TRKB ACTIVATION AS A NOVEL TARGET FOR DRUG RESISTANT TEMPORAL LOBE EPILEPSY: FROM ANIMAL MODELS TO THE HUMAN EPILEPTIC BRAIN

Current pharmacological treatments for epilepsy are purely symptomatic and are ineffective in about 30% of the patients. Therefore, there is an urgent need for novel disease-modifying therapies. Brain-derived neurotrophic factor (BDNF), acting through its high-affinity receptor TrkB, is known to play a key role in epileptogenesis and seizure recurrence. However, BDNF itself is not suitable as a therapeutic agent due to its poor bioavailability. This study examined 7,8-dihydroxyflavone (7,8-DHF), an antioxidant and TrkB agonist, as a potential anti-epileptogenic and/or anti-epileptic therapy. A one-week treatment with a low (5 mg/kg) but not a higher (10 mg/kg) daily dose of 7,8-DHF exerted strong anti-epileptogenic effects in the rat lithium-pilocarpine model of epilepsy, delaying seizure onset after status epilepticus, reducing spontaneous seizure frequency and improving cognitive outcomes. These dose-dependent effects correlated with distinct TrkB phosphorylation patterns and differential activation of TrkB-related signaling pathways. Ongoing studies are evaluating 7,8-DHF as a putative anti-epileptic drug in the rat pilocarpine model. In this case, a two-week treatment at both doses was found to arrest disease progression and slightly improve cognitive outcomes, supported by preferential activation of specific TrkB-dependent intracellular signaling pathways. Moreover, electrophysiological recordings using both rat and human hippocampal tissue from patients with drug-resistant mesial temporal lobe epilepsy (mTLE), revealed enhanced GABAergic function and improved control of hyperexcitability, as previously shown for BDNF. This integrated preclinical and human ex vivo approach provides a strong foundation for future translational and clinical studies, especially considering that 7,8-DHF is already approved as a dietary supplement in several countries.