Abstract
BackgroundDesipramine is known principally as a tricyclic antidepressant drug used to promote recovery of depressed patients. It has also been used in a number of other psychiatric and medical conditions. The present study is the first to investigate the neuroprotective effect of desipramine.Methodology/Principal FindingsMes23.5 dopaminergic cells were used to examine neuroprotective effect of desipramine. Western blot, reverse transcription-PCR, MTT assay, siRNA transfection and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of desipramine. Desipramine induces endogenous anti-oxidative enzyme, heme oxygenase-1 (HO-1) protein and mRNA expression in concentration- and time-dependent manners. A different type of antidepressant SSRI (selective serotonin reuptake inhibitor), fluoxetine also shows similar effects of desipramine on HO-1 expression. Moreover, desipramine induces HO-1 expression through activation of ERK and JNK signaling pathways. Desipramine also increases NF-E2-related factor-2 (Nrf2) accumulation in the nucleus and enhances Nrf2-DNA binding activity. Moreover, desipramine-mediated increase of HO-1 expression is reduced by transfection with siRNA against Nrf2. On the other hand, pretreatment of desipramine protects neuronal cells against rotenone- and 6-hydroxydopamine (6-OHDA)-induced neuronal death. Furthermore, inhibition of HO-1 activity by a HO-1 pharmacological inhibitor, ZnPP IX, attenuates the neuroprotective effect of desipramine. Otherwise, activation of HO-1 activity by HO-1 activator and inducer protect 6-OHDA-induced neuronal death.Conclusions/SignificanceThese findings suggest that desipramine-increased HO-1 expression is mediated by Nrf2 activation through the ERK and JNK signaling pathways. Our results also suggest that desipramine provides a novel effect of neuroprotection, and neurodegenerative process might play an important role in depression disorder.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons of the substantia nigra (SN), giving rise to dopamine depletion in the striatum [1]
We identified the effect of desipramine on the regulation of heme oxygenase1 (HO-1) in Mes23.5 dopaminergic neurons
Clinical studies have suggested that depression and PD are closely related [46,47,48], and depression is a negative impact on the quality of life of PD patients and their families
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons of the substantia nigra (SN), giving rise to dopamine depletion in the striatum [1]. PD is well characterized by motor symptoms, clinical depression is the most common neuropsychiatric disorder in PD patients [2,3,4]. Depression has been classified as a disorder of the brain and CNS, and is manifested by a combination of symptoms that interferes with the ability to work, study, sleep, eat, and enjoy once pleasurable activities [9,10,11,12]. Desipramine is known principally as a tricyclic antidepressant drug used to promote recovery of depressed patients. It has been used in a number of other psychiatric and medical conditions. The present study is the first to investigate the neuroprotective effect of desipramine
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