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

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 6Hz 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 6Hz seizure test. Our results revealed only a weak anticonvulsant potential of the studied flavonoids because they showed anticonvulsant action at doses from 10 to 200mg/kg only in the 6Hz 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 60min. 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.

[1]  Sebastian P Fernandez,et al.  Central nervous system depressant action of flavonoid glycosides. , 2006, European journal of pharmacology.

[2]  Miller Al St. John's Wort (Hypericum perforatum): clinical effects on depression and other conditions. , 1998 .

[3]  M. Barton,et al.  Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy , 2001, Epilepsy Research.

[4]  Marjan Nassiri-Asl,et al.  The effects of rutin on a passive avoidance test in rats , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[5]  Marjan Nassiri-Asl,et al.  Comparison between the effects of quercetin on seizure threshold in acute and chronic seizure models , 2016, Toxicology and industrial health.

[6]  Peng Li,et al.  Medicinal compounds with antiepileptic/anticonvulsant activities , 2014, Epilepsia.

[7]  C. Rice-Evans,et al.  Flavonoids: antioxidants or signalling molecules? , 2004, Free radical biology & medicine.

[8]  Tilson Ha,et al.  A method for the routine assessment of fore- and hindlimb grip strength of rats and mice. , 1979 .

[9]  Byung-Hwan Lee,et al.  Differential regulations of quercetin and its glycosides on ligand-gated ion channels. , 2008, Biological & pharmaceutical bulletin.

[10]  Mehdi Sheikhi,et al.  Effects of rutin on oxidative stress in mice with kainic acid-induced seizure. , 2013, Journal of integrative medicine.

[11]  W. Hauser,et al.  The descriptive epidemiology of epilepsy—A review , 2009, Epilepsy Research.

[12]  A. Zamilpa,et al.  Antidepressant effect and pharmacological evaluation of standardized extract of flavonoids from Byrsonima crassifolia. , 2011, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[13]  M. Roghani,et al.  Inhibitory Effect of High Dose of the Flavonoid Quercetin on Amygdala Electrical Kindling in Rats , 2010 .

[14]  A. Kimball,et al.  Chemical protection against ionizing radiation. I. Sampling methods for screening compounds in radiation protection studies with mice. , 1957, Radiation research.

[15]  J. Spencer The interactions of flavonoids within neuronal signalling pathways , 2007, Genes & Nutrition.

[16]  Byung-Hwan Lee,et al.  Human glycine α1 receptor inhibition by quercetin is abolished or inversed by α267 mutations in transmembrane domain 2 , 2007, Brain Research.

[17]  S. Kulkarni,et al.  Protective effect of quercetin on alcohol abstinence-induced anxiety and convulsions. , 2005, Journal of medicinal food.

[18]  Byung-Hwan Lee,et al.  Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I. , 2005, Molecules and cells.

[19]  Z. Chi,et al.  Resveratrol pre-treatment reduces early inflammatory responses induced by status epilepticus via mTOR signaling , 2013, Brain Research.

[20]  A. Rodrigues,et al.  Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: evidence for the involvement of the serotonergic and noradrenergic systems. , 2008, European journal of pharmacology.

[21]  J. Rossier,et al.  Benzodiazepine impairs and β-carboline enhances performance in learning and memory tasks , 1986, Nature.

[22]  S. Chaki,et al.  Effects of quercetin on the sleep–wake cycle in rats: Involvement of gamma-aminobutyric acid receptor type A in regulation of rapid eye movement sleep , 2010, Brain Research.

[23]  P. Bhutada,et al.  Reversal by quercetin of corticotrophin releasing factor induced anxiety- and depression-like effect in mice , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[24]  I. Orhan,et al.  UPLC-TOF-MS analysis of Galium spurium towards its neuroprotective and anticonvulsant activities. , 2012, Journal of ethnopharmacology.

[25]  P. Wlaź,et al.  Effect of sildenafil, a selective phosphodiesterase 5 inhibitor, on the anticonvulsant action of some antiepileptic drugs in the mouse 6-Hz psychomotor seizure model , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[26]  M. Haghighi,et al.  Effects of quercetin on oxidative stress and memory retrieval in kindled rats , 2013, Epilepsy & Behavior.

[27]  Byung-Hwan Lee,et al.  Quercetin Inhibits α3β4 Nicotinic Acetylcholine Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes. , 2011, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[28]  Marjan Nassiri-Asl,et al.  The effects of rutin on the development of pentylenetetrazole kindling and memory retrieval in rats , 2010, Epilepsy & Behavior.

[29]  V. C. Filho,et al.  Quercetin: Further investigation of its antinociceptive properties and mechanisms of action , 2008, Archives of pharmacal research.

[30]  M. L. Vale,et al.  The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy , 2013, Molecular pain.

[31]  Jiang-Ning Zhou,et al.  Quercetin subunit specifically reduces GlyR-mediated current in rat hippocampal neurons , 2007, Neuroscience.

[32]  M. Bialer,et al.  Key factors in the discovery and development of new antiepileptic drugs , 2010, Nature Reviews Drug Discovery.

[33]  J. Spencer,et al.  Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects , 2012, Proceedings of the Nutrition Society.

[34]  F. Wilcoxon,et al.  A simplified method of evaluating dose-effect experiments. , 1948, The Journal of pharmacology and experimental therapeutics.

[35]  M. Barton,et al.  Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models , 2003, Epilepsy Research.

[36]  B. Havsteen,et al.  The biochemistry and medical significance of the flavonoids. , 2002, Pharmacology & therapeutics.

[37]  J. Goutman,et al.  Flavonoid modulation of ionic currents mediated by GABA(A) and GABA(C) receptors. , 2003, European journal of pharmacology.

[38]  J. Boissier,et al.  Une nouvelle méthode simple pour explorer l’action «tranquillisante»: le test de la cheminée , 1960 .

[39]  Marjan Nassiri-Asl,et al.  Anticonvulsive effects of intracerebroventricular administration of rutin in rats , 2008, Progress in Neuro-psychopharmacology and Biological Psychiatry.

[40]  Dong-Mei Wu,et al.  Quercetin activates AMP‐activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol‐induced neurotoxicity , 2010, The Journal of pathology.

[41]  J. Terao,et al.  Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo. , 2011, Food & function.

[42]  P. Govitrapong,et al.  Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice , 2011, Neurochemistry International.

[43]  Stephen P. H. Alexander Flavonoids as antagonists at A1 adenosine receptors , 2006, Phytotherapy research : PTR.

[44]  Hans-Georg Breitinger,et al.  Synergistic inhibition of glycinergic transmission in vitro and in vivo by flavonoids and strychnine. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[45]  A. Jäger,et al.  Flavonoids and the CNS , 2011, Molecules.

[46]  Wolfgang Löscher,et al.  Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs , 2011, Seizure.

[47]  B. Jeon,et al.  Ketogenic diet attenuates kainic acid-induced hippocampal cell death by decreasing AMPK/ACC pathway activity and HSP70 , 2009, Neuroscience Letters.