Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress

To better understand the neurotrophic function of the neurotransmitter nora drenaline, we have developed a model of mesencephalic cultures in which we find low concentrations (0.3-10 muM) of noradrenaline to be remarkably effe ctive in promoting long-term survival and function of dopaminergic neurons. This protective action reproduced the effect of caspase inhibition. It was atypical in that it occurred independently of adrenoceptor activation and was mimicked by some antioxidants, redox metal chelators and the hydroxyl r adical detoxifying enzyme catalase. Interestingly, intracellular reactive o xygen species (ROS) were drastically reduced by treatment with noradrenalin e, indicating that the neurotransmitter itself acted as an antioxidant. Pre vention of oxidative stress was, however, independent of the glutathione an tioxidant defense system. Chemical analogues of noradrenaline bearing two f ree hydroxyl groups in the ortho position of the aromatic ring (o-catechols ), as well as o-catechol itself, mimicked the survival promoting effects of the neurotransmitter, suggesting that this diphenolic structure was critic al for both neuroprotection and reduction of ROS production. Paradoxically, the autoxidation of noradrenaline and the ensuing production of quinone me tabolites may be required for both effects, as the neurotransmitter was spo ntaneously and rapidly degraded over time in the culture medium. These resu lts support the concept that central noradrenergic mechanisms have a neurop rotective role, perhaps in part by reducing oxidative stress.