Skip to main content
SpringerLink
Log in

Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Add-on therapy is a common strategy to improve efficacy and tolerability of antiepileptic drugs (AEDs). Anticonvulsant potential and appropriate safety of docosahexaenoic acid (DHA) makes it a promising candidate for combination therapy. We evaluated influence of DHA on anticonvulsant activity of AEDs phenytoin, valproate, and lamotrigine in maximal electroshock (MES), pentylenetetrazole (PTZ), and kindling models of epilepsy. The dose–response to DHA was obtained 15 min after intracerebroventricular (i.c.v.) injection in PTZ model of clonic seizures in mice, MES model of tonic seizures in mice, and kindling model of complex partial seizures in rats. The dose–response curve of valproate (30 min after i.p. injection to mice) in PTZ, phenytoin (60 min after i.p. injection to mice) in MES, and lamotrigine (60 min after i.p. injection to rats) in kindling models were obtained. Dose–response curves of the AEDs were then achieved in the presence of ED25 of DHA. DHA had no anticonvulsant effect in the MES model. However, it showed a dose-dependent protective effect against PTZ (ED50 = 0.13 μM) and kindled seizures (ED50 = 1.08 mM). DHA at ED25 caused a 3.6-fold increase in potency of valproate as its ED50 value from 117.5 (98.3–135.3) decreased to 32.5 (21.6–44.1) mg/kg. Moreover, a 4.9-fold increase in potency of lamotrigine occurred, as its ED50 value from 13.10 (11.50–14.9) decreased to 2.65 (0.8–5.6) mg/kg. CompuSyn analysis indicated synergistic anticonvulsant interaction between DHA and both valproate and lamotrigine. Co-administration strategy of the safe and inexpensive anticonvulsant compound DHA with AEDs should be favorably regarded in clinical studies of epilepsy treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahmadi A, Sayyah M, Khoshkholgh-Sima B, Choopani S, Kazemi J, Sadegh M, Moradpour F, Nahrevanian H (2013) Intra-hippocampal injection of lipopolysaccharide inhibits kindled seizures and retards kindling rate in adult rats. Exp Brain Res 226:107–120. doi:10.1007/s00221-013-3415-6

    Article  CAS  PubMed  Google Scholar 

  • Al Khayat HA, Awadalla MM, Al Wakad A, Marzook ZA (2010) Polyunsaturated fatty acids in children with idiopathic intractable epilepsy: serum levels and therapeutic response. J Pediatr Neurol 8(2):175–185. doi:10.3233/JPN-2010-0398

    Google Scholar 

  • Armijo JA, Shushtarian M, Valdizan EM, Cuadrado A, de las Cuevas I, Adín J (2005) Ion channels and epilepsy. Curr Pharm Des 11:1975–2003. doi:10.2174/1381612054021006

    Article  CAS  PubMed  Google Scholar 

  • Berry CB, Hayes D, Murphy A, Wiessner M, Rauen T, McBean GJ (2005) Differential modulation of the glutamate transporters GLT1, GLAST and EAAC1 by docosahexaenoic acid. Brain Res 1037:123–133. doi:10.1016/j.brainres.2005.01.008

    Article  CAS  PubMed  Google Scholar 

  • Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82. doi:10.1038/nrd2997

    Article  CAS  PubMed  Google Scholar 

  • Börjesson SI, Hammarström S, Elinder F (2008) Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids. Biophys J 95:2242–2253. doi:10.1529/biophysj.108.130757

    Article  PubMed Central  PubMed  Google Scholar 

  • Bromfield E, Dworetzky B, Hurwitz S, Eluri Z, Lane L, Replansky S, Mostofsky D (2008) A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav 12:187–190. doi:10.1016/j.yebeh.2007.09.011

    Article  PubMed  Google Scholar 

  • Chisari M, Shu HJ, Taylor A, Steinbach JH, Zorumski CF, Mennerick S (2010) Structurally diverse amphiphiles exhibit biphasic modulation of GABAA receptors: similarities and differences with neurosteroid actions. Br J Pharmacol 160:130–141. doi:10.1111/j.1476-5381.2010.00679.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446. doi:10.1158/0008-5472.CAN-09-1947

