Researchers studying temporal lobe seizures – the most common type of epilepsy – have discovered a compound that reduces seizures in the hippocampus, a region of the brain where many of these seizures originate. The compound, known as TC-2153, reduced the severity of seizures in mice.
Scientists report their findings in the journal Epilepsy.
“We found that TC-2153 ultimately reduces seizure severity in mice by decreasing the activity of hippocampal neurons,” said Jennifer Walters, PhD candidate at Urbana-Champaign of the University of Illinois, who led the research with Hee, a professor of molecular and integrative physiology at U. of I. Jung Chung.
In most temporal lobe epilepsies, seizures begin in the medial temporal lobe, which includes the hippocampus. And 60% or more of patients with medial temporal lobe epilepsy develop drug-resistant seizures, which correlate with the extent of neuronal death and inflammation in the hippocampus. »
Hee Jung Chung, U. of I. Professor of Molecular and Integrative Physiology
The hippocampus plays a central role in learning and memory, so anything that damages it can have devastating consequences for the individual, she said.
The strength of synaptic communication between neurons and the excitability of individual neurons can affect the likelihood of seizures occurring, Chung said.
The finding that TC-2153 decreased the occurrence of seizures was a surprise, the researchers said, because it is primarily known as an inhibitor of a brain-specific protein called STEP that reduces the strength of synaptic communication between cells. 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 the severity of seizures in both male and female mice.”
Female mice responded more to treatment with the compound than males. To determine if TC-2153 interacted with sex hormones, the team repeated the experiment in female mice whose ovaries had been removed.
“It completely abolished the effect of TC-2153,” Walters said. “Therefore, female sex hormones play a role in its effectiveness.” This finding may be relevant to the gender differences seen in temporal lobe epilepsy, she said.
Follow-up experiments in mouse brains and in neuronal cultures revealed a possible mechanism by which TC-2153 decreases seizure severity. The team found that the compound reduced the excitability of individual neurons, suggesting a novel function of STEP, Chung said.
“TC-2153 is a STEP inhibitor,” she said. “Until now, STEP has been known as a negative regulator of neuronal communication, but has never been implicated in regulating the excitability of individual neurons.”
Further studies will explore how TC-2153 works and test its effects on human neurons, the researchers said.
Chung is also a faculty member at the Beckman Institute for Advanced Science and Technology and the Carl R. Woese Institute for Genomic Biology in Illinois.
The National Institutes of Health, University of Illinois Campus Research Board, and Carle Illinois Collaborative supported this research.
University of Illinois at Urbana-Champaign
Walters, J. M. et al. (2022) Pharmacological inhibition of striatal-enriched protein tyrosine phosphatase by TC-2153 reduces hippocampal excitability and seizure propensity. Epilepsy. doi.org/10.1111/epi.17192.