Methylated flavonoids as anti-seizure agents: Naringenin 4′,7-dimethyl ether attenuates epileptic seizures in zebrafish and mouse models

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 GABA 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.

Dietary Flavonoids Interaction with CREB-BDNF Pathway: An Unconventional Approach for Comprehensive Management of Epilepsy

“…Pharmacological effects of flavonoids can be accredited to their antioxidant, anti-inflammatory properties or their potential to influence the signalling molecules in various cellular cascades. Flavonoids can interact directly with cellular receptors and proteins (kinases and enzymes), resulting in physiological responses and gene expression alterations that can lead to neuroprotection [17]. In epilepsy, following seizures the antioxidant defence mechanisms are diminished with the generation of free radicals in the brain.…”

Network Properties Revealed during Multi-Scale Calcium Imaging of Seizure Activity in Zebrafish

“…Brain-wide imaging during seizures, in contrast to invasive electrophysiological recordings, increases the likelihood that network patterns will be discovered. To this end, we combined well-established acute seizure (pentylenetetrazole; PTZ; Baraban et al, 2005; Baxendale et al, 2012; Afrikanova et al, 2013; Buenafe et al, 2013; Orellana-Paucar et al, 2013; Rahn et al, 2014; Siebel et al, 2015; Barbalho et al, 2016; Copmans et al, 2018) and non-seizure hyperexcitability (4-aminopyridine; 4-AP) models (Ellis et al, 2012; Kumar et al, 2016; Cassar et al, 2017; Winter et al, 2017) with spinning disk confocal microscopy, enabling fast (20–30 fps) in vivo imaging of network events. Imaging studies were performed at brain-wide and single-cell resolution levels.…”

Novel O-alkyl Derivatives of Naringenin and Their Oximes with Antimicrobial and Anticancer Activity

“…Recent reports showed that derivatives of naringenin with methyl groups attached to the C-7 and C-4′ positions exhibited a strong anti-seizures effect in a larval zebrafish model. Thus, sakuranetin and 7,4′-di- O -methylnaringenin were proposed as agents capable of attenuating epileptic attacks [15]. Another derivative, 7- O -butylnaringenin was described as a potent antibacterial agent in the treatment of infections caused by various common pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) [16] and Helicobacter pylori [17].…”