    Article  CAS  PubMed  Google Scholar 

  • Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681. doi:10.1124/pr.58.3.10

    Article  CAS  PubMed  Google Scholar 

  • Curatolo N, Lecointe C, Bordet R, Vallée L, Galabert C, Gressens P, Auvin S (2011) Oral administration of docosahexaenoic acid/eicosapentaeinoic acids is not anticonvulsant in rats: implications for translational research. Pediatr Res 70:584–588. doi:10.1203/PDR.0b013e31823277d9

    Article  CAS  PubMed  Google Scholar 

  • Danthi SJ, Enyeart JA, Enyeart JJ (2005) Modulation of native T-type calcium channels by omega-3 fatty acids. Biochem Biophys Res Commun 327:485–493. doi:10.1016/j.bbrc.2004.12.033

    Article  CAS  PubMed  Google Scholar 

  • DeGiorgio CM, Miller P, Meymandi S, Gornbein JA (2008) n-3 fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of SUDEP: clues from a pilot, double blind, exploratory study. Epilepsy Behav 13:681–684. doi:10.1016/j.yebeh.2008.08.001

    Article  PubMed  Google Scholar 

  • Demar Jr JC, Ma K, Chang L, Bell JM, Rapoport SI (2005) alpha-Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid. J Neurochem 94:1063–1076

    Article  CAS  PubMed  Google Scholar 

  • Gilby KL, Jans J, McIntyre DC (2009) Chronic omega-3 supplementation in seizure prone versus seizure-resistant rat strains: a cautionary tale. Neuroscience 163:750–758. doi:10.1016/j.neuroscience.2009.07.013

    Article  CAS  PubMed  Google Scholar 

  • Haley TJ, McCormick WG (1957) Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br J Pharmacol Chemother 12:12-15. doi: 10.1111/j.1476-5381.1957.tb01354.x

  • Hamano H, Nabekura J, Nishikawa M, Ogawa T (1996) Docosahexaenoic acid reduces GABA response in substantia nigra neuron of rat. J Neurophysiol 75:1264–1270

    CAS  PubMed  Google Scholar 

  • Kang JX, Leaf A (1996) Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. Proc Natl Acad Sci U S A 93:3542–3546

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kuo A, Smith MT (2014) Theoretical and practical applications of the intracerebroventricular route for CSF sampling and drug administration in CNS drug discovery research: a mini review. J Neurosci Methods 233:166–171. doi:10.1016/j.jneumeth.2014.06.006

    Article  CAS  PubMed  Google Scholar 

  • Lee DJ, Gurkoff GG, Goodarzi A, Muizelaar JP, Boggan JE, Shahlaie K (2014) Intracerebroventricular opiate infusion for refractory head and facial pain. World J Clin Cases 2(8):351–356. doi:10.12998/wjcc.v2.i8.351

    Article  PubMed Central  PubMed  Google Scholar 

  • Leifert WR, McMurchie EJ, Saint DA (1999) Inhibition of cardiac sodium currents in adult rat myocytes by n-3 polyunsaturated fatty acids. J Physiol 520:671–679. doi:10.1111/j.1469-7793.1999.00671.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Löscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 20(5):359–368. doi:10.1016/j.seizure.2011.01.003

    Article  PubMed  Google Scholar 

  • Löscher W, Fassbender CP, Nolting B (1991) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 8(2):79–94. doi:10.1016/0920-1211(91)90075-Q

    Article  PubMed  Google Scholar 

  • Löscher W, Klitgaard H, Twyman RE, Schmidt D (2013) New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 12:757–776. doi:10.1038/nrd4126

    Article  PubMed  Google Scholar 

  • Macdonald RL, Kelly KM (1995) Antiepileptic drug mechanisms of action. Epilepsia 36:S2–S12

    Article  CAS  PubMed  Google Scholar 

  • Musto AE, Gjorstrup P, Bazan NG (2011) The omega-3 fatty acid-derived neuroprotectin D 1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis. Epilepsia 52:1601–1608. doi:10.1111/j.1528-1167.2011.03081.x

