Inhibition of high affinity choline uptake in the rat brain by neurotoxins: effect of monosialoganglioside GM1.
Mustard derivatives of ethyl-choline and hemicholinium-3 have been suggested as possible specific cholinergic neurotoxins. In this study a structural analog of hemicholinium-3, a,a'-bis[di(2-chloroethyl)amino]-4,4'-2-biacetophenone (toxin 7), was added to synaptosomes prepared from the cortex, striatum or hippocampus of rat brain. Synaptosomal high affinity choline uptake (HACU) was significantly decreased in a dose-dependent manner by addition of toxin 7, while synaptosomal uptake of GABA or dopamine was not changed. Incubation of cortical synaptosomes with the monosialoganglioside GM1 prevented the decrease in HACU seen following administration of toxin 7. This preventative effect of GM1 was greater if GM1 was added prior to or concomitant with toxin 7, than if GM1 was added following toxin 7. Two newly synthesized hemicholinium-3 analogs, 4-[3'-di(2-chloroethyl)aminopropionyl]biphenyl (toxin 5) and 4-[3'-di(2-bromoethyl)aminopropionyl]biphenyl (toxin 6) caused a large decrease in HACU when added to cortical synaptosomes, this decrease was significantly greater than that seen with the same dose of toxin 7 or ethyl-choline aziridinium (AF64A). Ultrastructural changes in the synaptosomal membrane following incubation with toxin 7 or toxin 7 with GM1 were examined by electron microscopy. Development of a compound which is both a potent neurotoxin, and is specific for cholinergic neurons will allow new insights into the normal function of the cholinergic system in the CNS and provide animal models of disease states in which cholinergic degeneration is an important element.
Maysinger
D
D
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Leavitt
B R
BR
Zorc
B
B
Butula
I
I
Fernandes
L G
LG
Ribeiro-da-Silva
A
A
D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001692:Biological Transport; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008854:Microscopy, Electron; D015394:Molecular Structure; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001388:Aziridines; D001713:Biphenyl Compounds; D009466:Neuromuscular Blocking Agents; D009498:Neurotoxins; D009588:Nitrogen Mustard Compounds; D014316:Tritium; C081493:alpha, alpha'-bis(di(2-chloroethyl)amino)-4,4'-(2-biacetophenone); C081495:4-(3'-di(2-chloroethyl)aminopropionyl)biphenyl; C081494:4-(3'-di(2-bromoethyl)aminopropionyl)biphenyl; D005677:G(M1) Ganglioside; D005680:gamma-Aminobutyric Acid; C044894:ethylcholine aziridinium; D002794:Choline; D004298:Dopamine