Effect of quercetin and rutin in some acute seizure models in mice

https://doi.org/10.1016/j.pnpbp.2014.05.007Get rights and content

Highlights

  • Quercetin and rutin showed anticonvulsant action in the 6 Hz test in mice.

  • Quercetin and rutin did not influence seizure threshold in MEST and iv PTZ tests.

  • Quercetin did not change the action of VPA and LEV in the 6 Hz seizure test in mice.

  • Neither rutin nor quercetin produced any tested side effects in mice.

  • Quercetin with VPA or LEV did not induce any investigated side effects in mice.

Abstract

Quercetin is one of the most widely occurring flavonoid which is also often present in plants as glycosidic form — rutin. These compounds are ingredients of plant diet and are also present in numerous pharmaceutical preparations and diet supplements which are taken by patients suffering from epilepsy and treating with antiepileptic drugs (AEDs). Influence of these compounds on central nervous system-related effects was proved both in experimental and clinical studies. Their influence on anxiety, depression, memory processes and convulsant activity was reported. The aim of the present study was to investigate the effect of quercetin and rutin in some models of seizures, i.e., in the model of psychomotor seizures induced by 6 Hz stimulation, in the maximal electroshock seizure threshold and intravenous pentylenetetrazole tests in mice. We also examined a possible mechanism of anticonvulsant activity of quercetin and its influence on action of two AEDs, i.e., valproic acid and levetiracetam, in the 6 Hz seizure test. Our results revealed only a weak anticonvulsant potential of the studied flavonoids because they showed anticonvulsant action at doses from 10 to 200 mg/kg only in the 6 Hz test and did not change seizure thresholds in the remaining tests. Moreover, anticonvulsant action of the studied flavonoids was short-term, noted only at pretreatment time ranging between 30 and 60 min. The highest anticonvulsant activity of quercetin was correlated with its high plasma and brain concentration, which was revealed in a pharmacokinetic study. We did not note changes in the anticonvulsant action of the used AEDs combined with quercetin in the model of psychomotor seizures in mice. Neither quercetin and rutin nor combinations of quercetin with the studied AEDs produced any significant impairments of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test) and long-term memory (evaluated in the passive avoidance test) in mice. The results of the present study suggest that quercetin and rutin have only weak and short-term anticonvulsant potential. These flavonoids seem to be safe for patients with epilepsy because they neither changed activity of the studied AEDs nor produced any adverse effects.

Introduction

Epilepsy is one of the most common serious neurological disorders defined as recurrent and unprovoked epileptic seizures and diagnosed in around 50 million people worldwide. Despite implementation of numerous new antiepileptic drugs (AEDs) and improvement in their tolerability and/or safety in the last decades, the problem of pharmacoresistance in epileptic patients has not been solved. Clinically available AEDs fail to control epileptic activity in around 30% of patients and wherefore there is still a need for searching new therapeutic strategies for epileptic disorder (Banerjee et al., 2009). Promising source of new safe and effective anticonvulsant substances seems to be plants.

Rutin and quercetin belong to flavonoids — secondary metabolites of plants. These two compounds are the most widely widespread flavonoids in herbal and plant food, and they are chemically similar because rutin is a very common quercetin glycoside. The term flavonoids include more than 6000 structurally distinct plant pigments which are divided into several classes depending on their structure, i.e., flavan-3-ols, flavonols, flavanones, isoflavones, and anthocyanidins (Jager and Saaby, 2011). Since flavonoids are present in food and medicinal plants, they are consumed by humans. Their main sources are vegetables, fruits, tea and wine and the average daily intake of flavonoids by humans on a normal diet is 1–2 g/day (Havsteen, 2002). Flavonoids protect plants against ultraviolet radiation, microbial infections and both insect and mammalian herbivores. These compounds have been reported to have beneficial effects in numerous diseases in humans, including cancer and cardiovascular diseases. In addition, their antioxidant, antiinflammatory, antitumoral and antiviral properties were also noted (Fernandez et al., 2006). The ability of flavonoids to pass the blood–brain barrier causes numerous effects on the central nervous system, which was revealed both in the in vitro and in vivo studies (Jager and Saaby, 2011). In many cases the biological activity of flavonoids results from their antioxidant properties although they might also modulate cell activity through selective actions at different protein kinase and lipid kinase signaling pathways or bind to the ATP-binding sites of a large number of proteins (Dajas et al., 2013). Moreover, they might be ligands for benzodiazepine binding sites of the γ-aminobutyric acid type A (GABAA) receptor, which was confirmed by behavioral effects in animal models of anxiety, sedation and convulsions. Flavonoids might also affect the activity of other neurotransmitter systems. It was revealed that quercetin modulate activity of adenosine, serotonin, glycine and acetylcholine receptors (Lee et al., 2011, Nassiri-Asl et al., 2008, Sun et al., 2007, Williams et al., 2004).

