STUDIES ON MECHANISMS OF 6-HYDROXYDOPAMINE CYTOTOXICITY

  • 1 January 1976
    • journal article
    • research article
    • Vol. 54  (6) , 406-420
Abstract
The uptake-accumulation and binding of radioactivity in mouse heart after administration of the catecholamine neurotoxin [3H]6-hydroxydopamine (6-OH-DA, 1 or 3 mg/kg, i.v.) was investigated. A substantial portion (8-20%) of the radioactivity taken up and retained by the heart could not be extracted with perchloric acid, in all probability representing covalently bound oxidation products of 6-OH-DA to tissue proteins. Pharmacological analysis showed that a large part of this fraction was associated with the adrenergic nerves. The time-course of the perchloric acid resistant binding to the adrenergic nerves was parallel to that of the neurotoxic action of 6-OH-DA as evaluated by monitoring the change in [3H]noradrenaline uptake. Calculation of the intraneuronal 6-OH-DA concentration (average) needed to induce degeneration showed it to be in the order of 50 mM. The binding ratio for tritium deriving from [3H]6-OH-DA between the intraneuronal and extraneuronal compartments was 10,000-30,000, pointing to a very high neuronal specificity for 6-OH-DA. The covalent binding of oxidation products of [3H]6-OH-DA was considerably reduced after desipramine or 1-phenyl-3(2-thiazolyl)-2-thiourea administration, treatments both known to protect the adrenergic nerves from undergoing degeneration. Conversely the binding increased during conditions known to potentiate the neurotoxic action of 6-OH-DA; e.g., after monoamine oxidase inhibition with nialamide. Subcellular fractionation studies indicated that the predominant site of interaction between 6-OH-DA oxidation products and neuronal proteins is the cytoplasm and the axonal membrane. Analysis of the effect of in vivo administration of 6-OH-DA on the field-stimulated induced release of [3H]noradrenaline previously taken up in the adrenergic nerves showed a 6-OH-DA induced reduction in [3H]noradrenaline release which was approximately proportional to the reduction in the number of nerve terminals. These findings further support the view that 6-OH-DA acts largely in an all-or-none fashion with respect to the neurodegenerative action. Administration of [3H]dopamine also resulted in a fraction which was not extractable with perchloric acid, although this fraction was very small compared to that found after an equal dose of [3H]6-OH-DA. These data may indicate that oxidation products of dopamine can interact with tissue proteins. There is a close relationship between covalent binding of 6-OH-DA oxidation products to neuronal elements and the cytotoxic action of 6-OH-DA, indicating that this binding may play an important role in the neurodegenerative action of 6-OH-DA on catecholamine neurons.

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