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Abstract
Coumarins are a well-known group of plant secondary metabolites with various pharmacological activities, including antiseizure activity. In the search for new antiseizure drugs (ASDs) to treat epilepsy, it is yet unclear which types of coumarins are particularly interesting as a systematic analysis has not been reported. The current study performed behavioral antiseizure activity screening of 18 different coumarin derivatives in the larval zebrafish pentylenetetrazole (PTZ) model using locomotor measurements. Activity was confirmed for seven compounds, which lowered seizure-like behavior as follows: oxypeucedanin 38%, oxypeucedanin hydrate 74%, notopterol 54%, nodakenetin 29%, hyuganin C 35%, daphnoretin 65%, and pimpinellin 60%. These coumarins, together with nodakenin, underwent further antiepileptiform analysis by local field potential recordings from the zebrafish opticum tectum (midbrain). All of them, except for nodakenetin, showed pronounced antiepileptiform activity, decreasing PTZ-induced elevation in power spectral density (PSD) by 83–89% for oxypeucedanin, oxypeucedanin hydrate, and notopterol, 77% for nodakenin, 26% for nodakenetin, 65% for hyuganin C, 88% for daphnoretin, and 81% for pimpinellin. These data demonstrate the potential of diverse coumarin scaffolds for ASD discovery. Finally, the structural differences between active and inactive coumarins were investigated in silico for oxypeucedanin hydrate and byacangelicin for their interaction with GABA-transaminase, a hypothetical target.
Highlights
Epilepsy is a chronic neurological disease characterized by unprovoked recurrent epileptic seizures, affecting about 50 million people worldwide, and is still an important cause of disability and mortality today [1]
The larval zebrafish PTZ seizure model was used for the behavioral antiseizure activity screening of 18 different psoralen derivatives: linear furanocoumarins, dihydrofuranocoumarins, dihydropyranocoumarin, simple coumarin derivatives, and angular furanocoumarins (Figure 1)
The different coumarins were selected based on their structures and prior knowledge on their bioactivities
Summary
Epilepsy is a chronic neurological disease characterized by unprovoked recurrent epileptic seizures, affecting about 50 million people worldwide, and is still an important cause of disability and mortality today [1]. Epileptic seizures can be controlled with marketed antiseizure drugs (ASDs) in approximately 70% of patients, but, in 30% of patients, adequate seizure control is not achieved. The discovery of new ASDs, with novel mechanisms of action, is a very important area of research [2]. The discovery of new drug candidates with new mechanisms of action, with less severe adverse effects and greater availability for patients, is key for future epilepsy treatment. Within the last ten years, the FDA registered 10 different drugs in the therapy of, for example, seizures in Dravet and Lennox-Gastaut syndrome and partial-onset and tonic–clonic seizures. From all ASDs, only cannabidiol, gabapentine, and valproic acid (VPA) originate from natural products. VPA is an analogue of valeric acid—the natural product found in the plant
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