The latest research progress of epilepsy

September 22, 2019 / BIOON / -- this issue brings you the latest research progress on epilepsy I hope readers will like it 1 Nature: great progress! It is the first time to analyze the three-dimensional structure of human synaptic GABAA receptor It is expected to develop a new drug doi: 10.1038/s41586-018-0255-3 for the treatment of epilepsy and other neurological diseases Many drugs, whether legal or illegal, act on one of the most abundant and important neurotransmitter receptors in the brain: type a GABA receptor (GABAA receptor) Especially famous are benzodiazepine, which are used for anesthesia during surgery and for the treatment of epilepsy, anxiety and insomnia Two kinds of drugs are widely used in the treatment of epilepsy, anxiety and insomnia Understanding the three-dimensional structure of this receptor may one day lead to the development of better treatments for these diseases GABAA receptor binds to GABA, which is the main inhibitory or sedative neurotransmitter in adult brain In order to function properly, the brain needs to balance stimulatory and sedative signals GABAA receptor dysfunction is found in diseases characterized by hyperactivity in the brain, such as epilepsy In addition to the sedative benzodiazepines, GABAA receptor is a common target for barbiturates, anesthetics and alcohol All of these drugs act on the brain by increasing the activity of GABAA receptor, thus further inhibiting brain activity As we all know, the three-dimensional structure of GABAA receptor is difficult to be resolved by X-ray diffraction crystal analysis For a long time, this method has been regarded as the gold standard of structural biology It requires protein crystallization so that the protein structure can be determined from the X-ray diffraction pattern In a new study, researchers from the Southwestern Medical Center at the University of Texas in the United States sought the help of cryo em Using cryo EM technology, they successfully resolved the three-dimensional structure of GABAA receptor binding to GABA and flumazenil for the first time The relevant research results were published online in the journal Nature on June 27, 2018, with the title of "structure of a human synthetic GABAA receiver" The corresponding author is Dr Ryan Hibbs, assistant professor of neuroscience and Biophysics, Southwestern Medical Center, University of Texas The first author of this paper is Dr Shaotong Zhu, postdoctoral researcher of Hibbs laboratory The researchers used cells to express and purify the human synaptic GABAA receptor in flasks, and combined electrophysiological experiments with structural information obtained by cryo EM technology to test the effects of diazepam (a benzodiazepine) and flumazenil on the GABAA receptor, of which flumazenil was used to reverse anesthesia and to treat benzodiazepine overdose, Dr Hibbs "We were able to determine how GABA selectively binds to this receptor and explain why drugs such as benzodiazepines and flumazenil, which competitively act on the same site to reverse the effects of benzodiazepines, act specifically on this receptor," he said This has a profound impact on the understanding of drug binding mechanisms and the design of new drugs for the treatment of a variety of neurological diseases " 2 NAT commun: genetics reveals a new target for epilepsy doi: 10.1038/s41467-018-07524-z recently, a large-scale study led by scientists from rcsi (Royal College of surgery in Ireland) and other international researchers found 11 new genes related to epilepsy The study was published in the recent journal Nature communications It greatly promotes the understanding of the potential biological causes of epilepsy, and may provide information for the development of new treatment methods of epilepsy The researchers compared the DNA of more than 15000 epileptics with that of 30000 healthy people The results showed that 11 new genes were related to epilepsy Researchers found that most of the current antiepileptic drugs directly targeted one or more related genes, and indirectly identified another 166 drugs targeting the same gene "In addition to the biological insights provided by the findings, this study will encourage researchers to develop personalized and accurate treatments for patients with difficult and complex epilepsy This will provide better epilepsy therapy and will improve the quality of life of patients and their families, "said neuroscientist Norman Delanty, associate professor 3 Cell: shock! Intestinal bacteria play a key role in the antiepileptic effect of ketogenic diet doi: 10.1016/j.cell.2018.04.027 in a new study, researchers from UCLA identified specific intestinal bacteria that play an important role in the antiepileptic effect of high fat and low carbohydrate ketogenic diet The study is the first to establish a causal relationship between susceptibility to epilepsy and gut microbiota - about 100 trillion bacteria and other microbes in the human gut Relevant research results were published online in the cell Journal on May 24, 2018, under the title of "the gut microbiota mediates the anti sezure effects of the ketogenic sheet" The corresponding author is Dr Elaine Hsiao, assistant professor of comprehensive biology and physiology, UCLA Hsiao said the ketogenic diet has many health benefits, including fewer seizures in children with epilepsy who do not respond to antiepileptic drugs However, there is no clear explanation for how this diet can help children with epilepsy Researchers at Hsiao's