Monday , April 12 2021

Scientists solve the mystery of centuries-old neuroscience; responses can lead to treatment with epilepsy



PICTURE

PICTURE: Research team led by Harald Sontheimer (right), Virginia Tech Carilion Research Institute, discovered mysterious brain structures called perineuronal nets that help modulate electric impulse activity …
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Credit: Virginia Tech

Scientists from the Virginia Tech Carilion research institute have solved the 125-year brain secret and discovered potential treatment for acquired epilepsy.

Since 1893, scientists have known about mysterious structures called perinectonic waves wrapped around neurons, but the function of the network has remained unattainable.

Now, the research team was led by Harald Sontheimer, Director of the VTCRI Center for Biology in Health Care, Disease and Cure and Executive Director of Neuroscience, a part of the Virginia Tech College of Science, which found that networks modulate electrical impulses in the brain. Moreover, a stroke can arise if the nets grow.

Discovery, published today (Friday, 9 November) in Zagreb Nature of communication, has implications in various forms of acquired epilepsy, a type of seizure disorder that is caused by brain damage caused by trauma, infection, or brain tumors.

"We started investigating tumor-related epilepsy and we accidentally learned something else important about how the brain works in disease and health," Sontheimer said.

Researchers initially found their findings in a mouse model of epilepsy caused by deadly brain cancer known as glioblast, whose first symptom is often a seizure.

Glioblastoma is the only cancer whose growth is limited by space. Since skull blocks cancer by extending outwardly, the tumor produces an excitatory chemical neurotransmitter called glutamate in excessive quantities that kills adjacent healthy cells to stretch.

The researchers found that glutamate has targeted brain cells that produce a different chemical neurotransmitter called "GABA," which usually calms the neurons by disabling them to release electrical impulses after the messages are transmitted. Without GABA, the brain becomes too excited and can take advantage of it.

Apart from glutamate, the tumor also secretes an enzyme destined to destroy the surrounding extracellular matrix, a substance similar to the gel that holds the brain cells in place. Glioblastomas are very malignant and notoriously invasive – the enzyme is a knife that reduces cannabis cancer and allows it to freely migrate.

"We have also unexpectedly seen an enzyme that attacks attacking perineurons," Sontheimer said, pointing out that the networks are primarily wrapped around GABA inhibitory neurons, which help to prevent seizures. "It was a surprise to see this observer of the seizure effect after the neurons were seized by the nets."

The Italian neurobiologist Camillo Golgi was the first to identify the perineurope network in 1893 but misunderstood their function. Golgi called the "corks" network and said they were most likely to interfere with sending messages between the neurons.

On the contrary, Sontheimer found a network that enabled messaging. Neurons covered by perineuronic nets have reduced membrane capacity or ability to store electrical charges, meaning they can boost the pulse and replenish up to twice as fast as neuronal neurons.

When inhibitory neurons suddenly lose perineuronal nets, results may be catastrophic. The researchers applied an enzyme to the brain without tumors and saw that the enzyme degradation of the perineuronic nets was sufficient to cause seizures – even when neurons remained intact.

"Without perineuronal nets, inhibitory neurons would be too laid-back and hence the inhibition would become too small, too late, and even in the otherwise healthy brain," Sontheimer said, pointing out that the enzyme can devour the perineuronal network in less than 30 minutes. "Nobody thought these structures would have such a profound impact on how normal processes work."

Researchers are now investigating how perineuronal nets can play a role in other forms of acquired epilepsy, which may be a result of head injury or brain infection. Such clarification could lead researchers to discover potential pharmacological solutions.

"It is important to ascertain that tumor-induced disorder in perineuronal nets contributes to unbalanced inhibition neurotransmission suggests a new goal of therapeutic intervention in tumor-related seizure control," said H. White, PhD, professor and president of the Department of Pharmacy at the University of Washington School of Medicine in Seattle, Washington.

White, a renowned epileptic expert and anticonvulsant drug research, was not included in the Sontheimer study.

"While additional studies are needed, it is likely that the findings reported by Dr. Sontheimer and his team are applicable to other forms of acquired epilepsy in which brain injury is associated with increased inflammatory response," White said, pointing out implications for treatment and prevention of epilepsy are particularly impressive because current therapies are targeted at seizure control. "While the control of disease symptoms is significant, the results of this study point to a possible pathway to the modification of development and progression of epilepsy, which would reduce the overall burden on the patient."

According to the World Health Organization, more than 50 million people worldwide have epilepsy. About one-third of these people are not responding to current antiepileptic treatments.

"If we confirm the hypothesis that digestive perineurotic networks are responsible for other forms of acquired epilepsy, then potential treatment could be an enzyme inhibitor," Sontheimer said.

He noted that one such inhibitor was already approved by the FDA for other uses, but also warned that there is a significant amount of research to be conducted before their hypothesis is confirmed.

"New approaches to treatment of epilepsy are needed. I think this could be an effective way to control seizures," Sontheimer said. "And we solved the 125-year secret of neuroscience! That's what it's all about fundamental science – maintaining an open and thoughtful mind to answer the old and new issues."

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This study was supported by VTCRI, School of Neuroscience and National Institute of Neurological Disorders and Strokes. The contributors are Bhan Tewari, Postdoctoral Associate at Sontheimer's Laboratory at VTCRI; Lata Chaunsali, Sontheimer Laboratory Coordinator; Susan Campbell, Associate Professor of VTCRI and Department of Animal and Poultry Science at Virginia Tech; Dipan Patel, Postdoctoral Associate at Sontheimer's Laboratory; and Adam Goode, a student at the Virginia Tech Carilion Medical School, conducting research at the Sontheimer Laboratory.


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