Skip to main content
SpringerLink
Log in

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

  • Alzheimer's Disease and Related Disorders - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529

    Article  PubMed  CAS  Google Scholar 

  • 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 46:369–373

    PubMed  CAS  Google Scholar 

  • Ferguson SM, Blakely RD (2004) The choline transporter resurfaces: new roles for synaptic vesicles. Mol Interv 4:22–37

    Article  PubMed  CAS  Google Scholar 

  • 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 23:9697–9709

    PubMed  CAS  Google Scholar 

  • 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 222:140–145

    CAS  Google Scholar 

  • Hortnagl H (1994) AF64A-induced brain damage and its relation to dementia. J Neural Transm Suppl 44:245–257

    Google Scholar 

  • Jarrard LE, Kant GJ, Meyerhoff JL, Levy A (1984) Behavioral and neurochemical effects of intraventricular AF64A administration in rats. Pharmacol Biochem Behav 21:273–280

    Article  PubMed  CAS  Google Scholar 

  • Kasa P, Rakonczay Z, Gulya K (1997) The cholinergic system in Alzheimer`s disease. Prog Neurobiol 52:511–535

    Article  PubMed  CAS  Google Scholar 

  • 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 98:1–13

    Article  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, New York

    Google Scholar 

  • Perry EK, Walker M, Grace J, Perry RH (1999) Acetylcholine in mind: a neuro transmitter correlate of consciousness? Trends Neurosci 22:273–280

    Article  PubMed  CAS  Google Scholar 

  • Sarter M, Nelson CL, Bruno JP (2005) Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophr Bull 31(1):1–22

    Article  Google Scholar 

  • 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)

  • 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)

  • 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 306:821–827

    Article  PubMed  CAS  Google Scholar 

  • Zahniser NR, Doolen S (2001) Chronic and acute regulation of Na+/Cl--dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 92:21–55

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmacology Department IV, Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, 227-0033, Japan

    Tomoko Bessho, Ken Takashina & Junichi Eguchi

  2. Development Regulatory Affairs Department, Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan

    Teiko Komatsu

  3. Global Product Strategy Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan

    Ken-Ichi Saito

Authors
  1. Tomoko Bessho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ken Takashina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junichi Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Teiko Komatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken-Ichi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomoko Bessho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bessho, T., Takashina, K., Eguchi, J. et al. MKC-231, a choline-uptake enhancer: (1) long-lasting cognitive improvement after repeated administration in AF64A-treated rats. J Neural Transm 115, 1019–1025 (2008). https://doi.org/10.1007/s00702-008-0053-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-008-0053-4

Keywords

Search

Navigation