lab speculated that intestinal flora changed through this ketogenic diet and that the antiepileptic effect of this diet was important Hsiao's team looked at whether the gut microbiome affected the ketogenic diet's ability to prevent seizures, and if so, how the gut microbiome achieved these effects In the study of mice as a more comprehensive animal model of epilepsy, the researchers found that the diet significantly altered intestinal flora in less than four days, and that mice on the diet had significantly fewer seizures To test whether intestinal microflora is important in preventing seizures, the researchers analyzed the effects of a ketogenic diet on two types of mice: those that are kept as sterile in a sterile laboratory environment, and those that are treated with antibiotics to kill intestinal microbes "In these two mice, we found that the ketogenic diet was no longer effective in preventing seizures," said Christine Olson, the first author of the paper and a graduate student at Hsiao laboratory This suggests that intestinal flora is necessary for this diet to effectively reduce seizures " The researchers identified the exact nucleotide molecular sequence of the gut microbiome DNA in order to determine which bacteria were present and how well they were on the diet They identified two types of bacteria, akkermansia muciniphila and parabaracteroids, which increase their levels on a ketogenic diet and play a key role in providing this protection With this new knowledge, the researchers studied sterile mice given the two bacteria "We found that if we could give these two specific bacteria together, then we could restore the protective effect of the ketogenic diet on these mice," Olson said If we give one of these two bacteria, they won't stop the seizure This shows that these two different bacteria have a unique function when they both exist " The researchers measured the levels of hundreds of biochemical substances in the gut, blood and hippocampus, an area of the brain that plays an important role in spreading epilepsy They found that these bacteria, whose levels in the gut microbiome can be increased by a ketogenic diet, alter the levels of biochemical substances in the gut and blood in a way that affects neurotransmitters in the hippocampus How do these bacteria do this? "These bacteria increase the level of GABA, a neurotransmitter that silences neurons, relative to glutamate, a neurotransmitter that activates neurons to discharge," said Helen Vuong, a postdoctoral scholar at the Hsiao laboratory "This study encourages us to study whether similar effects of gut microbes are also observed in people on a ketogenic diet," Vuong said "These effects on health and disease are promising, but more research is needed to test whether the findings in mice also apply to humans," Hsiao said 4 Science: it is found that a group of specific nerve cells control the spread of epilepsy in the brain doi: 10.1126/science.aan4074 temporal lobe epilepsy is the most common form of epilepsy in adults In a new study, researchers from Stanford University School of Medicine found that activating a small group of nerve cells in the brain by experimental means can prevent seizures in temporal lobe epilepsy mice By contrast, deactivating these neurons, which neuroscientists call mossy cells, helps to spread local hyperactivity throughout the brain during seizures, leading to all behavioral symptoms of temporal lobe epilepsy The relevant research results were published in the Science Journal on February 16, 2018, and the title of the paper is "dent gyrus mossy cells control intermittent continuous sezures and spatial memory" The researchers found that deactivation of these neurons also induces a characteristic cognitive loss of chronic drug-resistant temporal lobe epilepsy in humans Epilepsy affects 65 million people worldwide, with 150000 new cases diagnosed each year in the United States alone Three fifths of epilepsy cases are temporal lobe epilepsy The gradual loss of protoplasmic astrocytes is a characteristic of the disease Protoplasmic astrocytes are known to be damaged by head trauma and reduced blood supply This brain injury then increases the risk of temporal lobe epilepsy The role of protoplasmic astrocytes in epilepsy has puzzled neuroscientists for decades This new study offers an explanation It points out a new starting point for the development of drugs that may provide therapeutic relief for patients with chronic drug-resistant epilepsy This chronic drug-resistant epilepsy is a debilitating disease that not only limits the lifestyle and career choices of patients, but also makes them prone to depression, anxiety and premature death "In principle, it is possible to develop targeted therapies for protoplasmic astrocytes to control seizures and the resulting cognitive deficits," said Ivan soltesz, Ph.D., senior author of the paper and professor of Neurosurgery at Stanford University School of medicine That's good, because at least 20 compounds that are now approved for use in patients fail 30 to 40 percent of the time " The correspondence author for this paper is Dr Anh bui, a former graduate student of soltesz Bui is now a medical student at the University of California, Irvine Electrical storm seizures in the brain are sometimes described as electrical storm in the brain This electrical storm usually starts at a single site in the brain, known as a lesion, where nerve cells (for unspecified reasons) begin to discharge repeatedly and synchronously They often expand from this focus