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

Institut National de la Santé et de la Recherche Médicale Unité 679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, (S.T., B.S.L., E.C.H., P.P.M.); and Centre de Recherche Pierre Fabre, Castres, France (M.M., F.C., P.P.M.)

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.

Address correspondence to: Patrick P. Michel, INSERM U679, Btiment Pharmacie, Hôpital de la Salpêtrière, 47 bd de l'Hôpital, 75013, Paris, France. E-mail: ppmichel{at}ccr.jussieu.fr

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				S. Traver, M. Marien, E. Martin, E. C. Hirsch, and P. P. Michel 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 Mol. Pharmacol., July 1, 2006; 70(1): 30 - 40. [Abstract] [Full Text] [PDF]