Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B

Copmans, Daniëlle; Kildgaard, Sara; Rasmussen, Silas Anselm; Ślęzak, Monika; Dirkx, Nina; Partoens, Michèle; Esguerra, Camila V.; Crawford, Alexander D.; Larsen, Thomas Ostenfeld; Witte, Peter de

doi:10.3390/md17110607

Cited by 25 publications

(40 citation statements)

References 60 publications

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“…The behavioral manifestation of seizures corresponds well with the high number of epileptiform-like discharges observed at the electroencephalographic (EEG) level, and compounds with anticonvulsant activity prevent PTZ-induced hyperlocomotion. Using the PTZ assay, different marine-derived, plant-derived, and synthetic compounds have been found to possess anticonvulsant activity [11][12][13][14][15]. The PTZ assay has been shown to correlate well with equivalent PTZ model in mice [11,12,15].…”

Section: Introductionmentioning

confidence: 99%

The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish

Gaweł

Kukuła-Koch

Nieoczym

et al. 2020

Cells

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Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood–brain barrier was determined via quantitative structure–activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.

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Section: Introductionmentioning

confidence: 99%

The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish

Gaweł

Kukuła-Koch

Nieoczym

et al. 2020

Cells

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“…Conversely, genetic models are clinically relevant because they recapitulate the genetic defect present in patients, often mimicking the pathophysiological features of the human disease, including recurrent spontaneous seizures. Both genetic and chemical models have been successfully used for screening of novel anti-seizure compounds (Baraban et al, 2013 ; Copmans et al, 2019 ). Notably, our KA larval model combines characteristics of both model types, because the chemical insult eventually results in spontaneous recurrent seizures, thus epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Pericardial Injection of Kainic Acid Induces a Chronic Epileptic State in Larval Zebrafish

Heylen

Pham

Meulemeester

et al. 2021

Front. Mol. Neurosci.

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Epilepsy is a common disorder of the brain characterized by spontaneous recurrent seizures, which develop gradually during a process called epileptogenesis. The mechanistic processes underlying the changes of brain tissue and networks toward increased seizure susceptibility are not fully understood. In rodents, injection of kainic acid (KA) ultimately leads to the development of spontaneous epileptic seizures, reflecting similar neuropathological characteristics as seen in patients with temporal lobe epilepsy (TLE). Although this model has significantly contributed to increased knowledge of epileptogenesis, it is technically demanding, costly to operate and hence not suitable for high-throughput screening of anti-epileptic drugs (AEDs). Zebrafish, a vertebrate with complementary advantages to rodents, is an established animal model for epilepsy research. Here, we generated a novel KA-induced epilepsy model in zebrafish larvae that we functionally and pharmacologically validated. KA was administered by pericardial injection at an early zebrafish larval stage. The epileptic phenotype induced was examined by quantification of seizure-like behavior using automated video recording, and of epileptiform brain activity measured via local field potential (LFP) recordings. We also assessed GFP-labeled GABAergic and RFP-labeled glutamatergic neurons in double transgenic KA-injected zebrafish larvae, and examined the GABA and glutamate levels in the larval heads by liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). Finally, KA-injected larvae were exposed to five commonly used AEDs by immersion for pharmacological characterization of the model. Shortly after injection, KA induced a massive damage and inflammation in the zebrafish brain and seizure-like locomotor behavior. An abnormal reorganization of brain circuits was observed, a decrease in both GABAergic and glutamatergic neuronal population and their associated neurotransmitters. Importantly, these changes were accompanied by spontaneous and continuous epileptiform brain discharges starting after a short latency period, as seen in KA rodent models and reminiscent of human pathology. Three out of five AEDs tested rescued LFP abnormalities but did not affect the seizure-like behavior. Taken together, for the first time we describe a chemically-induced larval zebrafish epilepsy model offering unique insights into studying epileptogenic processes in vivo and suitable for high-throughput AED screening purposes and rapid genetic investigations.

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“…The potential of marine alkaloids to assist in the management of seizures has been explored in vivo ( Table 2 ). A recent experiment evaluated the antiseizure effect of TMC-120A and -120B ( Figure 3 ; compounds 21 and 22 , respectively) in both mouse and zebrafish models [ 26 ]. In the mouse model, a significant reduction in seizure duration was observed using 10 mg/kg of any of the two alkaloids.…”

Section: Marine Alkaloids With Biological Activity In Vivomentioning

confidence: 99%

“…Although this scenario is an important advance towards the use of marine alkaloids in disease management, the majority of marine alkaloids do not reach the in vivo level. A relevant example that shows the small fraction of compounds with potential biological effects from the huge number of candidates is the screening carried out by Copmans et al [ 26 ]. In this study, more than 2000 marine extracts were screened for in vivo characterization of antiseizure activity.…”

Section: Chemical Modification and Synthesis Of Marine Alkaloidsmentioning

confidence: 99%

“…An interesting approach to overcome the individual limitations of each animal model is the evaluation using more than one animal model in order to obtain a more comprehensive, detailed, and better replication of a given human disease [ 68 ]. For instance, Copmans et al [ 26 ] explored the use of both mice and zebrafish models to test the antiseizure effect of TMC-120A ( 21 ) and TMC-120B ( 22 ). The results from both animal models indicate a congruent interpretation of the potential biological effect to manage seizures.…”

Section: Animal Model Context and Further Considerations For Bioactive Marine Alkaloidsmentioning

confidence: 99%

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Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

Munekata¹,

Pateiro²,

Conté-Júnior

et al. 2021

Marine Drugs

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Marine alkaloids comprise a class of compounds with several nitrogenated structures that can be explored as potential natural bioactive compounds. The scientific interest in these compounds has been increasing in the last decades, and many studies have been published elucidating their chemical structure and biological effects in vitro. Following this trend, the number of in vivo studies reporting the health-related properties of marine alkaloids has been increasing and providing more information about the effects in complex organisms. Experiments with animals, especially mice and zebrafish, are revealing the potential health benefits against cancer development, cardiovascular diseases, seizures, Alzheimer’s disease, mental health disorders, inflammatory diseases, osteoporosis, cystic fibrosis, oxidative stress, human parasites, and microbial infections in vivo. Although major efforts are still necessary to increase the knowledge, especially about the translation value of the information obtained from in vivo experiments to clinical trials, marine alkaloids are promising candidates for further experiments in drug development.

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Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B

Cited by 25 publications

References 60 publications

The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish

The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish

Pericardial Injection of Kainic Acid Induces a Chronic Epileptic State in Larval Zebrafish

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

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