Epilepsy Research
Volume 22, Issue 1 , Pages 1-11 , September 1995

Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA

  • Arie Goldlust

      Affiliations

    • Department of Biotechnology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
  • ,
  • Ti-Zhi Su

      Affiliations

    • Department of Biotechnology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
  • ,
  • Devin F. Welty

      Affiliations

    • Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
  • ,
  • Charles P. Taylor

      Affiliations

    • Neuroscience Pharmacology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
  • ,
  • Dale L. Oxender

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: (313) 996-7601; fax: (313) 998-5970.
    • Department of Biotechnology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., 2800 Plymouth Rd., Ann Arbor, MI 48105, USA

Received 5 April 1994 ,Accepted 3 April 1995.

References 

  1. Bartoszyk GD, Meyerson N, Reimann W, Satzinger G, von Hodenberg A. Gabapentin. In:  Meldrum B,  Porter RJ editor. New Anticonvulsant Drugs. London: John Libbey; 1986;p. 147–163
  2. Brookes N. Effect of intracellular glutamine on the uptake of large neutral amino acids in astrocytes: Concentrative Na+-independent transport exhibits metastability. J. Neurochem. 1992;59:227–235
  3. Chadwick D. Gabapentin. In:  Pisani F,  Perucca E,  Avanzini G,  Richens A editor. New Antiepileptic Drugs. Amsterdam: Elsevier; 1991;p. 183–186
  4. Cooper AJL, McDonald JM, Gelbard AS, Gledhill RF, Duffy TE. The metabolic fate of 13N-labeled ammonia in rat brain. J. Biol. Chem. 1979;254:4982–4992
  5. Dodd PR, Hardy JA, Oakley AE, Edwardson JA, Perry EK, Delaunoy JP. A rapid method for preparing synaptosomes: Comparison with alternative procedures. Brain Res. 1981;226:107–118
  6. Erecinska M, Nelson D. Activation of glutamate dehydrogenase by leucine and its nonmetabolizable analogue in rat brain synaptosomes. J. Neurochem. 1990;54:1335–1343
  7. Erecinska M, Nelson D, Silver IA. Neurotransmitter amino acids in the CNS. I. Regional changes in amino acid levels in rat brain during ischemia and reperfusion. Brain Res. 1984;304:9–22
  8. Gotz E, Feuerstein TJ, Lais A, Meyer DK. Effects of gabapentin on release of γ-aminobutyric acid from slices of rat neostriatum. Arzneim.-Forsch. Drug Res. 1993;43:636–638
  9. Harper AE. Thoughts on the role of branched-chain α-keto acid dehydrogenase complex in nitrogen metabolism. Ann. N.Y. Acad. Sci. 1989;573:267–273
  10. Heini HG, Gebhardt R, Brecht A, Mecke D. Purification and characterization of rat liver glutaminase. Eur. J. Biochem. 1987;162:541–546
  11. Hertz L, Schousboe A. Metabolism of glutamate and glutamine in neurons and astrocytes in primary cultures. In: 2nd ed..  Kvamme E editors. Glutamine and Glutamate in Mammals. Vol. 2:New York: CRC Press; 1988;p. 39–55
  12. Jessy J, Murthy ChRK. Elevation of transamination of branched-chain amino acids in brain in acute ammonia toxicity. Biochem. Int. 1985;7:1027–1031
  13. Jessy J, Murthy ChRK. Cellular and subcellular branched-chain keto acid decarboxylase in rat brain and its response to hyperammonemia. Ann. N.Y. Acad. Sci. 1989;573:447–449
  14. Jessy J, Raghavendra Rao VL, Murthy ChRK. Effects of partial hepatectomy on the enzymes of cerebral glutamate and branched-chain amino acid metabolism. Biochem. Int. 1990;20:107–115
  15. Kocsis JD, Honmou O. Gabapentin increases GABA-induced depolarization in rat neonatal optic nerve. Neurosci. Lett. 1994;169:181–184
  16. Lai JCK, Walsh JM, Dennis SC, Clark JB. Synaptic and non-synaptic mitochondria from rat brain: Isolation and characterization. J. Neurochem. 1977;28:625–631
  17. Löscher W, Honack D, Taylor CP. Gabapentin increases aminooxyacetic acid-induced GABA accumulation regions of rat brain. Neurosci. Lett. 1991;128:150–154
  18. Mans AM, Biebuyck JF, Hawkins RA. Ammonia selectively stimulates neutral amino acid transport across blood-brain barrier. Am. J. Physiol. 1983;245:C74–C77
  19. McMahon HT, Nicholls DG. Barium-evoked glutamate release from guinea-pig cerebrocortical synaptosomes. J. Neurochem. 1993;61:110–115
