Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons - dissociation from cholesterol homeostasis
Résumé
In search for antidepressants' mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different antidepressants on autophagic processes in rat primary astrocytes and neurons. Autophagy plays a significant role in controlling protein turn-over and energy supply. Both, the tricyclic antidepressant amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced up-regulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II positive structures indicative of autophagosomes which associated with acidic vacuoles in a time-dependent fashion. Deletion of Atg5 representing a central mediator of autophagy in mouse embryonic fibroblasts led to abrogation of AMI-induced LC3B-I/II conversion. In contrast, venlafaxin, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class III PI3 kinase-dependent pathways since 3-methyladenine slightly diminished AMI effects. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI and CIT mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct antidepressant promote autophagy in neural cells, with important implications on energy homeostasis.
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