The Neurotransmitter Noradrenaline Rescues Septal Cholinergic Neurons in Culture from Degeneration Caused by Low-Level Oxidative Stress

Abstract

We have developed a model system in which rat basal forebrain cholinergic neurons degenerate progressively when maintained in culture conditions that make them susceptible to low-level oxidative stress. In this study, we showed that cholinergic neurons identified by acetylcholinesterase cytochemistry or choline acetyl transferase immunocytochemistry are rescued efficiently by the neurotransmitter noradrenaline (NA). The effect of NA required neither adrenoceptor activation nor intracellular accumulation. NA operated via a mechanism that precluded activation of a cell death pathway in which reactive oxygen species (ROS) and proapoptotic caspases were crucially involved. It is noteworthy that NA remained protective even when applied late in the degenerative process but before intracellular ROS began to increase. The high efficacy of iron chelators and catalase in preventing the death of cholinergic neurons in this model suggested that NA neutralized the effects of hydroxyl radicals produced through a Fenton-type reaction. Pyrocatechol [the diphenolic moiety of NA] was sufficient in itself to prevent ROS production and cholinergic cell demise, indicating that the catechol structure was instrumental for the neuroprotective function of NA. Therefore, the noncatecholic neurotransmitter GABA failed to prevent neurodegeneration. Nerve growth factor and brain derived neurotrophic factor, two trophic peptides for septal cholinergic neurons, did not afford protection by themselves and did not improve neuroprotection provided by NA. However, in the presence of NA, they both retained their efficacy to stimulate cholinergic parameters. These data indicate that NA-based therapeutic strategies may be of interest in such neurodegenerative conditions as Alzheimer's disease, where progressive cholinergic deficits occur.

The Phenotypic Differentiation of Locus Ceruleus Noradrenergic Neurons Mediated by Brain-Derived Neurotrophic Factor Is Enhanced by Corticotropin Releasing Factor through the Activation of a cAMP-Dependent Signaling Pathway

“…Consistent with previous studies, we found that BDNF had the capacity of increasing the number of TH ϩ neurons in LC cultures (Holm et al, 2003;Traver et al, 2005). CRF, which was inactive by itself, greatly improved the trophic effect of BDNF.…”

“…Intraneuronal accumulation of NA via active transport was monitored in LC cultures using a protocol adapted from Traver et al (2005). In brief, after preincubation for 10 min in 500 l of D-PBS containing 5 mM glucose and 100 M ascorbic acid, the uptake was initiated by addition of 50 nM [ 3 H]NA (37 Ci/mmol) to the cultures and terminated after 15 min by removal of the incubation medium followed by two rapid washes with ice-cold D-PBS.…”

Reduced Tissue Levels of Noradrenaline Are Associated with Behavioral Phenotypes of the TgCRND8 Mouse Model of Alzheimer's Disease

“…The loss of NA and its trophic effects on forebrain cholinergic activity can cause cognitive as well as depressive symptoms in AD (reviewed in Marien et al, 2004;Herrmann et al, 2004). In mice, dexefaroxan improves cognition and can prevent cholinergic atrophy (Debeir et al, 2002;Traver et al, 2005) following basal forebrain cholinergic damage. Dexefaroxan may alleviate behavioral despair, by enhancing both noradrenergic and cholinergic transmission.…”

The Alpha2-Adrenoceptor Antagonist Dexefaroxan Enhances Hippocampal Neurogenesis by Increasing the Survival and Differentiation of New Granule Cells

“…The individual contributions and possible interactions of all these receptors on neurogenesis remain subject to further investigation. A receptor-independent effect of noradrenaline that can act as an antioxidant might also promote neuronal survival (Traver et al, 2005;Troadec et al, 2001).…”