Neurochemical Research

, Volume 30, Issue 5, pp 677–683 | Cite as

Topiramate does not Alter the Kinetics of Arachidonic or Docosahexaenoic Acid in Brain Phospholipids of the Unanesthetized Rat

  • Ho-Joo Lee
  • Sandra Ghelardoni
  • Lisa Chang
  • Francesca Bosetti
  • Stanley I. Rapoport
  • Richard P. Bazinet
Article

Abstract

Interest in the potential therapeutic utility of topiramate for treating bipolar disorder was stimulated by published reports of investigator-initiated open label clinical studies. Because chronic lithium, carbamazepine and valproate decrease the turnover of arachidonic acid (AA) but not docosahexaenoic acid (DHA) in brain phospholipids of the awake rat, we tested if topiramate would produce similar results. Rats received either topiramate (20 mg/kg twice per day) or vehicle for 14 days and then while unanesthetized were infused intravenously with either [1-14C] AA or [1-14C] DHA for 5 min while blood was collected from the femoral artery at fixed times. Topiramate did not alter the incorporation rate of AA or DHA from their respective brain acyl-CoA pool into brain phospholipids, nor the turnover of AA and DHA in brain phospholipids. The results of our study indicate that topiramate does not possess a pharmacological property that three drugs with proven efficacy in treating bipolar disorder have in common.

Keywords

Arachidonic acid brain bipolar disorder mood stabilizer anti-epileptic topiramate lithium mania turnover metabolism kinetics 

