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Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism

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Abstract

Rationale

When administered chronically to rats, drugs that are effective in bipolar disorder—lithium and the anticonvulsants, valproic acid and carbamazepine—have been shown to downregulate the expression of certain enzymes involved in brain arachidonic acid (AA) release and cyclooxygenase (COX)-mediated metabolism. Phase II clinical trials with the anticonvulsant topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-d-fructopyranose sulfamate] suggest that this drug may also be effective for bipolar disorder.

Objectives

To see if topiramate has effects similar to those of the other three drugs, we administered topiramate to rats for 14 days at 20 mg/kg, p.o. twice daily.

Results

Compared with p.o. vehicle, topiramate treatment did not significantly affect the brain activity or protein level of cytosolic phospholipase A2, secretory PLA2, or Ca2+-independent iPLA2. Additionally, brain protein levels of COX-1, COX-2, 5-lipoxygenase, and cytochrome P450 epoxygenase were unchanged.

Conclusions

These results suggest that topiramate does not modify expression of the enzymes involved in brain AA metabolism that have been shown to be targeted by lithium, valproic acid, or carbamazepine. If topiramate proves effective in bipolar disorder, it may not act by modulating brain AA metabolism. In view of the proven anticonvulsant effect of topiramate, our results also suggest that the AA cascade is not involved in the antiseizure properties of the drug.

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Abbreviations

AA:

arachidonic acid

COX:

cyclooxygenase

CYP:

cytochrome P450 epoxygenase

HPMC:

hydroxypropylmethylcellulose

5-LO:

lipoxygenase

OD:

optical density

PGE2:

prostaglandin E2

PLA2:

phospholipase A2

cPLA2:

cytosolic PLA2

sPLA2:

secretory PLA2

iPLA2:

Ca2+-independent PLA2

sn :

stereospecifically numbered

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Acknowledgements

This research was supported by the Intramural Program of the National Institute on Aging, NIH, as well as by a grant awarded to S.I. Rapoport by Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD) entitled, “Effect of chronic administration of Topiramate, a drug used to treat bipolar disorder, on brain arachidonic acid signaling in awake rats.” The authors thank Dr. Richard Shank of J&JPRD for help in designing the topiramate administration regimen for this protocol, Dr. Kenneth Setchell (Children’s Hospital Medical Center, Cincinnati, OH) for measuring plasma topiramate, and Mr. Festus Ehizielen at the NIH for technical support.

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Authors and Affiliations

  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Bldg. 10, Rm. 6N202, Bethesda, MD, 20892, USA

    Sandra Ghelardoni, Richard P. Bazinet, Stanley I. Rapoport & Francesca Bosetti

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  1. Sandra Ghelardoni
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  2. Richard P. Bazinet
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  3. Stanley I. Rapoport
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  4. Francesca Bosetti
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Correspondence to Francesca Bosetti.

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Ghelardoni, S., Bazinet, R.P., Rapoport, S.I. et al. Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism. Psychopharmacology 180, 523–529 (2005). https://doi.org/10.1007/s00213-005-2189-3

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