under the drug’s influence, these mice had about the same number of seizures as mice that hadn’t had any cells implanted.
Dissections also showed that the implanted cells survived in the hippocampus.
Shetty says the treatment could be suitable for people whose seizures originate in a small part of their hippocampus, and whose only other option is surgery to remove that part. They could try a cell implant instead, and if something went wrong, they could have all the graft removed along with the epileptic brain tissue. And if the therapeutic cells were made from a patient’s own skin, they wouldn’t need medicines to stop rejection.
The study isn’t proof this approach will work, though, says Bruno Frenguelli at the University of Warwick, UK. The rats were given implants soon after their brain damage, and it isn’t clear if the technique would help people with seizures stemming from a head injury in the past, which is a common cause of epilepsy.
Journal reference: PNAS, DOI: 10.1073/pnas.1814185115
SOURCE: Written By C. Wilson for NewScientist.com
With funding from NIH Phase II SBIR grant, Neuroene Therapeutics will take the next steps toward bringing their vitamin K analogues for drug-resistant epilepsy to clinical trial
Neuroene Therapeutics, a start-up company founded by mitochondrial biologist Sherine S. L. Chan, Ph.D. and medicinal chemist C. James Chou, Ph.D. of the Medical University of South Carolina, has received a $1.5 million NIH Phase II Small Business Innovation Research grant to optimize vitamin K analogues that could improve seizure control in patients with drug-resistant epilepsy. Richard Himes, Ph.D., a chemist at the College of Charleston, serves as the company’s Chief Scientific Officer.
Photo: Dr. Chan and Dr. Chou are the founders of Neuroene Therapeutics, an MUSC start-up company that was awarded a 1.5M SBIR Phase II grant to develop a novel anti-seizure compound for drug-resistant epilepsy.
Of the 3.4 million Americans estimated to have epilepsy, one third do not receive adequate seizure control with current medications, either because the drugs do not work for them or because they cannot tolerate the drug’s side effects.
The SBIR grant will enable Neuroene Therapeutics to test the efficacy and safety of its lead compounds, which are analogues of a naturally occurring form of vitamin K that is essential for mitochondrial and neuronal health.
“Mitochondria are the powerhouses of the cell, and the brain needs a lot of energy for its function. A particular form of vitamin K protects the integrity of the mitochondria and helps them produce enough energy for brain cells,” explained Chan.
The form of vitamin K needed by the brain is not the same as the vitamin K we get from foods in our diet. The vitamin K we eat must first be processed by intestinal bacteria before transport to the brain, and then within neurons must be converted into the specific form of Vitamin K that is needed for mitochondrial and neuronal health.
Because the compound developed by Neuroene Therapeutics mimics this specific form of Vitamin K that the neuron needs (not the ingested form) and because it travels directly to the brain, it bypasses the need for transport systems.
“Unlike other vitamin K analogues, which require additional processing before they are in a usable form, our compounds are a direct substitute for the active form and go directly to the brain where they are needed,” said Chou.
Early testing of these vitamin K analogues by the MUSC investigators with pilot funding from the South Carolina Clinical and Translational Research Institute, a Clinical and Translational Science Awards hub funded by the National Institutes of Health, showed significantly reduced seizure activity with little toxicity in a zebrafish model. Testing in mouse seizure models at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program confirmed those findings.
With assistance from the MUSC Foundation for Research Development, Chan and Chou established Neuroene Therapeutics in 2015 and received a patent on their lead compounds earlier this year.
The current SBIR award will enable additional testing of the compounds’ efficacy and safety at the University of Utah’s Anticonvulsant Drug Development Program, directed by Karen Wilcox, Ph.D., which has robust rodent models of drug-resistant epilepsy. By the end of the two years of SBIR funding, Neuroene Therapeutics will have identified the lead compound to take forward into clinical trial.
Although Neuroene Therapeutics is focused currently on developing its lead compound for drug-resistant epilepsy, Chan and Chou are also studying whether vitamin K analogues could improve outcomes in other difficult-to-treat neurological diseases. They already have some promising preclinical data in Parkinson’s disease and mitochondrial DNA depletion syndrome. In addition, they speculate that the compounds could also be relevant to Alzheimer’s disease.
Apolipoprotein E4, one of the strongest genetic risk markers for late-onset Alzheimer’s disease, has a role to play in vitamin K transport. It is possible, then, that mitochondrial dysfunction due to insufficient transport of vitamin K could be implicated in Alzheimer’s and, if so, these brain-penetrating vitamin K analogues could bypass the transport process, thus improving mitochondrial health and disease outcome.
About Neuroene Therapeutics
Neuroene Therapeutics is a startup biotechnology company developing novel Vitamin K-based therapeutics for neurological disorders such as epilepsy. The company originated from collaborative research between Medical University of South Carolina investigators C. James Chou, Ph.D., and Sherine Chan, Ph.D., who cofounded and continue to lead Neuroene Therapeutics. Visit us at neuroenetherapeutics.com.
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 700-bed medical center, which includes a nationally recognized Children’s Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic programs or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.
About the South Carolina Clinical and Translational Research Institute
The South Carolina Clinical and Translational Research (SCTR) Institute is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise, and streamlining research-related processes to bring about large-scale, change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice.
About MUSC Foundation for Research Development
FRD has served as MUSC’s technology transfer office since 1998. During that period, FRD has filed patent applications on more than 400 technologies, resulting in over 150 U.S issued patents. Additionally, FRD has executed more than 150 licenses and spun out more than 50 startup companies. MUSC startups have had products approved by the FDA and acquired by publicly traded corporations while attracting substantial investment dollars into South Carolina. Innovations from MUSC, including medical devices, therapies and software, are positively impacting health care worldwide. Please visit us online at frd.musc.edu.
Source: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Researchers are hoping an electronic device used to detect, stop and prevent epileptic seizures in mice can be used to treat other neurological disorders, according to a study published in Science Advances.
In the study led by a U.K. research team, scientists looked at the benefits of “direct in situ electrophoretic drug delivery to treat neurological disorders.” The team developed a neural probe with a microfluidic ion pump for on-demand drug delivery and electrodes for recording neural activity.
“The (device) works by electrophoretically pumping ions across an ion exchange membrane and thereby delivers only the drug of interest and not the solvent,” wrote lead author Christopher M. Proctor, of the University of Cambridge, and colleagues. “This ‘dry’ delivery enables precise drug release into the brain region with negligible local pressure increase.”
The device’s therapeutic potential was then implanted and tested on anesthetized mice in which seizure-like events (SLEs) were induced. According to the study, the probe was able to detect the pathological activity and stop seizures by delivering the drug directly to the source. Based on the results, researchers are hoping further development of the device could be used to treat other neurological disorders.
“The (microfluidic ion pump) probe demonstrated the capability to detect, stop, and even completely prevent SLEs in an animal model by timely delivery of inhibitory neurotransmitters to the seizure source,” the authors concluded. “Although this work is focused on epilepsy treatment, we anticipate that tailored engineering of the (microfluidic ion pump) platform will enable additional applications for electrophoretic drug delivery in neural interfacing and the treatment of neurological disorders.”