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Researchers Identify Pathway in Temporal Lobe Epilepsy and Potential Therapeutic Target


NEW ORLEANS—Administering a Wnt antagonist after seizures are induced in a mouse model of temporal lobe epilepsy modulates neuronal network remodeling, offering new insight into a potential therapeutic target, researchers said here at the American Epilepsy Society annual meeting.

The Wnt pathway has many roles in the nervous system, making it an intriguing area of study in epilepsy, said presenter Kunal Gupta, MBBChir, PhD, chief resident in neurological surgery at Oregon Health & Science University.

"Within the nervous system, it is involved in axon pathfinding, dendrite outgrowth, neurogenesis, as well as behavioral tasks in mice, including memory and learning," he explained. "Epilepsy is characterized by a number of these neuronal changes, which have been proposed to be responsible for seizure production. It is therefore possible that Wnts are at least partly responsible for the production and maintenance of epileptic networks."

"We demonstrate that the Wnt pathway is critical to changes in neuronal behavior in the dentate gyrus and is dysregulated early in the post-ictal period," he and colleagues wrote in their abstract. "These changes are especially marked in the peri-ictal zones and may underlie the formation of epileptic foci away from the primary ictal zone. Therapies targeting Wnt activity and network remodeling may prevent the acquisition of delayed epilepsy in high-risk patients."

For the experiment, researchers injected kainic acid into the hippocampus, inducing generalized seizures, and afterward assessed the response in four quadrants — the ictal zone, or the ipsilateral dorsal region; the peri-ictal zones of the ipsilateral ventral region; contralateral dorsal region; and contralateral ventral region farthest from the injection site.

They found a 1.9-fold increase in neurogenesis (p<.05) and a 2.4-fold increase in dendrite arbor length (p<.05) in peri-ictal regions, and decreased neurogenesis in the ictal zone two weeks after the injection.

The research team administered a Wnt antagonist, XAV939, daily for two weeks after the injection. With that drug, they saw a 1.6-fold increase in dendritic arborization (p<.05), while neurogenesis remained unchanged.

In a transcriptional analysis, they found dysregulation of Wnt genes — Wnt 5A, Wnt 7A, Wnt 9A and DKK1 (p<.005 for the Wnt genes and p<.05 for DKK1).

"Intriguingly, certain Wnt genes demonstrated differential patterns of dysregulation between the ictal and peri-ictal zones," the study authors said. "These transcriptional changes might underpin the development of delayed epilepsy in this model."

Dr. Gupta said the goal would be to reduce seizure burden after inciting events by targeting the Wnt pathway but he acknowledged there is a lot that is not known.

"Initial studies would look for changes in post-ictal neuronal network remodeling to see if these changes normalize to baseline and if normal synaptic connections are maintained," he said. "Given the extensive scope of the Wnt pathway and its various roles in normal physiological processes, the key will be targeting the appropriate pathway and limiting off-target effects. Studies in a range of model platforms including in vitro and in vivo will help define these better and allow advancement to pre-clinical trials."

Astrid Nehlig, PhD, research director at the National Institute of Health and Medical Research in Strasbourg, France, said that finding involvement of the Wnt pathway in neuronal remodeling after seizures in this model is "no big surprise."

"The strong seizures that occur in this model generate a devastating insult, which most likely involves a large number of pathways," she said. "At this point, nobody is able to tell what really happens during these changes and which ones are really critical that, if stopped, would prevent the disease."

She added that "the solution is likely going to come from studies using combined treatments."

"The study authors describe a pathway that appears to be involved in the process. But nobody can tell whether acting on this pathway would be sufficient to prevent or change the severity of epilepsy."

Drs. Gupta and Nelig reported no disclosures.


AES Abstract 1.104: Gupta K, Schnell E. The small molecule WNT antagonist XAV939 modulates neuronal-network remodeling in a translational mouse model of temporal lobe epilepsy.