Abbreviations

AA

arachidonic acid

DHA

docosahexaenoic acid

PC

choline glycerophospholipid

PS

phosphatidylserine

PI

phosphatidylinositoI

PE

ethanolamine glycerophospholipid

FAME

fatty acid methyl ester

sn

stereospecifically numbered

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ben-Menachem, E., Henriksen, O., Dam, M., Mikkelsen, M., Schmidt, D., Reid, S., Reife, R., Kramer, L., Pledger, G, Karim, R. 1996Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizuresEpilepsia37539543PubMedGoogle Scholar
  2. 2.
    Privitera, M., Fincham, R., Penry, J., Reife, R., Kramer, L., Pledger, G., Karim, R. 1996Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study GroupNeurology4616781683PubMedGoogle Scholar
  3. 3.
    Faught, E., Wilder, B. J., Ramsay, R. E., Reife, R. A., Kramer, L. D., Pledger, G. W., Karim, R. M. 1996Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study GroupNeurology4616841690PubMedGoogle Scholar
  4. 4.
    Tassinari, C. A., Michelucci, R., Chauvel, P., Chodkiewicz, J., Shorvon, S., Henriksen, O., Dam, M., Reife, R., Pledger, G., Karim, R. 1996Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsyEpilepsia37763768PubMedGoogle Scholar
  5. 5.
    Biton, V., Montouris, G. D., Ritter, F., Riviello, J. J., Reife, R., Lim, P., Pledger, G. 1999A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study GroupNeurology5213301337PubMedGoogle Scholar
  6. 6.
    Brandes, J. L., Saper, J. R., Diamond, M., Couch, J. R., Lewis, D. W., Schmitt, J., Neto, W., Schwabe, S., Jacobs, D. 2004Topiramate for migraine prevention: A randomized controlled trialJAMA291965973CrossRefPubMedGoogle Scholar
  7. 7.
    Vieta, E., Sanchez-Moreno, J., Goikolea, J. M., Torrent, C., Benabarre, A., Colom, F., Martinez-Aran, A., Reinares, M., Comes, M., Corbella, B. 2003Adjunctive topiramate in bipolar II disorderWorld J. Biol. Psychiatry4172176PubMedGoogle Scholar
  8. 8.
    Vieta, E., Goikolea, J. M., Olivares, J. M., Gonzalez-Pinto, A., Rodriguez, A., Colom, F., Comes, M., Torrent, C., Sanchez-Moreno, J. 20031-year follow-up of patients treated with risperidone and topiramate for a manic episodeJ. Clin. Psychiatry64834839PubMedGoogle Scholar
  9. 9.
    Marcotte, D. 1998Use of topiramate, a new anti-epileptic as a mood stabilizerJ. Affect. Disord.50245251CrossRefPubMedGoogle Scholar
  10. 10.
    Calabrese, J. R., Keck, P. E.,Jr., McElroy, S. L., Shelton, M. D. 2001A pilot study of topiramate as monotherapy in the treatment of acute maniaJ. Clin. Psychopharmacol.21340342CrossRefPubMedGoogle Scholar
  11. 11.
    McElroy, S. L., Suppes, T., Keck, P. E., Frye, M. A., Denicoff, K. D., Altshuler, L. L., Brown, E. S., Nolen, W. A., Kupka, R. W., Rochussen, J., Leverich, G. S., Post, R. M. 2000Open-label adjunctive topiramate in the treatment of bipolar disordersBiol. Psychiatry4710251033CrossRefPubMedGoogle Scholar
  12. 12.
    Poulsen, C. F., Simeone, T. A., Maar, T. E., Smith-Swintosky, V., White, H. S., Schousboe, A. 2004Modulation by topiramate of AMPA and kainate mediated calcium influx in cultured cerebral cortical, hippocampal and cerebellar neuronsNeurochem. Res.29275282CrossRefPubMedGoogle Scholar
  13. 13.
    Angehagen, M., Ben-Menachem, E., Shank, R., Ronnback, L., Hansson, E. 2004Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation levelJ. Neurochem.88320325PubMedGoogle Scholar
  14. 14.
    Angehagen, M., Ben-Menachem, E., Ronnback, L., Hansson, E. 2003Topiramate protects against glutamate- and kainate-induced neurotoxicity in primary neuronal-astroglial culturesEpilepsy Res.546371CrossRefPubMedGoogle Scholar
  15. 15.
    Gryder, D. S., Rogawski, M. A. 2003Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neuronsJ. Neurosci.2370697074PubMedGoogle Scholar
  16. 16.
    Jahromi, S. S., Pelletier, M. R., McDonald, P. J., Khosravani, H., Carlen, P. L. 2000Antiepileptic efficacy of topiramate: assessment in two in vitro seizure modelsBrain Res.8722028CrossRefPubMedGoogle Scholar
  17. 17.
    Gibbs, J. W.,3rd, Sombati, S., DeLorenzo, R. J., Coulter, D. A. 2000Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neuronsEpilepsia41S10S16Google Scholar
  18. 18.
    Kaminski, R. M., Banerjee, M., Rogawski, M. A. 2004Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonistNeuropharmacology4610971104CrossRefPubMedGoogle Scholar
  19. 19.
    Rapoport, S. I., Bosetti, F. 2002Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder?Arch. Gen. Psychiatry59592596CrossRefPubMedGoogle Scholar
  20. 20.
    Sun, G. Y., Xu, J., Jensen, M. D., Simonyi, A. 2004Phospholipase A2 in the central nervous system: Implications for neurodegenerative diseasesJ. Lipid Res.45205213CrossRefPubMedGoogle Scholar
  21. 21.
    Robinson, P. J., Noronha, J., DeGeorge, J. J., Freed, L. M., Nariai, T., Rapoport, S. I. 1992A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: Review and critical analysisBrain Res. Brain Res. Rev.17187214CrossRefPubMedGoogle Scholar
  22. 22.
    DeGeorge, J. J., Noronha, J. G., Bell, J., Robinson, P., Rapoport, S. I. 1989Intravenous injection of (1-14C) arachidonate to examine regional brain lipid metabolism in unanesthetized ratsJ. Neurosci. Res.24413423CrossRefPubMedGoogle Scholar
  23. 23.
    Cunnane, S. C., Ryan, M. A., Nadeau, C. R., Bazinet, R. P., Musa-Veloso, K., McCloy, U. 2003Why is carbon from some polyunsaturates extensively recycled into lipid synthesis?Lipids38477484PubMedGoogle Scholar
  24. 24.
    Chang, M. C., Grange, E., Rabin, O., Bell, J. M., Allen, D. D., Rapoport, S. I. 1996Lithium decreases turnover of arachidonate in several brain phospholipidsNeurosci. Lett.220171174CrossRefPubMedGoogle Scholar
  25. 25.
