Desipramine Protects Neuronal Cell Death and Induces Heme Oxygenase-1 Expression in Mes23.5 Dopaminergic Neurons

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.

Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism

“…It has been identified as a potential therapeutic target in CNS inflammatory and neurodegenerative diseases. Our previous study also revealed that CoPP protected neuronal cells against rotenone-and 6-hydroxydopamine-induced neuronal death [20]. CoPPinduced HO-1 may offer a protective role in cold injuryinduced cerebral cortex damage and neurological/behavioral impairment [64].…”

“…In addition, induction of HO-1 expression also contributes to the anti-inflammatory effects in murine macrophages through suppressing iNOS and COX-2 expression [18]. We have published several studies that induction of HO-1 expression is a potential therapeutic strategy for microglial-related neuroinflammatory responses [19] and neuroprotective effects [20][21]. The significant facts indicated that the importance of HO-1 in regulation inflammatory response HO-1 reduces microglia activation by inhibiting ROS production and via PI3K/Akt signaling pathways [22].…”

20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway

“…NQO1 is a cytoplasmic two electron reductase that catalyzes the reduction of a wide range of substrates, including quinones, quinone-imines, and nitro-compounds [31] . Thus, the up-regulation of HO-1 and NQO1 in response to oxidative stresses provides an effective endogenous antioxidant defense mechanism in rotenone-induced PC12 cells [32,33] . To determine whether the Nrf2/ARE/HO-1 signaling pathway is involved in the neuroprotective effect of 20C, we investigated the changes in the Nrf2/ARE/HO-1 signaling pathway in the 20C-treated cells.…”

Drug target identification at the crossroad of neuronal apoptosis and survival

“…Accumulating evidence indicates a dual role of Ccl2 in neuronal survival [86,87]. While drugs like bindarit downregulate Ccl2 and protect neurons [88], noradrenaline transporter inhibitors like desipramine elicit neuroprotection by upregulating the expression of Ccl2 [89,90].…”