MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats.
The effect of MKC-231 on acetylcholine (ACh) synthesis and release was studied in the hippocampus of normal and AF64A-treated rats. AF64A (3 nmol/brain, i.c.v.) produced significant reduction of high-affinity choline uptake (HACU) and high K+-induced ACh release in hippocampal synaptosomes. Treatments with MKC-231 (10(-8) and 10(-7) M) showed significant reverse of the decrease in both HACU and ACh release. In hippocampal slices superfused with choline-containing artificial cerebro-spinal fluid (ACSF), high K+-induced ACh release was gradually decreased by repeated alteration of resting and high K+ stimulations in AF64A-treated rats. However, addition of MKC-231 (10(-8) to 10(-7) M) in the superfusate reduces this decrease. In vivo microdialysis studies indicate MKC-231 (10 mg/kg, p.o.) significantly reversed reduction of basal ACh concentrations in AF64A-treated rats, measured by radioimmunoassay without a cholinesterase inhibitor in the perfusate. These results indicate MKC-231 improves AF64A-induced cholinergic hypofunction by enhancing HACU, subsequently facilitating ACh synthesis and release in vitro and in vivo.
Takashina
Ken
K
Pharmacology Department IV, Pharmacology Laboratory, Research Division 1000, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. takashina.ken@mh.mt-pharma.co.jp
Bessho
Tomoko
T
Mori
Reiko
R
Eguchi
Junichi
J
Saito
Ken-Ichi
K
D000109:Acetylcholine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000648:ultrastructure; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*; D013619:Tacrine / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
D001388:Aziridines; D002800:Cholinesterase Inhibitors; D009466:Neuromuscular Blocking Agents; D011804:Quinolines; D014316:Tritium; D013619:Tacrine; C044894:ethylcholine aziridinium; D002794:Choline; D000109:Acetylcholine; D011188:Potassium; C092988:MKC 231