Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2015

Open Access 01-12-2015 | Research article

Valerenic acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish)

Authors: Bianca A. Torres-Hernández, Lisa M. Del Valle-Mojica, José G. Ortíz

Published in: BMC Complementary Medicine and Therapies | Issue 1/2015

Login to get access

Abstract

Background

Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis. Our aims were to examine the anticonvulsant properties of valerenic acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs.

Methods

All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, valerenic acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with valerenic acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p < 0.05 level of significance. All treatments were compared with the untreated animals and with the other pretreatments.

Results

After exposure to pentylenetetrazole, zebrafish exhibited a series of stereotypical behaviors prior to the appearance of clonic-like movements—convulsions. Both valerenic acid and valerian extracts (aqueous and ethanolic) significantly extended the latency period to the onset of seizure (convulsion) in adult zebrafish. The ethanolic valerian extract was a more potent anticonvulsant than the aqueous extract. Valerenic acid and both valerian extracts interacted synergistically with clonazepam to extended the latency period to the onset of seizure. Phenytoin showed interaction only with the ethanolic valerian extracts.

Conclusions

Valerenic acid and valerian extracts have anticonvulsant properties in adult zebrafish. Valerian extracts markedly enhanced the anticonvulsant effect of both clonazepam and phenytoin, and could contribute to therapy of epileptic patients.
Appendix
Available only for authorised users
Literature
1.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51:676–85.CrossRefPubMed
2.
3.
4.
5.
Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy Behav. 2002;3:338–42.CrossRefPubMed
6.
Chen H-F, Tsai Y-F, Lin Y-P, Shih M-S, Chen J-C. The relationships among medicine symptom distress, self-efficacy, patient-provider relationship, and medication compliance in patients with epilepsy. Epilepsy Behav. 2010;19:43–9.CrossRefPubMed
7.
Enríquez-Cáceres M, Soto-Santillana M. Non-compliance with pharmacological treatment in patients with epilepsy. Rev Neurol. 2006;42:647–54.PubMed
8.
Hessen E, Lossius MI, Reinvang I, Gjerstad L. Influence of major antiepileptic drugs on attention, reaction time, and speed of information processing: results from a randomized, double-blind, placebo-controlled withdrawal study of seizure-free epilepsy patients receiving monotherapy. Epilepsia. 2006;47:2038–45.CrossRefPubMed
9.
Luna-Tortós C, Fedrowitz M, Löscher W. Evaluation of transport of common antiepileptic drugs by human multidrug resistance-associated proteins (MRP1, 2 and 5) that are overexpressed in pharmacoresistant epilepsy. Neuropharmacology. 2010;58:1019–32.CrossRefPubMed
10.
Lazarowski A, Lubieniecki F, Camarero S, Pomata H, Bartuluchi M, Sevlever G, et al. Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. Pediatr Neurol. 2004;30:102–6.CrossRefPubMed
11.
McConnell BV, Applegate M, Keniston A, Kluger B, Maa EH. Use of complementary and alternative medicine in an urban county hospital epilepsy clinic. Epilepsy Behav. 2014;34:73–6.CrossRefPubMed
12.
Metcalfe A, Williams J, McChesney J, Patten SB, Jetté N. Use of complementary and alternative medicine by those with a chronic disease and the general population--results of a national population based survey. BMC Complement Altern Med. 2010;10:58.CrossRefPubMedPubMedCentral
13.
Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States. Natl Health Stat Report. 2007;2008:1–23.
14.
15.
Lucas RA, Gilfillan DJ, Bergstrom RF. A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Eur J Clin Pharmacol. 1998;54:639–43.CrossRefPubMed
16.
Landmark Johannessen C, Patsalos PN. Interactions between antiepileptic drugs and herbal medicines. Boletín Latinoam y del Caribe Plantas Med y Aromáticas. 2008;7:108–18.
17.
Kupiec T, Raj V. Fatal seizures due to potential herb-drug interactions with Ginkgo biloba. J Anal Toxicol. 2005;29:755–8.CrossRefPubMed
18.
Monograph. Monograph. Valeriana officinalis. Altern Med Rev. 2004;9:438–41.
19.
20.
Tagarelli G, Tagarelli A, Liguori M, Piro A. Treating epilepsy in Italy between XIX and XX century. J Ethnopharmacol. 2013;145:608–13.CrossRefPubMed
