Coumarins As Potential Supportive Medication for the Treatment Of
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REVIEW Acta Neurobiol Exp 2019, 79: 126–132 DOI: 10.21307/ane‑2019‑011 Coumarins as potential supportive medication for the treatment of epilepsy Jarosław Bryda1,2, Mirosław Zagaja2, Aleksandra Szewczyk2 and Marta Andres‑Mach2* 1 Department of Veterinary Hygiene, Voivodship Veterinary Inspectorate, Lublin, Poland, 2 Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland, * E‑mail: [email protected] Epilepsy, one of the most common neurological disorders, is a chronic disease of the brain manifested by seizures due to sudden, spontaneous bioelectrical discharges in nerve cells. An estimated 50 million people worldwide suffer from epilepsy. Antiepileptic drugs are the mainstream treatment for epilepsy; however, the drug resistance occurring in 20‑30% of patients and side effects of available medications have resulted in a search for natural remedies that can support disease therapy. Coumarins may be a promising option. They are a group of natural plant‑derived substances of great interest due to their broad spectrum of biological activities, including potent pharmacological properties. Recent data from experimental models demonstrates the possibility for coumarin use as a supporting treatment of epileptic seizures. This article focuses on the most recent research reports available in the literature relating to the use of several selected coumarins in different experimental models of epilepsy. Key words: coumarins, antiepileptic drugs, epilepsy INTRODUCTION tutions in the skeleton affect the diverse pharmacolog‑ ical activities of coumarins (Kumar et al., 2015; Kubrak Coumarins are organic, biologically active com‑ et al., 2017). Coumarins are mainly found in secondary pounds belonging to the benzopyrone family (1,2‑ben‑ plant metabolites, acting as growth regulators, con‑ zopyrones or 2H‑1‑benzopyran‑2‑ones). They are di‑ trolling biochemical transformations and demonstrat‑ vided into four subtypes based on their chemical struc‑ ing defensive properties against infection (Chattha et ture. Simple coumarins are formed by benzene rings al., 2018). They are also found in some bacteria, fungi fused with α‑pirons which are hydroxylated, alkoxyl‑ or sponges and can be synthesized chemically (Matos ated or alkylated at the C7, C6 and C3 positions of ben‑ et al., 2015). zopyrone. Isocoumarin derivatives are formed by two Coumarins and coumarin‑related compounds pos‑ rings: benzene and α‑isopirone with substituents in po‑ sess a wide range of pharmacological profiles. Their sitions C3, C6, C7 and C8. Furanocoumarins, consisting properties and their impact on the cardiovascular sys‑ of a five‑membered furan ring fused with coumarin, are tem (Najmanova et al., 2015), nervous system (Skalic‑ divided into two types – psoralen, at the C6‑C7 posi‑ ka‑Woźniak et al., 2016), body immunity (Rohini et al., tions, or angelicin, at the C7‑C8 position. Pyranocou‑ 2014) and digestive system (Popp et al., 2017) are cur‑ marins, with substituents, condense a six‑membered rently being researched. New derivatives are still being pyran ring with a coumarin ring at the C6‑C7 position discovered and synthesized due to their potential uses. (Mead et al., 1958; Jain et al., 2012; Medina et al., 2015). Recent studies have revealed the effective use of © 2019 by Acta Neurobiologiae Experimentalis © 2019 by Acta Neurobiologiae Variable chemical structures and a diversity of substi‑ coumarins in cancer therapy as medicaments and for Received 30 October 2018, accepted 12 February 2019 Acta Neurobiol Exp 2019, 79: 126–132 Coumarins in the treatment of epilepsy 127 mitigating the effects of radiotherapy (Rohini et al., animal models for assessing potential anticonvulsant 2014). One of the most common coumarins, warfarin properties of drugs is the maximal electroshock sei‑ (4‑hydroxycoumarin), is used in medicine as an oral zure (MES) test in rodents (Castel‑Branco et al., 2009). anticoagulant (Kumar et al., 2015). Antitumor activi‑ It allows for the modeling of specific pharmacodynam‑ ty has been demonstrated for osthole in the suppres‑ ic effects required to protect against seizures. Addi‑ sion of the spread of breast cancer cells. Tests with tionally, it is possible to assess the bioavailability of bioluminescence have shown that osthole inhibits the a given substance based on the analysis of its concen‑ promoter of matrix metalloproteinase‑2 (MMP‑2) and tration in specific brain structures in post‑mortem tis‑ indirectly inhibits the activity of this enzyme, which sue preparations (Rogawski et al., 2006). may lead to inhibition of tumor migration (Yang et Anticonvulsant effects of coumarins are likely re‑ al., 2010). Anticancer properties were also exhibited lated to their influence