Experiments in Unifies rodents indicate that this technique promotes the reprogramming of diseased neurons, interrupting crises.
Researchers from the Escola Paulista de Medicina of the Federal University of São Paulo (EPM-Unifesp) investigated, through animal experiments, how high-frequency deep brain stimulation (DBS) can help control epilepsy, a neurological disease characterized as abnormal and excessive. Electrical surges in the brain that repeat and cause seizures. The latest results have been published in the journal Brain Stimulation.
The study, coordinated by Professor Lucien Cuvolan, showed that stimulating the anterior nucleus of the thalamus with electrodes implanted in the central part of the brain is capable of suppressing epileptic seizures in the long term by increasing the production of adenosine, a substance produced by the metabolism energetic. in cells it plays an important role in the process of communication between neurons.
The article is the result of the project “The contribution of adenosine to the antiepileptic role of deep brain stimulation in the anterior nucleus of the thalamus”, developed with the support of the Fundación de Amparo a Pesquisa do Estado de São Paulo (Fapesp). The research is now continuing, in a new phase, in partnership with Rutgers University in the United States.
“When a person has epilepsy, they have a higher amount of adenosine kinase [ADK] in the brain. This enzyme methylate’s the DNA of neurons, a biochemical modification [that adds a methyl group to the molecule] that alters the expression of genes Essentially this changes the function of the cell and may be one of the factors responsible for generating epileptic seizures So when we see that an increase in adenosine with deep brain stimulation leads to a decrease in the enzyme adenosine kinase, we see that there is also a decrease in these crises. We conclude that a kind of neuronal reprogramming is possible. Participation in epilepsy circuits. Our hypothesis is that by stimulating the anterior nucleus of the hypothalamus, an increase in adenosine and a decrease in adenosine kinase lead to an attenuation and even the remission of the crises in some cases, by acting on the transmission of the DNA present in the cells of these circuits brain,” he explains.
The hypothesis that is being tested in the experimental model, with rodents, is that brain tissue can undergo changes in its DNA. “The effect of treating epileptic seizures with deep brain stimulation is gradual in nature, that is, the seizures are reduced over the course of treatment. They do not stop suddenly. This suggests that adenosine may act beyond the simple binding to its receptors, in various “Other mechanisms. One of them, for example, would be the stabilization of the voltage of the neuronal membranes. This is a mechanism that we have yet to investigate further, but there is a strong indication that it may occur.”
According to Luciene, the discovery is important because, in the long term, it could help develop less invasive treatments for patients who do not have an indication for surgery.
We understand that this mechanism of adenosine works as if we are teaching the cell to return to normal. If we are right, we can, for example, start thinking about strategies and treatments for epilepsy itself and not just to reduce seizures, as we have done so far,” the researcher explains to Agência Fapesp.
Epilepsy currently affects more than 50 million people worldwide and about 3 million Brazilians, according to the World Health Organization (WHO). About 70% of cases are controlled with appropriate medications, however, 30% do not respond to medications and there are few alternatives for them, including resection surgery, which involves removing the area of the brain where the seizures occur . it’s happening. When this area is well defined in the patient, the probability of long-term control is reasonably high. However, this does not always happen. In some patients, it is not possible to know where the attacks started, or even if it is known, sometimes it is not possible to be successful with this technique.
For this reason, the Unifesp group is trying, through experiments with rodents, to understand how it can open up other fronts for the treatment of epilepsy, especially of the temporal lobe, which affects 30% of people with the disease.
Surgery to implant electrodes that lead to deep brain stimulation was recently approved in the United States and Brazil as an alternative treatment option for patients who no longer respond to drug therapy. Although clinical studies show that a large number of them reduce seizures, the mechanism of action is still poorly studied.
“In 2010, another important clinical discovery by another group of researchers showed that epilepsy patients who underwent this surgery and had electrodes implanted in the anterior nucleus of the thalamus had a gradual reduction in seizures over years of stimulation Many showed a complete reversal of the condition between two and five years of treatment, with a significant improvement in quality of life, they still lack an understanding of how and why this happened, he says.
The Role Of The Hypothalamus In Epilepsy
The hypothalamus is a kind of “on and off” switch for our actions. It is located centrally in the brain, which receives information from all sensory pathways and distributes it to the cortex. It also establishes important connections between the systems involved in the generation and propagation of limbic epileptic seizures. When an epileptic seizure begins (in a cortical area), necessarily, this information immediately passes through the thalamus and is distributed throughout the circuit, returning to the cerebral cortex from where the manifestations appear in the patient. That is why she was chosen to study at Unifesp, according to Luciene.
“What we’re trying to do, when we’re investigating what’s going on in deep brain stimulation, is prevent this seizure information that occurred at a certain point in the brain from reaching other areas, so that the seizure doesn’t spread.” , explains the coordinator of the study.
According to the scientist, the clinical manifestation of an epileptic seizure is related to the region of the brain where it occurs. The seizure may be rapid or prolonged; with or without change of consciousness; with motor, sensory or sensory phenomena; individually or in groups; When a person is awake or while sleeping, for example. It all depends on where it originated in the brain.
“It’s like an orchestra, your nervous system prepares you to respond, and the thalamus will be the guardian of the throne within this circuit, which includes the hippocampus and other limbic structures that characterize temporal lobe epilepsy”, explains the professor.
“If we modulate the activity of the hypothalamus, through deep brain stimulation, when it goes to speak to the cortex, it will block this transmission of information. Epileptic seizures can lead to responses to muscle contractions and even loss of consciousness. The crisis only has motor expression, for example, if it reaches the motor cortex, which will give the neurons of the spinal cord the disposition of the muscles to contract or not, then, could it happen that a person has a crisis in the hippocampus and if it doesn’t get to the cortex? exposed to these secretions. or lose consciousness,” he explains.
Next Steps
In this next step, says Lucien, the researchers want to understand, among other things, how nerve cell DNA methylation occurs after adenosine kinase is depleted, the process of altering cell function.
“We have seen that adenosine kinase is decreased, which results in DNA methylation at a certain level in mice with epilepsy, but now I am testing to measure exactly this methylation,” he wonders.
In addition, it is also necessary to understand, from now on, that new substances or drugs can be developed to help treat patients, since the mechanism of action of DBS in epilepsy has been understood.
We are conducting a systematic review of experimental models of epilepsy using deep brain stimulation and analyzing a large amount of data. Let’s do more complex DNA analysis, to see what really changes. Whether or not this methylation or methylation will generate different proteins to be transcribed, whether or not the DNA is altered after stimulation. But these are expensive experiences. We are going to present other projects. It would be great if we had a product, maybe a patent, says the researcher.
Christian Jiménez, María Luisa Mota Polo and Eduardo Díaz, from the Department of Physiology at Unifesp, as well as Eric Hargreaves, from the Jersey Shore University Medical Center, and Detlev Buisson, from the Robert Wood School of Medicine also participated in the research. Johnson of Rutgers University. .