21.
Spinella M. Herbal medicines and epilepsy: the potential for benefit and adverse effects. Epilepsy Behav. 2001;2:524–32.CrossRefPubMed
22.
Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158:2200–11.CrossRefPubMed
23.
Khayat Nouri MH, Abbas Abad AN. Gabaergic system role in aqueous extract of Valeriana officinalis L. root on PTZ-induced clonic seizure threshold in mice. African J Pharm Pharmacol. 2011;5:1212–7.CrossRef
24.
Rezvani ME, Roohbakhsh A, Allahtavakoli M, Shamsizadeh A. Anticonvulsant effect of aqueous extract of Valeriana officinalis in amygdala-kindled rats: possible involvement of adenosine. J Ethnopharmacol. 2010;127:313–8.CrossRefPubMed
25.
Hiller K-O, Zetler G. Neuropharmacological studies on ethanol extracts of valeriana officinalisL.: behavioural and anticonvulsant properties. Phyther Res. 1996;10:145–51.CrossRef
26.
Upton R, Petrone C (Eds): Valerian Root Valeriana Officinalis Analytical, Quality Control, and Therapeutic Monograph. Santa Cruz, CA: American Herbal Pharmacopoeia (AHP); 1999.
27.
Patočka J, Jakl J. Biomedically relevant chemical constituents of Valeriana officinalis. J Appl Biomed. 2010;8:11–8.CrossRef
28.
Gao XQ, Björk L. Valerenic acid derivatives and valepotriates among individuals, varieties and species of Valeriana. Fitoterapia. 2000;71:19–24.CrossRefPubMed
29.
Khom S, Baburin I, Timin E, Hohaus A, Trauner G, Kopp B, et al. Valerenic acid potentiates and inhibits GABA(A) receptors: molecular mechanism and subunit specificity. Neuropharmacology. 2007;53:178–87.CrossRefPubMed
30.
Benke D, Barberis A, Kopp S, Altmann K-H, Schubiger M, Vogt KE, et al. GABA A receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts. Neuropharmacology. 2009;56:174–81.CrossRefPubMed
31.
Del Valle-Mojica LM, Ortíz JG. Anxiolytic properties of valeriana officinalis in the zebrafish: a possible role for metabotropic glutamate receptors. Planta Med. 2012;78:1719–24.CrossRefPubMed
32.
Circosta C, De Pasquale R, Samperi S, Pino A, Occhiuto F. Biological and analytical characterization of two extracts from Valeriana officinalis. J Ethnopharmacol. 2007;112:361–7.CrossRefPubMed
33.
Mussulini BHM, Leite CE, Zenki KC, Moro L, Baggio S, Rico EP, et al. Seizures induced by pentylenetetrazole in the adult zebrafish: a detailed behavioral characterization. PLoS One. 2013;8, e54515.CrossRefPubMedPubMedCentral
34.
Afrikanova T, Serruys A-SK, Buenafe OEM, Clinckers R, Smolders I, de Witte P a M, et al. Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. PLoS One. 2013;8:e54166.CrossRefPubMedPubMedCentral
35.
Wong K, Stewart A, Gilder T, Wu N, Frank K, Gaikwad S, et al. Modeling seizure-related behavioral and endocrine phenotypes in adult zebrafish. Brain Res. 2010;1348:209–15.CrossRefPubMed
36.
Baraban SC, Taylor MR, Castro PA, Baier H. Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression. Neuroscience. 2005;131:759–68.CrossRefPubMed
37.
Baxendale S, Holdsworth CJ, Meza Santoscoy PL, Harrison MRM, Fox J, Parkin C a, et al. Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures. Dis Model Mech. 2012;5:773–84.CrossRefPubMedPubMedCentral
38.
Berghmans S, Hunt J, Roach A, Goldsmith P. Zebrafish offer the potential for a primary screen to identify a wide variety of potential anticonvulsants. Epilepsy Res. 2007;75:18–28.CrossRefPubMed
39.
Del Valle-Mojica LM, Cordero-Hernández JM, González-Medina G, Ramos-Vélez I, Berríos-Cartagena N, Torres-Hernández B, et al. Aqueous and ethanolic Valeriana officinalis extracts change the binding of ligands to glutamate receptors. Evid Based Complement Alternat Med. 2011;2011:Article ID 891819.
40.
Gerlai R, Lee V, Blaser R. Effects of acute and chronic ethanol exposure on the behavior of adult zebrafish (Danio rerio). Pharmacol Biochem Behav. 2006;85:752–61.CrossRefPubMedPubMedCentral
41.
Hortopan GA, Dinday MT, Baraban SC. Zebrafish as a model for studying genetic aspects of epilepsy. Dis Model Mech. 2010;3:144–8.CrossRefPubMed
42.
43.
Fleming A. Zebrafish as an alternative model organism for disease modelling and drug discovery: implications for the 3Rs. Natl Cent Replace Refinement Reduct Anim Res 2007:1–7.
44.
Nicholas JM, Ridsdale L, Richardson MP, Ashworth M, Gulliford MC. Trends in antiepileptic drug utilisation in UK primary care 1993–2008: cohort study using the General Practice Research Database. Seizure. 2012;21:466–70.CrossRefPubMed
45.
