Journal of Neural Transmission

, Volume 115, Issue 7, pp 1019–1025 | Cite as

MKC-231, a choline-uptake enhancer: (1) long-lasting cognitive improvement after repeated administration in AF64A-treated rats

  • Tomoko BesshoEmail author
  • Ken Takashina
  • Junichi Eguchi
  • Teiko Komatsu
  • Ken-Ichi Saito
Alzheimer's Disease and Related Disorders - Original Article


MKC-231 is reported to increase high-affinity choline uptake (HACU) in vitro and improve learning impairment on a single oral administration in AF64A-treated rats. In this study, we investigated the effects of repeated administration of MKC-231 (1 and 3 mg/kg, p.o., 8 days) on learning impairment in the water-maze task in AF64A-treated rats 1, 24, 48, and 72 h after the last dose. Significant cognitive improvement was observed for 24 h, however, concentration measurement studies indicated MKC-231 was not detected in the brain by this time. We also studied the effects of 8-days repeated administration of MKC-231 on HACU 1, 24, 48, and 72 h after the last dose and observed an increase of HACU similar in time course with cognitive improvement. From these results, we discussed the possibility that MKC-231 could induce long-lasting procognitive effects by changing the choline transporter regulation system.


MKC-231 AF64A High-affinity choline uptake (HACU) Water-maze 


  1. Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529PubMedCrossRefGoogle Scholar
  2. Bessho T, Takashina K, Tabata R, Oshima C, Chaki H, Yamabe H, Egawa M, Tobe A, Saito K-I (1996) Effects of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro [2,3-b] quinolin-4-yl) acetoamide on deficits of water maze learning in rats. Arzneimittelforschung 46:369–373PubMedGoogle Scholar
  3. Ferguson SM, Blakely RD (2004) The choline transporter resurfaces: new roles for synaptic vesicles. Mol Interv 4:22–37PubMedCrossRefGoogle Scholar
  4. Ferguson SM, Savchenko V, Apparsundaram S, Zwick M, Wright J, Heilman C, Yi H, Levey AI, Blakely RD (2003) Vesicular localization and activity-dependent trafficking of presynaptic choline transporters. J Neurosci 23:9697–9709PubMedGoogle Scholar
  5. Fisher A, Mantione CR, Abraham DJ, Hanin I (1982) Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo J Pharmcol Exp Ther 222:140–145Google Scholar
  6. Hortnagl H (1994) AF64A-induced brain damage and its relation to dementia. J Neural Transm Suppl 44:245–257Google Scholar
  7. Jarrard LE, Kant GJ, Meyerhoff JL, Levy A (1984) Behavioral and neurochemical effects of intraventricular AF64A administration in rats. Pharmacol Biochem Behav 21:273–280PubMedCrossRefGoogle Scholar
  8. Kasa P, Rakonczay Z, Gulya K (1997) The cholinergic system in Alzheimer`s disease. Prog Neurobiol 52:511–535PubMedCrossRefGoogle Scholar
  9. Murai S, Saito H, Abe E, Masuda Y, Odashima J, Itoh T (1994) MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice. J Neural Transm 98:1–13CrossRefGoogle Scholar
  10. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, New YorkGoogle Scholar
  11. Perry EK, Walker M, Grace J, Perry RH (1999) Acetylcholine in mind: a neuro transmitter correlate of consciousness? Trends Neurosci 22:273–280PubMedCrossRefGoogle Scholar
  12. Sarter M, Nelson CL, Bruno JP (2005) Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophr Bull 31(1):1–22CrossRefGoogle Scholar
  13. Takashina K, Bessho T, Mori R, Eguchi J, Saito K-I (2008a) MKC-231, a choline uptake enhancer: (2) effect on synthesis and release of acetylcholine in AF64A-treated rats. J Neural Transm (in press)Google Scholar
  14. Takashina K, Bessho T, Mori R, Kawai K, Eguchi J, Saito K-I (2008b) MKC-231, a choline uptake enhancer: (3) mode of action of MKC-231 in the enhancement of high-affinity choline uptake. J Neural Transm (in press)Google Scholar
  15. Terry AV Jr, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer`s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827PubMedCrossRefGoogle Scholar
  16. Zahniser NR, Doolen S (2001) Chronic and acute regulation of Na+/Cl--dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 92:21–55PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Tomoko Bessho
    • 1
    Email author
  • Ken Takashina
    • 1
  • Junichi Eguchi
    • 1
  • Teiko Komatsu
    • 2
  • Ken-Ichi Saito
    • 3
  1. 1.Pharmacology Department IV, Pharmacology Laboratory, Research DivisionMitsubishi Tanabe Pharma CorporationYokohamaJapan
  2. 2.Development Regulatory Affairs Department, Development DivisionMitsubishi Tanabe Pharma CorporationTokyoJapan
  3. 3.Global Product Strategy DepartmentMitsubishi Tanabe Pharma CorporationTokyoJapan

Personalised recommendations