    Article  CAS  PubMed  Google Scholar 

  • Nabekura J, Noguchi K, Witt MR, Nielsen M, Akaike N (1998) Functional modulation of human recombinant gamma-aminobutyric acid type A receptor by docosahexaenoic acid. J Biol Chem 273:11056–11061. doi:10.1074/jbc.273.18.11056

    Article  CAS  PubMed  Google Scholar 

  • Paul G, Zachrisson O, Varrone A, Almqvist P, Jerling M, Lind G, Rehncrona S, Linderoth B, Bjartmarz H, Shafer LL, Coffey R, Svensson M, Mercer KJ, Forsberg A, Halldin C, Svenningsson P, Widner H, Frisén J, Pålhagen S, Haegerstrand A (2015) Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients. J Clin Invest 25(3):1339–1346. doi:10.1172/JCI79635

    Article  Google Scholar 

  • Perucca E (2005) An introduction to antiepileptic drugs. Epilepsia 46:31–37

    Article  CAS  PubMed  Google Scholar 

  • Poling JS, Vicini S, Rogawski MA, Salem Jr N (1996) Docosahexaenoic acid block of neuronal voltage-gated K+ channels: subunit selective antagonism by zinc. Neuropharmacology 35:969–982. doi:10.1016/0028-3908(96)00127-X

    Article  CAS  PubMed  Google Scholar 

  • Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294

    Article  CAS  PubMed  Google Scholar 

  • Sayyah M, Moaied S, Kamalinejad M (2005) Anticonvulsant activity of Heracleum persicum seed. J Ethnopharmacol 98:209–211. doi:10.1016/j.jep.2004.12.026

    Article  CAS  PubMed  Google Scholar 

  • Schlanger S, Shinitzky M, Yam D (2002) Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients. Epilepsia 43(1):103–104. doi:10.1046/j.1528-1157.2002.13601.x

    Article  CAS  PubMed  Google Scholar 

  • Seebungkert B, Lynch JW (2002) Effects of polyunsaturated fatty acids on voltage-gated K+ and Na+ channels in rat olfactory receptor neurons. Eur J Neurol 16:2085–2094. doi:10.1046/j.1460-9568.2002.02288.x

    Google Scholar 

  • Søgaard R, Werge TM, Bertelsen C, Lundbye C, Madsen KL, Nielsen CH, Lundbaek JA (2006) GABA (A) receptor function is regulated by lipid bilayer elasticity. Biochemistry 45:13118–13129. doi:10.1021/bi060734

    Article  PubMed  Google Scholar 

  • Sutula TP (1990) Experimental models of temporal lobe epilepsy: new insights from the study of kindling and synaptic reorganization. Epilepsia 31:S45–S54

    Article  PubMed  Google Scholar 

  • Taha AY, Burnham WM, Auvin S (2010a) Polyunsaturated fatty acid and epilepsy. Epilepsia 51:1348–1358. doi:10.1111/j.1528-1167.2010.02654.x

    Article  CAS  PubMed  Google Scholar 

  • Taha AY, Jeffrey MA, Tasha NM, Bala S, Burnham WM (2010b) Acute administration of docosahexaenoic acid increase resistance to pentylenetetrazole-induced seizure in rats. Epilepsy Behav 17:336–343. doi:10.1016/j.yebeh.2010.01.001

    Article  PubMed  Google Scholar 

  • Taha AY, Ryan MA, Cunnane SC (2006) Markedly raised intake of saturated and monounsaturated fatty acids in rats on a high-fat ketogenic diet does not inhibit carbon recycling of 13C-alpha-linolenate. Lipids 41:933–935

    Article  CAS  PubMed  Google Scholar 

  • Taha AY, Trepanier MO, Ciobanu FA, Taha NM, Ahmed M, Zeng Q, Cheuk WI, Ip B, Filo E, Scott BW, Burnham WM, Bazinet RP (2013a) A minimum of 3 months of dietary fish oil supplementation is required to raise amygdaloid afterdischarge seizure thresholds in rats, implications for treating complex partial seizures. Epilepsy Behav 27:49–58. doi:10.1016/j.yebeh.2012.12.004

