Selective cholinergic neurotoxin: AF64A's effects in rat striatum.
The selective neurotoxic effects of the aziridinium ion of ethylcholine (AF64A) have been examined after stereotaxic injection into the rat striatum. In a dose-response study (2-26 nmol), 8 nmol caused a 46% decrease in striatal choline acetyltransferase (CAT) activity with minimal effects on the activities of glutamate decarboxylase (GAD) and tyrosine hydroxylase (TH) at 7 days. Maximal CAT reductions of 78-82% occurred with doses of 16-26 nmol which also caused dose-related decreases in GAD and TH activities that paralleled the progressive decrements in CAT. A time course study with 8 nmol indicated a rapid 20% reduction of CAT activity by 12 h and an additional gradual fall of 20% over the next week; TH and GAD activities were not significantly reduced. The selective inhibition of CAT activity persisted for at least 3 months. Histological examination of Nissl stained sections revealed an area of nonspecific damage at the injection site with an abrupt border surrounded by apparently normal striatal neuropil; however; neuronal perikarya staining intensely for acetylcholinesterase were not reduced. These preliminary findings strongly suggest that AF64A has selective neurotoxic effects against striatal cholinergic neurons while relatively sparing striatal GABAergic intrinsic neurons or dopaminergic afferents.
D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors; D002799:Cholinergic Fibers / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D004298:Dopamine / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D009435:Synaptic Transmission / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D001388:Aziridines; D001389:Azirines; D005680:gamma-Aminobutyric Acid; C044894:ethylcholine aziridinium; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D002794:Choline; D004298:Dopamine