    Lee, H., Rao, J., Chang, L., Rapoport, S., and Bazinet R. 2004. The effects of chronic carbamazepine, an antibipolar disorder drug, on the turnover of arachidonic and docosahexaenoic acids in brain phospholipids of the awake rat. Soc. Neurosci.Google Scholar
  26. 26.
    Chang, M. C., Contreras, M. A., Rosenberger, T. A., Rintala, J. J., Bell, J. M., Rapoport, S. I. 2001Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizersJ. Neurochem.77796803CrossRefPubMedGoogle Scholar
  27. 27.
    Chang, M. C., Bell, J. M., Purdon, A. D., Chikhale, E. G., Grange, E. 1999Dynamics of docosahexaenoic acid metabolism in the central nervous system: Lack of effect of chronic lithium treatmentNeurochem Res.24399406CrossRefPubMedGoogle Scholar
  28. 28.
    Ghelardoni, S., Tomita, Y. A., Bell, J. M., Rapoport, S. I., Bosetti, F. 2004Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brainBiol. Psychiatry56248254CrossRefPubMedGoogle Scholar
  29. 29.
    Rintala, J., Seemann, R., Chandrasekaran, K., Rosenberger, T. A., Chang, L., Contreras, M. A., Rapoport, S. I., Chang, M. C. 199985 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brainNeuroreport1038873890PubMedGoogle Scholar
  30. 30.
    Weerasinghe, G. R., Seemann, R., Rapoport, S. I., Bosetti, F. 2003Lithium chloride, administered chronically to rats, does not affect the fractional phosphorylation of brain cytosolic phospholipase A2, while reducing its net protein levelBrain Res. Bull.59303306CrossRefPubMedGoogle Scholar
  31. 31.
    Bosetti, F., Rintala, J., Seemann, R., Rosenberger, T. A., Contreras, M. A., Rapoport, S. I., Chang, M. C. 2002Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brainMol. Psychiatry7845850CrossRefPubMedGoogle Scholar
  32. 32.
    Bosetti, F., Weerasinghe, G. R., Rosenberger, T. A., Rapoport, S. I. 2003Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and -2 in rat brainJ. Neurochem.85690696PubMedGoogle Scholar
  33. 33.
    Bazinet, R., Rao, J., Chang, L., Rapoport, S. I., and Lee, H. 2005. Chronic Valproate Does Not Alter The Kinetics Of Docosahexaenoic Acid Within Brain Phospholipids Of The Unanesthetized Rat. Psychopharmacology (Berl). In Press.Google Scholar
  34. 34.
    Ghelardoni, S., Bazinet, R., Rapoport, S., and Bosetti, F. 2004. Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism. Psychopharmacology, In Press.Google Scholar
  35. 35.
    York, D. A., Singer, L., Thomas, S., Bray, G. A. 2000Effect of topiramate on body weight and body composition of osborne-mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAsNutrition16967975CrossRefPubMedGoogle Scholar
  36. 36.
    Shaldubina, A., Einat, H., Szechtman, H., Shimon, H., Belmaker, R. H 2002Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorderJ. Neural Transm.109433440CrossRefPubMedGoogle Scholar
  37. 37.
    Rapoport, S. I., Chang, M. C., Spector, A. A. 2001Delivery and turnover of plasma-derived essential PUFAs in mammalian brainJ. Lipid Res.42678685PubMedGoogle Scholar
  38. 38.
    BipolarNews org. (2004) Research News. Topiramate in bipolar disorder. 2004.Google Scholar
  39. 39.
    Sachs G., Kushner S., Wang D., Olson W., Capece J., Fazzio L., N, R. (2004) Topiramate in adults with acute bipolar I mania: Pooled results. American Psychiatric Association Annual Meeting. NR365.Google Scholar
  40. 40.
    Sachs, G. S. 2003Decision tree for the treatment of bipolar disorderJ. Clin. Psychiatry.643540Google Scholar
  41. 41.
    Yatham, L. N. 2004Newer anticonvulsants in the treatment of bipolar disorderJ. Clin. Psychiatry652835Google Scholar
  42. 42.
    Deutsch, J., Rapoport, S. I., Purdon, A. D. 1997Relation between free fatty acid and acyl-CoA concentrations in rat brain following decapitationNeurochem. Res.22759765CrossRefPubMedGoogle Scholar
  43. 43.
    Skipski, V. P., Good, J. J., Barclay, M., Reggio, R. B. 1968Quantitative analysis of simple lipid classes by thin-layer chromatographyBiochim. Biophys. Acta1521019PubMedGoogle Scholar
  44. 44.
    Makrides, M., Neumann, M. A., Byard, R. W., Simmer, K., Gibson, R. A. 1994Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infantsAm. J. Clin. Nutr.60189194PubMedGoogle Scholar
  45. 45.
    Deutsch, J., Grange, E., Rapoport, S. I., Purdon, A. D. 1994Isolation and quantitation of long-chain acyl-coenzyme A esters in brain tissue by solid-phase extractionAnal. Biochem.220321323CrossRefPubMedGoogle Scholar
  46. 46.
    Grange, E., Deutsch, J., Smith, Q. R., Chang, M., Rapoport, S. I., Purdon, A. D. 1995Specific activity of brain palmitoyl-CoA pool provides rates of incorporation of palmitate in brain phospholipids in awake ratsJ. Neurochem.6522902298PubMedGoogle Scholar
  47. 47.
    Stoll, A. L., Severus, W. E., Freeman, M. P., Rueter, S., Zboyan, H. A., Diamond, E., Cress, K. K., Marangell, L. B. 1999Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trialArch. Gen. Psychiatry56407412CrossRefPubMedGoogle Scholar
  48. 48.
    Contreras, M. A., Chang, M. C., Rosenberger, T. A., Greiner, R. S., Myers, C. S., Salem, N.,Jr., Rapoport, S. I. 2001Chronic nutritional deprivation of n-3 alpha-linolenic acid does not affect n-6 arachidonic acid recycling within brain phospholipids of awake ratsJ. Neurochem.7910901099CrossRefPubMedGoogle Scholar
  49. 49.
    Contreras, M. A., Rapoport, S. I. 2002Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissuesCurr. Opin. Lipidol.13267272CrossRefPubMedGoogle Scholar
  50. 50.
    Bazinet, R. P., Douglas, H., Cunnane, S. C. 2003Whole-body utilization of n-3 PUFA in n-6 PUFA-deficient ratsLipids38187189PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Ho-Joo Lee
    • 1
  • Sandra Ghelardoni
    • 1
  • Lisa Chang
    • 1
  • Francesca Bosetti
    • 1
  • Stanley I. Rapoport
    • 1
  • Richard P. Bazinet
    • 1
  1. 1.Brain Physiology and Metabolism SectionNational Institute on Aging, National Institutes of HealthBethesdaUSA

Personalised recommendations