    Article  PubMed  Google Scholar 

  • Taha AY, Zahid T, Epps T, Trepanier MO, Burnham WM, Bazinet RP, Zhang L (2013b) Selective reduction of excitatory hippocampal sharp waves by docosahexaenoic acid and its methyl ester analog ex-vivo. Brain Res 1537:9–17. doi:10.1016/j.brainres.2013.09.004

    Article  CAS  PubMed  Google Scholar 

  • Tigerholm, J, Börjesson SI, Lundberg L, Elinder F, Fransén E (2012) Dampening of hyperexcitability in CA1 pyramidal neurons by polyunsaturated fatty acids acting on voltage-gated ion channels. PLoS One 7:e44388. doi: 10.1371/journal.pone.0044388

  • Trépanier MO, Lim J, Lai TK, Cho HJ, Domenichiello AF, Chen CT, Taha AY, Bazinet RP, Burnham WM (2014) Intraperitoneal administration of docosahexaenoic acid for 14 days increases serum unesterified DHA and seizure latency in the maximal pentylenetetrazole model. Epilepsy Behav 33:138–143. doi:10.1016/j.yebeh.2014.02.020

    Article  PubMed  Google Scholar 

  • Trépanier MO, Taha AY, Mantha RL, Ciobanu FA, Zeng QH, Tchkhartichvili GM, Domenichiello AF, Bazinet RP, Burnham WM (2012) Increases in seizure latencies induced by subcutaneous docosahexaenoic acid are lost at higher doses. Epilepsy Res 99:225–232. doi:10.1016/j.eplepsyres.2011.12.001

    Article  PubMed  Google Scholar 

  • Vreugdenhil M, Bruehl C, Voskuyl RA, Kang JX, Leaf A, Wadman WJ (1996) Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci U S A 93:12559–12563

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Voskuyl RA, Vreugdenhil M, Kang JX, Leaf A (1998) Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur J Pharmacol 341:145–152. doi:10.1016/S0014-2999(97)01467-2

    Article  CAS  PubMed  Google Scholar 

  • White HS (1999) Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 40:S2–S10

    Article  CAS  PubMed  Google Scholar 

  • Willis S, Samala R, Rosenberger TA, Borges K (2009) Eicosapentaenoic and docosahexaenoic acids are not anticonvulsant or neuroprotective in acute mouse seizure models. Epilepsia 50:138–142. doi:10.1111/j.1528-1167.2008.01722.x

    Article  CAS  PubMed  Google Scholar 

  • Xiao YF, Gomez AM, Morgan JP, Lederer WJ, Leaf A (1997) Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A 94:4182–4187

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xiao YF, Kang JX, Morgan JP, Leaf A (1995) Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A 92:11000–11004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xiao Y, Li X (1999) Polyunsaturated fatty acids modify mouse hippocampal neuronal excitability during excitotoxic or convulsant stimulation. Brain Res 846:112–121. doi:10.1016/S0006-8993(99)01997-6

    Article  CAS  PubMed  Google Scholar 

  • Young C, Gean PW, Chiou LC, Shen YZ (2000) Docosahexaenoic acid inhibits synaptic transmission and epileptiform activity in the rat hippocampus. Synapse 37:90–94

    Article  CAS  PubMed  Google Scholar 

  • Yuen AW, Sander JW, Fluegel D, Patsalos PN, Bell GS, Johnson T, Koepp MJ (2005) Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav 7:253–258. doi:10.1016/j.yebeh.2005.04.014

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by grant no. 594 from Pasteur Institute of Iran. The authors appreciate the expert advice of Professor Ronald J Tallarida regarding drug combination analysis.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Basic Science, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

    Hakimeh Gavzan & Vahab Babapour

  2. Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran

    Hakimeh Gavzan & Mohammad Sayyah

  3. Biotechnology Research Center, Drug Design and Bioinformatics Group, Pasteur Institute of Iran, Tehran, Iran

    Soroush Sardari

Authors
  1. Hakimeh Gavzan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Sayyah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soroush Sardari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vahab Babapour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Sayyah.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gavzan, H., Sayyah, M., Sardari, S. et al. Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models. Naunyn-Schmiedeberg's Arch Pharmacol 388, 1029–1038 (2015). https://doi.org/10.1007/s00210-015-1135-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-015-1135-0

Keywords

Search

Navigation