Nerve terminal damage in cerebral ischemia: protective effect of alpha-methyl-para-tyrosine.
Mongolian gerbils were treated with alpha-methyl-para-tyrosine methyl ester (AMPT, a tyrosine hydroxylase inhibitor), in order to decrease brain levels of catecholamines. Six hours later, unilateral ischemic stroke was induced by ligation of the left common carotid artery. The delayed degeneration of nerve terminals was studied sixteen hours later by measuring the high-affinity uptake of radiolabeled transmitters by isolated synaptosomes. Dopamine, serotonin and glutamate terminals were studied. AMPT-treated gerbils were compared to untreated (no AMPT) animals; 220 gerbils were studied. AMPT pretreatment (100, 250 and 400 mg/kg) produced a dose-dependent protection of all three types of nerve terminals. In the absence of AMPT pretreatment, the uptake of radiolabeled transmitters by the ischemic hemisphere, expressed as a percentage of that seen in the contralateral (unaffected) side of the brain, was as follows (mean +/- SEM): 27.3 +/- 5.2% for dopamine terminals, 49.5 +/- 6.2% for serotonin terminals, and 42.7 +/- 5.3% for glutamate terminals. Protection was essentially complete at a dose of 400 mg AMPT per kg. The number of animals with significant damage to nerve terminals was reduced from 38.5% in untreated animals to 11.1% in animals treated with AMPT 400 mg/kg. Although the nerve terminals were protected, gerbils still showed the behavioral signs of unilateral stroke due to the permanent occlusion of the left carotid. These results indicate that endogenous dopamine may play a significant role in ischemic damage to nerve terminals in the cerebrum.
Weinberger
J
J
Nieves-Rosa
J
J
Cohen
G
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology*; D002339:Carotid Arteries / Q000601:surgery; D002395:Catecholamines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005849:Gerbillinae; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D008026:Ligation; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology*; D009411:Nerve Endings / Q000187:drug effects / Q000473:pathology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D002395:Catecholamines; D005971:Glutamates; D008781:Methyltyrosines; D018377:Neurotransmitter Agents; D012701:Serotonin; D018698:Glutamic Acid; C022260:alpha-methyltyrosine methyl ester; D004298:Dopamine