DESTRUCTION OF SYMPATHETIC-NERVE TERMINALS BY 6-HYDROXYDOPAMINE - PROTECTION BY 1-PHENYL-3-(2-THIAZOLYL)-2-THIOUREA, DIETHYLDITHIOCARBAMATE, METHIMAZOLE, CYSTEAMINE, ETHANOL AND NORMAL-BUTANOL

Abstract

1-Phenyl-3-(2-thiazolyl)-2-thiourea (PTTU) administered i.p. to mice prevented the neurodegenerative actions of subsequently injected (1 h later) 6-hydroxydopamine (6-OHDA) or 6-aminodopamine on peripheral adrenergic nerve terminals. Destruction of nerve terminals was studied in vitro in the left atrium by measuring the accumulation of 3H-norepinephrine (3H-NE), and in the iris by 3H-NE accumulation and fluorescence microscopy methods. Strong protection was observed at 4, 24 and 72 h after 6-OHDA. The degree of protection was dose-dependent and showed step-wise decrements for concentrations of PTTU below 200 mg/kg (i.e., 100, 50 and 20 mg/kg) or concentrations of 6-OHDA .cntdot. HBr above 7.5 mg/kg (i.e., 10, 20 and 50 mg/kg). Protection also fell off at time intervals > 1 h after administration of PTTU (i.e., 3 and 5 h). The appearance (fluorescence microscopy) of the nerve plexus of fully protected mice and the remaining plexus in partially protected mice was essentially normal at 24 h, except for infrequent large swellings. PTTU was a very effective scavenger of hydroxyl radicals; the formation and scavenging of these radicals was studied by gas chromatography in a system in which the hydroxyl radicals (which were generated during the autoxidation of 6-aminodopamine) gave rise to ethylene, a hydrocarbon gas. Other hydroxyl radical scavengers, i.e., diethyldithiocarbamate and methimazole, exhibited a protective action on sympathetic nerves in the left atrium; PTTU, diethyldithiocarbamate and methimazole are also recognized as Cu chelating compounds. Ethanol, n-butanol and cysteamine, well known hydroxyl radical scavengers, also exhibited some degree of protection against 6-OHDA. Blockade of transport of 6-OHDA into sympathetic nerves was ruled out as a protective mechanism by the observation that none of the protective compounds inhibited the accumulation of tritium by the left atrium when 3H-NE was injected in place of 6-OHDA. The mechanism of action for these protective agents was not definitively established, but scavenging of cytotoxic hydroxyl radicals within neurons may play a significant role.