The effect of rutin and quercetin in animal models of seizures was investigated previously and their anticonvulsant properties were demonstrated both in mice and rats (Baluchnejadmojarad et al., 2010, Joshi et al., 2005, Nassiri-Asl et al., 2008, Nassiri-Asl et al., 2010a, Nassiri-Asl et al., 2013a). Moreover, quercetin revealed neuroprotective effects on hippocampal injury induced by status epilepticus (Hu et al., 2011). The studied flavonoids also exhibit other neuroprotective properties in animal models, i.e. they improve memory and learning abilities (Nassiri-Asl et al., 2010b, Nassiri-Asl et al., 2013a, Tongjaroenbuangam et al., 2011) and have antidepressant action as compounds of extracts from herbs (Herrera-Ruiz et al., 2011, Machado et al., 2008). Lu et al. (2010) reported that quercetin improved the behavioral performance of mice fed a high-cholesterol diet both in the step-through test and the Morris water maze task. This effect seemed to be connected to inhibition of AMP-activated protein kinase (AMPK) by quercetin and might be utilized in therapy and prevention of Alzheimer's disease (Lu et al., 2010).

Taking into consideration the above it might be postulated that flavonoids, which are natural compounds known from folk medicine, make a good source of modern drugs. They might also contribute to the discovery of new AEDs with novel structures and better safety and efficacy. Therefore, the aim of the present study was to investigate the action of rutin and quercetin in some mouse models of acute seizures, i.e., in the 6 Hz seizure, maximal electroshock seizure threshold (MEST) and intravenous (iv) PTZ seizure threshold tests. We examined the combination of quercetin with a selective and reversible AMPK inhibitor — compound C, to estimate some possible mechanism of anticonvulsant action of quercetin in the 6 Hz test. Since both rutin and quercetin are essential components of the human diet and some medicaments, they might influence the activity of AEDs in epileptic patients. Therefore, in the present study we also investigated the influence of quercetin on the anticonvulsant action of two AEDs, i.e., the classical AED — valproic acid (VPA) and the second generation AED — levetiracetam (LEV), in the 6 Hz model in mice. Because the administration of both rutin and quercetin results in the production of the same metabolites, i.e., sulfates and glucuronides of quercetin (Terao et al., 2011, Yang et al., 2005), experiments estimating interactions with AEDs and pharmacokinetic studies were performed only for quercetin. Moreover, some acute side effects provoked either by rutin, quercetin or combinations of quercetin with the studied AEDs were examined in the chimney test, step-through passive avoidance task and grip-strength test in mice.

Section snippets

Animals

Male Swiss mice weighing 23–28 g obtained from a licensed breeder (Laboratory Animals Breeding, Słaboszów, Poland) were used in the study. The animals were housed in the polycarbonate cages under strictly controlled conditions (ambient temperature 20–23 °C, relative humidity 45–55%, a 12/12 light/dark cycle with the light on at 6:00 a.m., chow pellets and tap water continuously available). Mice were used in the study after at least one week of acclimatization. All experiments were performed at the

Time-course and dose–response relationship for rutin and quercetin in the 6 Hz seizure test in mice

Rutin and quercetin (both administered at a dose of 400 mg/kg, ip) exhibited statistically significant anticonvulsant effect 30 and 60 min after their injection in the 6 Hz seizure test in mice (one-way ANOVA: rutin, F(5,48) = 10.01, p < 0.0001; quercetin, F(5,48) = 4.180, p = 0.0031). Rutin increased the seizure threshold from 10.715 (9.984–11.500) mA in the control group to 14.125 (12.693–15.719) mA and to 13.910 (12.739–15.189) mA 30 and 60 min after its administration, respectively. The seizure

Discussion

Plants, that are the part of human diet and are often used as alternative medicines, provide numerous ingredients which might interact functionally with different organ systems in human body. Among these plant-derived compounds are flavonoids which recently have attracted interest because of their biological activities to human health, also because of their influence on central nervous system effects (Fernandez et al., 2006). The influence of flavonoids on anxiety (Joshi et al., 2005),

Conflict of interest

None of the authors has any conflict of interest in the context of this work.

Acknowledgments

This study was supported by Funds for Statutory Activity of Maria Curie-Skłodowska University, Lublin, Poland. Dr. Dorota Nieoczym and Dr. Katarzyna Socała were supported by the Foundation for Polish Science. We thank Nina Kowalczyk and Mateusz Pieróg for the skillful technical assistance. The authors are grateful for the generous gift of quercetin and rutin from Polpharma S.A., Starogard Gdański, Poland.

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