Haroon A, Tripathi M, Khanam R, Vohora D. Antiepileptic drugs prescription utilization behavior and direct costs of treatment in a national hospital of India. Ann Indian Acad Neurol. 2012;15:289–93.CrossRefPubMedPubMedCentral
46.
Golmohammadi R, Pejhan A, Azhdari-Zarmehri H, Mohammad-Zadeh M. The role of ethanol on the anticonvulsant effect of valproic acid and cortical microvascular changes after epileptogenesis in mice. Neurol Sci. 2013;34:1125–31.CrossRefPubMed
47.
Cuttle L, Munns AJ, Hogg NA, Scott JR, Hooper WD, Dickinson RG, et al. Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation. Drug Metab Dispos. 2000;28:945–50.PubMed
48.
49.
Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, Shader RI. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol. 1997;44:495–8.CrossRefPubMedPubMedCentral
50.
Andersson T, Miners JO, Veronese ME, Birkett DJ. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol. 1994;38:131–7.CrossRefPubMedPubMedCentral
51.
Donovan JL, DeVane CL, Chavin KD, Wang J-S, Gibson BB, Gefroh HA, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Dispos. 2004;32:1333–6.CrossRefPubMed
52.
Hellum BH, Hu Z, Nilsen OG. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes. Basic Clin Pharmacol Toxicol. 2007;100:23–30.CrossRefPubMed
53.
Hellum BH, Hu Z, Nilsen OG. Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes. Basic Clin Pharmacol Toxicol. 2009;105:58–63.CrossRefPubMed
54.
Awad R, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT. Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system. Can J Physiol Pharmacol. 2007;85:933–42.CrossRefPubMed
55.
Oliva I, González-Trujano ME, Arrieta J, Enciso-Rodríguez R, Navarrete A. Neuropharmacological profile of hydroalcohol extract of Valeriana edulis ssp. procera roots in mice. Phytother Res. 2004;18:290–6.CrossRefPubMed
56.
Celis CT, Rincón J, Guerrero MF. Pharmacological activity on central nervous system of the ethanolic extract and the alcaloidal fraction of Valeriana pavonii. Rev Col Cienc Quím Farm. 2007;36:11–22.
57.
Giraldo SE, Rincón J, Puebla P, Marder M, Wasowski C, Vergel N, et al. Isovaleramide, an anticonvulsant molecule isolated from Valeriana pavonii. Biomedica. 2010;30:245–50.CrossRefPubMed
58.
Alfaro JM, Ripoll-Gómez J, Burgos JS. Kainate administered to adult zebrafish causes seizures similar to those in rodent models. Eur J Neurosci. 2011;33:1252–5.CrossRefPubMed
59.
Wong K, Elegante M, Bartels B, Elkhayat S, Tien D, Roy S, et al. Analyzing habituation responses to novelty in zebrafish (Danio rerio). Behav Brain Res. 2010;208:450–7.CrossRefPubMed
60.
Siebel AM, Piato AL, Capiotti KM, Seibt KJ, Bogo MR, Bonan CD. PTZ-induced seizures inhibit adenosine deamination in adult zebrafish brain membranes. Brain Res Bull. 2011;86:385–9.CrossRefPubMed
61.
Lee Y, Kim D, Kim Y-H, Lee H, Lee C-J. Improvement of pentylenetetrazol-induced learning deficits by valproic acid in the adult zebrafish. Eur J Pharmacol. 2010;643:225–31.CrossRefPubMed
62.
Mares P. Age- and dose-specific anticonvulsant action of bumetanide in immature rats. Physiol Res. 2009;58:927–30.PubMed
63.
Ginsberg G, Hattis D, Sonawane B, Russ A, Banati P, Kozlak M, et al. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci. 2002;66:185–200.CrossRefPubMed
Metadata
Title
Valerenic acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish)
Authors
Bianca A. Torres-Hernández
Lisa M. Del Valle-Mojica
José G. Ortíz
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2015
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-015-0731-3

Other articles of this Issue 1/2015

BMC Complementary Medicine and Therapies 1/2015 Go to the issue

Research article

Constitutional multicenter bank linked to Sasang constitutional phenotypic data

Research article

Antimicrobial evaluation of plants used for the treatment of diarrhoea in a rural community in northern Maputaland, KwaZulu-Natal, South Africa

Research article

Anticancer activity of 7-epiclusianone, a benzophenone from Garcinia brasiliensis, in glioblastoma

Research article

Purification, characterization and anti-aging capacity of mycelia zinc polysaccharide by Lentinus edodes SD-08

Research article

Selenium added unripe carica papaya pulp extracts enhance wound repair through TGF-β1 and VEGF-a signalling pathway

Research article

Phytochemical constituents and biological activities of different extracts of Strobilanthes crispus (L.) Bremek leaves grown in different locations of Malaysia