Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2

Biopharmaceutics and Drug Disposition

Volumn 24, Issue 8, 2003, Pages 357-365

  Inano, Akihiro ^a   Sai, Yoshimichi ^a,b   Nikaido, Hiroko ^a   Hasimoto, Noriyoshi ^a   Asano, Masahide ^a   Tsuji, Akira ^a,b   Tamai, Ikumi ^b,c  

^a KANAZAWA UNIVERSITY   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^c TOKYO UNIVERSITY OF SCIENCE   (Japan)

Author keywords

Acetyl L carnitine; Blood brain barrier; Microdialysis; OCTN2; Transport

Indexed keywords

CARNITINE TRANSPORTER; CARRIER PROTEIN; LEVACECARNINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD BRAIN BARRIER; BRAIN REGION; CARNITINE DEFICIENCY; CONTROLLED STUDY; DISEASE MODEL; DRUG BRAIN LEVEL; DRUG PENETRATION; DRUG TRANSPORT; DRUG UPTAKE; EXTRACELLULAR FLUID; IN VIVO STUDY; ISOTOPE LABELING; MALE; MICRODIALYSIS; MOUSE; NONHUMAN; PROTEIN BINDING; PROTEIN DEFECT; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN SYNTHESIS; RADIOACTIVITY; THALAMUS; WILD TYPE;

ACETYLCARNITINE; ANIMALS; BLOOD-BRAIN BARRIER; CARRIER PROTEINS; INJECTIONS, INTRAVENOUS; MALE; MEMBRANE PROTEINS; MICE; MICE, INBRED C3H; MICE, KNOCKOUT; MICRODIALYSIS; ORGANIC CATION TRANSPORT PROTEINS; TIME FACTORS; TISSUE DISTRIBUTION;

EID: 0242624720     PISSN: 01422782     EISSN: None     Source Type: Journal    
DOI: 10.1002/bdd.371     Document Type: Article

References (32)

1. Bremer J. Carnitine in intermediary metabolism: The metabolism of fatty acid esters of carnitine by mitochondria. J Biol Chem 1962; 237: 3628-3632.
2. Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol Psychiatry 2000; 5: 616-632.
3. Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-L-carnitine in early onset AD. Neurology 2000; 55: 805-810.
4. Ishii T, Shimpo Y, Matsuoka Y, Kinoshita K. Anti-apoptotic effect of acetyl-L-carnitine and L-carnitine in primary cultured neurons. Jpn J Pharmacol 2000; 83: 119-124.
5. Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 2002; 99: 1870-1875.
6. Liu J, Killilea DW, Ames BN. Age-associated mitochondrial oxidative decay: Improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-α-lipoic acid. Proc Natl Acad Sci USA 2002; 99: 1876-1881.
7. Liu J, Head E, Gharib AM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc Natl Acad Sci USA 2002; 99: 2356-2361.
8. Wawrzenczyk A, Nalecz KA, Nalecz MJ. Effect of externally added carnitine on the synthesis of acetylcholine in rat cerebral cortex cells. Neurochem Int 1995; 26: 635-641.
9. Brooks JO 3rd, Yesavage JA, Carta A, Bravi D. Acetyl-L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Int Psychogeriatr 1998; 10: 193-203.
10. Thal LJ, Carta A, Clarke WR, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology 1996; 47: 705-711.
11. Tamai I, Ohashi R, Nezu J, et al. Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem 1998; 273: 20378-20382.
12. Tamai I, Ohashi R, Nezu J, et al. Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem 2000; 275: 40064-40072.
13. +-coupled transport of L-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim Biophys Acta 2001; 1512: 273-284.
14. Wu X, Hunag W, Prasad PD, et al. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmcol Exp Ther 1999; 290: 1482-1492.
15. Koizumi T, Nikaido H, Hayakawa J, Nonomura A, Yoneda T. Infantile disease with microvesicular fatty infiltration of viscera spontaneously occurring in the C3H-H-2° strain of mouse with similarities to Reye's syndrome. Lab Anim 1988; 22: 83-87.
16. Koizumi A, Nozaki J, Ohura T, et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet 1999; 8: 2247-2254.
17. Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genet 1999; 21: 91-94.
18. Yokogawa K, Yonekawa M, Tamai I, et al. Loss of wild-type carrier-mediated L-carnitine transport activity in hepatocytes of juvenile visceral steatosis mice. Hepatology 1999; 30: 997-1001.
19. Kido Y, Tamai I, Ohnari A, et al. Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood-brain barrier. J Neurochem 2001; 79: 959-969.
20. Zhu Y, Wong PSH, Cregor M, Gitzen J, Coury LA, Kissinger PT. In vivo microdialysis and reverse phase ion pair liquid chromatography/tandem mass spectrometry for the determination and identification of acetylcholine and related compounds in rat brain. Rapid Commun Mass Spectrom 2000; 14: 1695-1700.
21. Longo A, Bruno G, Curti S, Mancinelli A, Miotto G. Determination of L-carnitine in human plasma by high-performance liquid chromatography after pre-column derivatization with 1-aminoanthracene. J Chromatogr B 1996; 686: 129-139.
22. Marzo A, Curti S. L-Carnitine moiety assay: an up-to-date reappraisal covering the commonest methods for various applications. J Chromatogr B 1997; 702: 1-20.
23. Yokogawa K, Higashi Y, Tamai I, et al. Decreased tissue distribution of L-carnitine in juvenile visceral steatosis mice. J Pharmacol Exp Ther 1999; 289: 224-230.
24. Hashimoto N, Suzuki F, Tamai I, et al. Gene-dose effect on carnitine transport activity in embryonic fibroblasts of JVS mice as a model of human carnitine transporter deficiency Biochem Pharmacol 1998; 55: 1729-1732.
25. 11C] acetyl-L-carnitine into the brain: a PET study. Biochem Biophys Res Commun 1997; 231: 488-493.
26. +-dependent carnitine transport by organic cation transporter (OCTN2): Its pharmacological and toxicological relevance. J Pharmacol Exp Ther 1999; 291: 778-784.
27. Ohashi R, Tamai I, Nezu J, et al. Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol Pharmcol 2001; 59: 358-366.
28. Ramsay RR, Gandour RD, van der Leji FR. Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 2001; 1546: 21-43.
29. Elmquist WF, Sawchuk RJ. Application of microdialysis in pharmacokinetic studies. Pharm Res 1997; 14: 267-288.
30. Sun H, Bungay PM, Elmquist WF. Effect of capillary efflux transport inhibition on the determination of probe recovery during in vivo microdialysis in the brain. J Pharmacol Exp Ther 2001; 297: 991-1000.
31. de Lange ECM, de Bock G, Schinkel AH, de Boer AG, Breimer DD. BBB transport and P-glycoprotein functionality using MDR1A (- / -) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123. Pharm Res 1998; 15: 1657-1665.
32. Aureli T, Di Cocco ME, Puccetti C, et al. Acetyl-L-carnitine modulates glucose metabolism and stimulates glycogen synthesis in rat brain. Brain Res 1998; 796: 75-81.