  20. Meldrum BS. GABAergic mechanisms in the pathogenesis and treatment of epilepsy. Br. J. Clin. Pharmacol. 1989;27:3S–11S
  21. Meldrum BS. Excitatory amino acids in epilepsy and potential novel therapies. Epilepsy Res. 1992;12:189–196
  22. Palaiologos G, Hertz L, Schousboe A. Evidence that aspartate aminotransferase activity and ketodicarboxylate carrier function are essential for the biosynthesis of transmitter glutamate. J. Neurochem. 1988;51:317–320
  23. Palaiologos G, Hertz L, Schousboe A. Role of aspartate aminotransferase and mitochondrial dicarboxylate transport for release of endogenously and exogenously supplied neurotransmitter in glutamatergic neurons. Neurochem. Res. 1989;14:359–366
  24. Rao TI, Rao GN, Swamy M, Sadasivudu B. Studies on metabolism of branched chain amino acids in brain and other tissues of rat with special reference to leucine. J. Neurosci. Res. 1982;7:387–395
  25. Roberts S, Morelos BS. Regulation of cerebral metabolism of amino acids. IV. Influence of amino acid levels on leucine uptake, utilization and incorporation into protein in vivo. J. Neurochem. 1965;12:373–387
  26. Rowe WB, Ronzio RA, Wellner VP, Meister A. Glutamine synthetase (sheep brain). Meth. Enzymol. 1970;17A:900–910
  27. Shank RP, Aprison MH. Present status and significance of the glutamine cycle in neural tissues. Life Sci. 1981;28:837–842
  28. Shank RP, Bennet DJ. 2-Oxoglutarate transport: A potential mechanism for regulating glutamate and tricarboxylic acid cycle intermediates in neurons. Neurochem. Res. 1993;18:401–410
  29. Skeie B, Petersen AJ, Manner T, Askanazi J, Steen PA. Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats. Pharm. Biochem. Behav. 1994;48:101–103
  30. Skeie B, Petersen AJ, Manner T, Askanazi J, Jellum E, Steen PA. Branched-chain amino acids increase the seizure threshold to picrotoxin in rats. Pharm. Biochem. Behav. 1992;43:669–671
  31. Silverman RB, Andruszkiewicz R, Nanavati SM, Taylor CP, Vartanian MG. 3-Alkyl-4 aminobutyric acids: The first class of anticonvulsant agent that activates l-glutamic acid decarboxylase. J. Med. Chem. 1991;34:2295–2298
  32. Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm. Res. 1993;10:276–281
  33. Su TZ, Lunney E, Campbell G, Oxender DL. Transport of gabapentin, a γ-amino acid drug, by system L α-amino acid transporters: A comparative study in astrocytes, synaptosomes and CHO cells. J. Neurochem. 1995;64:2125–2131
  34. Taylor CP, Vartanian MG, Andruszkiewicz R, Silverman RB. 3-Alkyl GABA and 3-alkylglutamic acid analogues: Two new classes of anticonvulsant agents. Epilepsy Res. 1992;11:103–110
  35. Thurlow RJ, Brown JP, Gee NS, Hill DR, Woodruff GN. [3H]-gabapentin may label a system-L like neutral amino acid carrier in brain. Eur. J. Pharmacol. 1993;247:247–345
  36. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet. 1990;335:1114–1117
  37. US Gabapentin Study Group Number 5. Gabapentin as add-on therapy in refractory partial epilepsy: A double-blind, placebo-controlled, parallel-group study. Neurology. 1993;43:2292–2298
  38. Vollmer KO, von Hodenberg A, Kille EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneim.-Forsch. Drug Res. 1986;36:830–839
  39. Welty DF, Schielke GP, Vartanian MG, Taylor CP. Gabapentin anticonvulsant action in rats: Disequilibrium with peak drug concentration in plasma and brain microdialysate. Epilepsy Res. 1993;16:175–181
  40. Yudkoff M, Daikhin Y, Lin Z-P, Nissim I, Stern J, Pleasure D, et al. Interrelationships of leucine and glutamate metabolism in cultured astrocytes. J. Neurochem. 1994;62:1192–1202
  41. Yudkoff M, Nissim I, Kim S, Pleasure D, Hummeler K, Segal S. [15N]-Leucine as a source of [15N]-glutamate in organotypic cerebellar explants. Biochem. Biophys. Res. Commun. 1983;115:174–179
  42. Yudkoff M, Nissim I, Hertz L. Precursor of glutamic acid nitrogen in primary neuronal cultures: Studies with 15N. Neurochem. Res. 1990;15:1191–1196

PII: 0920-1211(95)00028-9

Epilepsy Research
Volume 22, Issue 1 , Pages 1-11 , September 1995