Help people with drug-resistant epilepsy out of treatment

June 28 will celebrate the 17th International Epilepsy Care Day, and this year’s theme is “Standardized Care for Epilepsy: From In-Hospital to Out-of-Hospital”.

Not long ago, a research team from the School of Life Sciences of Nanjing University and Nanjing Gulou Hospital revealed for the first time the presence of reactive astrocytes (LARA) with lipid accumulation in the brains of patients with temporal lobe epilepsy (TLE), and pointed out the role of such cells in promoting the development of epilepsy, which is expected to provide a new treatment option for drug-resistant epilepsy. The research was published in Nature Neuroscience.

Chen Zhangpeng, a distinguished assistant researcher at Nanjing University, said in a recent interview with China Science News: “Our team began to study temporal lobe epilepsy in 2018, hoping to start from neuropharmacology to help epilepsy patients get out of the dilemma of drug resistance. ”

Do ex vivo epilepsy brain film model drug screening and validation. Photo courtesy of interviewee

Why temporal lobe epilepsy is studied

Previous studies have shown that epilepsy is one of the neurological disorders characterized by convulsions and loss of consciousness, with an incidence of nearly 1%. According to clinical data, two-thirds of epilepsy patients can be cured clinically, that is, after 2~3 years of formal anti-epileptic drug treatment, slow drug reduction can be achieved.

“Temporal lobe epilepsy is the most common type of focal epilepsy, and about 30% of patients with temporal lobe epilepsy will gradually develop drug-refractory epilepsy, and these patients have very limited treatment except surgery.” Chen Zhangpeng told China Science News, “The operation requires craniotomy, which is expensive, traumatic, and has many postoperative complications, which ordinary families cannot afford.” The original intention of our research is to start from traditional pharmacology, find targets and new drugs for the treatment of epilepsy, control costs, and reduce patients’ pain. ”

A study presented by the American Epilepsy Society at its 2014 annual meeting showed that cannabidiol, a component of marijuana, played a role in the clinical symptoms of children with epilepsy that are currently ineffective in treatment, reducing seizure rates by 32%.

In order to further understand the relationship between cannabidiol and epilepsy, Professor Yan Chao’s research group of Nanjing University began to study epilepsy in 2018, hoping to find a target for the treatment of epilepsy through the pre-collated cases. In that year, Chen Zhangpeng, who graduated with a doctorate, joined the research group to participate in related research.

The study found that the two main pathological features of the epileptogenic area of patients with drug-refractory epilepsy are neuronal death and the production of glial scars, one of the main components of glial scars is reactive astrocytes. Reactive astrocytes here are found in a variety of neurological diseases such as Alzheimer’s disease and multiple sclerosis, and are closely related to disease progression.

However, in temporal lobe epilepsy, the functional role of reactive astrocytes and their molecular characteristics remain unclear.

Previously unreported subtypes are found

Chen Zhangpeng introduced that this study first analyzed the magnetic resonance imaging spectral data of patients with drug-resistant temporal lobe epilepsy (TLE), and found that there was a significant enhancement of lipid signal on the epileptogenic side and the healthy side of the same patient, indicating abnormal accumulation of lipids on the epileptogenic side.

In order to explore whether abnormal lipid accumulation can lead to changes in the expression of genes related to lipid metabolism, the researchers collected 4 drug-resistant TLE patients and 4 age-matched normal brain tissue samples for single-cell nuclear RNA sequencing analysis, and found that neurons and astrocytes of TLE patients had abnormal activation of lipid metabolism and transport signaling pathways, among which astrocytes were particularly prominent, and apolipoprotein E (APOE) was significantly expressed in astrocytes.

In this regard, the researchers hypothesized that under chronic epilepsy conditions, lipids first accumulate in neurons, and astrocytes-derived APOE transports lipids into astrocytes, causing lipid accumulation in astrocytes. Further experiments have tested this hypothesis.

What is “extraordinary” about this group of astrocytes that are highly expressing APOE and have abnormal lipid accumulation? The researchers divided the astrocytes cluster into 6 subpopulations, one of which had significantly higher expression of genes related to lipid metabolism and transport and exhibited the highest levels of APOE expression.

“The transcriptome characteristics of this subgroup are different from those of the previously reported reactive astrocyte subtype and are a completely new subtype, so we defined this subgroup as lipid-packed reactive astrocytes and named LARA.” Chen Zhangpeng told China Science News.

Next, they systematically studied the functional phenotype of LARA in temporal lobe epilepsy and found that LARA has epileptogenic effects, and mainly exerts seizure-promoting functions through adenosine A2AR.

“Both the use of inhibitors to inhibit adenosine A2AR and the use of virus-specific knockdown of adenosine A2AR on star glue improved the number and duration of seizures in mice with temporal lobe epilepsy.” Chen Zhangpeng said, “Studying how lipid metabolism regulates the mechanism of epilepsy provides us with a good treatment strategy and target for the treatment of epilepsy. ”

Some of the difficulties encountered in the study

“In the study, we need to take samples from clinical patients to measure their EEG signatures.” Chen Zhangpeng told China Science Daily about the difficulties encountered in the process of combining basic research and clinical research, “After obtaining fresh samples from the clinic, high activity needs to be guaranteed during the period from the hospital to the laboratory, but it is often difficult to ensure it for various reasons. ”

In order to maintain the high activity of the sample, Chen Zhangpeng and others read a lot of materials and borrowed relevant foreign literature to try to establish a drug screening platform that can maintain the high electrophysiological activity of the sample. “Our platform is also the first platform established in China, which can ensure that the sample activity meets the needs of the experiment.”

In addition, Chen Zhangpeng also found that there is only a 50% success rate when obtaining samples in the clinic, he explained: “The acquisition of samples has a lot to do with the location of surgery and operation techniques, half of the failures are acceptable, and we will try to optimize them in the future.” ”

“There will be various difficulties in doing research, the experimental platform level is quite good, and sometimes there is a node that does not know how to go down, fortunately we have successfully solved it.” Chen Zhangpeng hopes that the detours he has taken can be avoided by his peers and students.

“In our study, we found that if the traditional way is used, the model of kainic acid (KA) is not very stable, and the results are quite different.” Chen Zhangpeng said, “In the modeling of temporal lobe epilepsy, the pathological manifestations of KA-induced mice with temporal lobe epilepsy are more obvious when the symptoms are more severe, but the mice are easy to die at this time, so the modeling needs to be careful.” ”

At the end of the interview, Chen Zhangpeng told reporters that this study had tried to submit to journals with higher impact factors, but was rejected for various reasons, which does not rule out that it is related to the relatively small research field. “When submitting the Nature Neuroscience, a number of reviewers made very demanding requests and suggested that we change all 2D multiplex fluorescent labels to 3D multiplex fluorescent labels, which is a huge task and we have not done 3D reconstruction before, which brings a lot of challenges.”

The final published paper received high praise from anonymous reviewers: “The role of astrocytes in epilepsy has not been fully studied, and this study provides convincing evidence.” (Source: Shen Chunlei, China Science News)

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