on the ionotropic receptor for by imperatorin, esculetin, chartreusin and fraxetin γ‑aminobutyric acid (GABA). This was demonstrated with various mechanisms of action (Luo et al., 2011). by studies in which furanocoumarins were found to be Interestingly, coumarins have been shown to possess partial benzodiazepine receptor antagonists, inhibiting strong anti‑inflammatory properties. This is due to the binding [3H] of diazepam to these receptors (Sing‑ their antioxidant activity and effect on reactive ox‑ huber et al., 2011). In this study, which examined the ygen species. Esculetin exhibited protective effects effects of eighteen furanocoumarins on GABA‑induced on rat intestines in colitis (Witaicenis et al., 2010). chloride currents (IGABA), seven compounds showed In other studies, extracts used externally have been a greater than 20% enhancement of IGABA. Similar re‑ shown to reduce skin inflammation and edema (Kwon sults were obtained in studies of coumarins isolated et al., 2011). Derivatives such as esculetin, fraxetin from Angelica pubescens (L.) that described their GAB‑ and daphnetin exhibit antioxidant activity, acting as AA receptor‑modulating activity (Zaugg et al., 2011). In inhibitors of the lipoxygenase and cyclooxygenase vivo analysis of the anticonvulsive activity of couma‑ enzyme pathways (Kirsch et al., 2016). In vitro studies rins suggests they may indirectly act to increase GABA on coumarin compounds have served to demonstrate concentration in the CNS by affecting the activity of their antimicrobial and antifungal activity. Tests car‑ glutamic acid decarboxylase (Luszczki et al., 2007a; Sin‑ ried out on Staphylococcus aureus, Bacillus subtilis and ghuber et al., 2011; Zaugg et al., 2011). Escherichia coli strains revealed a much stronger an‑ Recent research provides evidence of positive sup‑ tibacterial effect of synthetic coumarin compounds porting effects for coumarin compounds on the con‑ compared to several conventional antibiotics (Vyas ventional AEDs (Table I, Table II). The promising phar‑ et al., 2012). Much research has been devoted to the macological activity was demonstrated by the simple effect of coumarins on the central nervous system coumarins osthole and umbelliferone and also by sev‑ (CNS). Therefore, numerous experimental studies fo‑ eral furanocoumarins – xanthotoxin and imperatorin cus on disorders such as epilepsy, schizophrenia, de‑ (Luszczki et al., 2007a; 2009; 2010; 2011). pressive and anxiety disorders or Alzheimer’s disease (Skalicka‑Woźniak et al., 2016). Osthole Possible anticonvulsant properties Osthole (7‑methoxy‑8‑(3‑methyl‑2‑butenyl)‑2H‑1‑ of natural coumarins ‑benzopyran‑2‑one) is a simple natural origin coumarin, which occurs in several medicinal plants such as Cnidium Epileptic seizures are the result of excessive abnor‑ monnieri (L.) or Angelica pubescens (L.). Both in vitro and mal neuronal activity in the brain. The primary treat‑ in vivo studies have revealed that osthole demonstrates ment for epilepsy is the administration of antiepileptic neuroprotective (Liu et al., 2010), osteogenic (Ming et drugs (AEDs). These drugs reduce the frequency of sei‑ al., 2011), immunomodulatory (Liao et al., 2010), anti‑ zures and help patients control seizure occurrence. Un‑ cancer (Yang et al., 2010; Kao et al., 2012), hepatoprotec‑ fortunately, a significant proportion of patients exhibit tive (Zhang et al., 2011), anticoagulant and antimicrobial little or no improvement with current drug therapies. properties (Rosselli et al., 2007). Moreover, the issue of chronic side effects due to the The neuroprotective effects of osthole are related drugs is also significant (Sharma et al., 2013). to an increase in neuronal conduction in the hippo‑ Experimental epileptic models are used to assess campus. Osthole affects the membrane receptors by the activity of potential anticonvulsant drugs and increasing the release of glutamate from rat hippo‑ enable an estimation of the clinical profile of a sub‑ campal nerve terminals. It facilitated 4‑aminopyridine stance’s action on the CNS. One of the basic in vivo (4‑AP‑)‑evoked glutamate release by activating N‑ and 128 J. Bryda et al. Acta Neurobiol Exp 2019, 79: 126–132 Table I. Effect of coumarins on the anticonvulsant activity of conventional antiepileptic drugs against maximal electroshock‑induced seizures in mice. CBZ PB PHT VPA References ED50 (mg/kg) ED50 (mg/kg) ED50 (mg/kg) ED50 (mg/kg) 10.3 19.6 12.8 247.9 Imperatorin + AEDs Luszczki et al., 2007 6.0 12.2 8.5 213.4 8.87 18.17 9.2 212.5 Osthole + AEDs Luszczki et al., 2010; 2011 6.89 12.35 7.48 173.8 13.97 35.39 13.26 281.4 Umbelliferon + AEDs Zagaja et al., 2015a 11.76 21.78 10.84 215.5 13.97 35.39 13.26 281.4 Xanthotoxin + AEDs Zagaja et al., 2015b 5.01 27.87 12.21 195.5 Results are presented as median effective doses (ED50