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

Abstract

To better understand the neurotrophic function of the neurotransmitter noradrenaline, we have developed a model of mesencephalic cultures in which we ®nd low concentrations (0.3±10 mM) of noradrenaline to be remarkably effective 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 radical detoxifying enzyme catalase. Interestingly, intracellular reactive oxygen species (ROS) were drastically reduced by treatment with noradrenaline, indicating that the neurotransmitter itself acted as an antioxidant. Prevention of oxidative stress was, however, independent of the glutathione antioxidant defense system. Chemical analogues of noradrenaline bearing two free 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 critical for both neuroprotection and reduction of ROS production. Paradoxically, the autoxidation of noradrenaline and the ensuing production of quinone metabolites may be required for both effects, as the neurotransmitter was spontaneously and rapidly degraded over time in the culture medium. These results support the concept that central noradrenergic mechanisms have a neuroprotective role, perhaps in part by reducing oxidative stress.

Neutrophil Gelatinase-Associated Lipocalin Expresses Antimicrobial Activity by Interfering withl-Norepinephrine-Mediated Bacterial Iron Acquisition

“…In a first growth experiment, iron-limited cultures with 10 3 CFU/ml starting inocula were supplemented with 50 M NE, holotransferrin (holoTf), apotransferrin (apoTf), NGAL, and FeCl 3 in different combinations. An NE concentration of 50 M previously was identified to be optimal for the growth of E. coli under similar in vitro conditions (9) and furthermore corresponds to the physiological situation, for example, during traumatic injury in vivo (24,55,56). The concentration of 50 M for Tf was chosen according to its abundance in vivo (48).…”

“…In E. coli, the utilization of NE as a direct iron source seems to be strain specific, since defective Ent biosynthesis did not result in NE-dependent growth stimulation in the mutant strains AN193 entA Ϫ (9) and NCTC12900 (O157:H7) entA 55 Fe isotope in strain E2348/69 (O127:H6), thus proving the potential for cellular uptake of iron-complexed NE (23). Notably, when an S. enterica iroN fepA double mutant was compared to an iroN fepA cir triple mutant, the latter was not growth supported by NE in vivo (60), indicating that the ability of direct Fe III ⅐ (NE) 3 utilization varies with the individual uptake systems present in E. coli and its relatives.…”

In vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects of Δ3,2-hydroxybakuchiol isolated from Psoralea corylifolia (L.)

“…3A). NE is able to activate neurotrophins such as nerve growth factor and brain derived neurotrophic factor [31], and NE itself has antioxidant properties and trophic effects on dopaminergic neurons [32,33]. Damage to the norepinephrinergic system markedly deteriorated motor activity deficits in MPTP-treated mice [34], NET blockade by nisoxetine confers protection against dopaminergic lesion [35], and NET-knockout produces antiparkinsonism-like effects [35] in this PD model.…”

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

“…The effects of Mn on NE biology may potentially result from perturbations in the locus coeruleus, the main noradrenergic region of the brain (Troadec et al 2001), and the neuromodulatory effect the region exerts on the nigrostriatal dopaminergic pathway (Meyer and Quenzer 2005). Studies using α2-adrenergic receptor antagonist treatment in rodents showed that attenuating NE neurotransmission significantly depleted DA release in the striatum, mimicking the neurochemistry observed due to PD (Lategan et al 1990).…”