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Methylated Flavonoids as Anti-Seizure Agents: Naringenin 4',7-dimethyl Ether Attenuates Epileptic Seizures in Zebrafish and Mouse Models

Methylated Flavonoids as Anti-Seizure Agents: Naringenin 4',7-dimethyl Ether Attenuates Epileptic Seizures in Zebrafish and Mouse Models

Daniëlle Copmans, Adriana M Orellana-Paucar, Gert Steurs, Yifan Zhang, Annelii Ny, Kenn Foubert, Vasiliki Exarchou, Aleksandra Siekierska, Youngju Kim, Wim De Borggraeve, Wim Dehaen, Luc Pieters, Peter A M de Witte

Neurochem Int. 2018 Jan;112:124-133.

PMID: 29174382

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP29424962	Naringenin 4′,7-dimethyl ether		29424-96-2	Price

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