Epilepsy is a neurological disease that affects more than 70 million people worldwide and is characterized by the presence of spontaneous unprovoked recurrent
seizures. Existing anti-seizure drugs (ASDs) have side effects and fail to control
seizures in 30% of patients due to drug resistance. Hence, safer and more efficacious drugs are sorely needed.
Flavonoids are polyphenolic structures naturally present in most plants and consumed daily with no adverse effects reported. These structures have shown activity in several seizure and
epilepsy animal models through allosteric modulation of GABAA receptors, but also via potent anti-inflammatory action in the brain. As such, dietary
flavonoids offer an interesting source for ASD and anti-epileptogenic drug (AED) discovery, but their pharmaceutical potential is often hampered by metabolic instability and low oral bioavailability. It has been argued that their drug-likeness can be improved via methylation of the free
hydroxyl groups, thereby dramatically enhancing metabolic stability and membrane transport, facilitating absorption and highly increasing bioavailability. Since no scientific data is available regarding the use of methylated
flavonoids in the fight against
epilepsy, we studied
naringenin (NRG),
kaempferol (KFL), and three methylated derivatives, i.e.,
naringenin 7-O-methyl
ether (NRG-M),
naringenin 4',7-dimethyl
ether (NRG-DM), and
kaempferide (4'-O-methyl kaempferol) (KFD) in the zebrafish
pentylenetetrazole (PTZ) seizure model. We demonstrate that the methylated
flavanones NRG-DM and NRG-M are highly effective against PTZ-induced
seizures in larval zebrafish, whereas NRG and the
flavonols KFL and KFD possess only a limited activity. Moreover, we show that NRG-DM is active in two standard acute mouse seizure models, i.e., the timed i.v. PTZ seizure model and the 6-Hz psychomotor seizure model. Based on these results, NRG-DM is proposed as a lead compound that is worth further investigation for the treatment of
generalized seizures and drug-resistant
focal seizures. Our data therefore highlights the potential of methylated
flavonoids in the search for new and improved ASDs.