TrkB activation as a novel target for drug resistant temporal lobe epilepsy: from animal models to the human epileptic brain

Epilepsy is one of the most common chronic neurological disorders. Unfortunately, all pharmacological agents that are currently in use are merely symptomatic, because they may only quench seizures but do not target the causes of the disease. Furthermore, a high percentage of patients (about 30%) do not respond to any of these drugs. It is urgently needed to identify new treatment options for these pharmaco-resistant patients, and ideally these new treatments should not be symptomatic on seizures but capable of changing the natural history of the disease (i.e., disease-modifying).

Previous evidence showed that brain derived neurotrophic factor (BDNF), through the activation of its high-affinity receptor TrkB, may play a kay role in the generation and recurrence of seizures. However, BDNF cannot be used as a regular drug because, due to its peptidic nature, it cannot cross the blood-brain barrier when peripherally administered and has a short half-life.

Here, we propose to investigate an antioxidant agent and TrkB receptor agonist, 7,8-dihydroxyflavone (7,8-DHF) and another TrkB receptor agonist, LM22A-4 as putative anti-epileptic drugs. Therefore, we will test them in a relevant animal model of mesial temporal lobe epilepsy (mTLE) and in human mTLE tissue surgically resected from drug-resistant patients. Specifically, our study on the animal model will provide information on efficacy against seizures, epilepsy-associated comorbidities and induced pathological traits (such as hippocampal sclerosis and gliosis). These experiments will also provide information on the safety of these drugs. Subsequently, we will perform electrophysiological recordings on both rodent and human hippocampal slices, to determine whether 7,8-DHF and LM22A-4 can enhance GABAergic function and control hyperexcitability, as previously shown for BDNF.

This project is endowed with strong industrial interest since 7,8-DHF, a flavonoid with antioxidant effects, can be found in several plants and its use is already approved by EMA. Our unique combination of in vivo and ex vivo preclinical data with ex vivo human data will set the ground for future translational and clinical studies.