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Team identifies compound with powerful anti-seizure effects

Researchers studying temporal lobe epilepsy, the most common type of epilepsy, discovered a chemical that decreases seizures in the hippocampus, which is where many of these seizures start. 

The scientists report their findings in the journal Epilepsia. In mice, the chemical TC-2153 reduced the intensity of seizures.

“We found that TC-2153 ultimately reduces seizure severity in mice by decreasing the activity of hippocampal neurons,” said Jennifer Walters who led the research with Prof. Hee Jung Chung. “In most temporal lobe epilepsy, the seizures start in the medial temporal lobe, which includes the hippocampus. And 60% or more of patients who have medial temporal lobe epilepsy develop drug-resistant seizures, which correlate with the extent of neuronal death and inflammation in the hippocampus”, said Chung.

Because the hippocampus is so important for learning and memory, any damage to it can have serious ramifications for the individual. According to Chung, the degree of synaptic connectivity between neurons and the excitability of individual neurons can influence the likelihood of seizures. The discovery that TC-2153 reduced the likelihood of seizures was unexpected, according to the researchers, because it is best recognized as an inhibitor of a brain-specific enzyme called STEP, which weakens synaptic transmission between neurons.

“We hypothesized that seizure activity would increase when we used TC-2153 because STEP inhibition would increase synaptic communication,” Walters said. “But we found that it actually reduced seizure severity in both male and female mice.”

The female mice were more responsive to the chemical than the male mice. The researchers repeated the experiment on female mice that had its ovaries removed to see if TC-2153 interacted with sex hormones.

“That completely abolished the effect from the TC-2153,” Walters said. “Therefore, female sex hormones play a role in its efficacy.” This finding may be related to sex differences seen in temporal lobe epilepsy, she said.

A probable mechanism by which TC-2153 reduces seizure severity was discovered in follow-up investigations in mice brains and neuronal culture. According to Chung, the scientists discovered that the molecule lowered the excitability of individual neurons, implying that STEP had a new function.

“TC-2153 is a STEP inhibitor,” she said. “So far, STEP has been known as a negative regulator of neuronal communication but was never implicated in regulating the excitability of individual neurons”, Chung said.

Further studies will look at how TC-2153 works and will test its effects in human neurons, the researchers said.

Team identifies compound with powerful anti-seizure effects

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