Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole

Abstract

Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D2 receptors and 5-hydroxytryptamine (5-HT) 5-HT1A receptors, and antagonistic activity at 5-HT2A receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT1A receptor antagonist WAY-100635, but not the dopamine D2 receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors and BAPTA-AM, a chelator of intracellular Ca2+, blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90α in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90α RNA interference, but not by the negative control of Hsp90α. These findings suggest that both 5-HT1A receptor activation and Ca2+ signaling via IP3 receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90α protein expression may form part of the therapeutic mechanism for this drug.

Hippocampal expression of heat shock proteins in mesial temporal lobe epilepsy with psychiatric comorbidities and their relation to seizure outcome

“…Our previous studies with two different patients cohorts have showed decreased mossy fiber sprouting in MTLE patients with psychosis, 6,7 which might be related to decreased synaptic markers found in schizophrenia, 36 as well as to the decreased HSP90 expression we reported here. Of note, despite the HSP90 augmentation in PC12 cell culture shown with aripiprazole, 35 we found decreased HSP90 expression in the granular layer and subiculum of MTLE+P patients taking haloperidol. Possible explanations include a diverse action of haloperidol on HSP90 levels or, in case of similar effect, different outcomes would be expected when comparing in vitro and in vivo situations due to significant increase of system complexity.…”

“…In addition to the role in prevention of microtubule disassembly, HSP90, unlike other HSPs, may initiate neurite outgrowth, . In fact, a recent study by Ishima et al . suggests that treatment with the atypical antipsychotic drug aripiprazole may potentiate nerve growth factor (NGF)‐induced neurite outgrowth through enhanced HSP90 expression, although it is unclear how HSP90 contributes to its therapeutic effect.…”

“…In addition to the role in prevention of microtubule disassembly, 33 HSP90, unlike other HSPs, may initiate neurite outgrowth,. 34 In fact, a recent study by Ishima et al 35 suggests that treatment with the atypical antipsychotic drug aripiprazole may potentiate nerve growth factor (NGF)-induced neurite outgrowth through enhanced HSP90 expression, although it is unclear how HSP90 contributes to its therapeutic effect. Our previous studies with two different patients cohorts have showed decreased mossy fiber sprouting in MTLE patients with psychosis, 6,7 which might be related to decreased synaptic markers found in schizophrenia, 36 as well as to the decreased HSP90 expression we reported here.…”

Effects of antipsychotic drugs on neurites relevant to schizophrenia treatment

“…D2R partial agonist aripiprazole is used to treat psychiatric disorders including schizophrenia, major depression, bipolar, and autism. Cell culture studies show that aripiprazole potentiates nerve growth factor‐induced neurite outgrowth in PC12 cells . Brexpiprazole has a similar pharmacological profile to aripiprazole and also significantly potentiated nerve growth factor–induced neurite outgrowth in PC12 cells in a concentration‐dependent manner .…”

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“…NGF binds to its recep-tor and activates the ERK/CREB pathway, leading to the downstream c-FOS, EGR1, c-JUN, FOSB, and JUNB expression to promote neurite outgrowth in PC12, and treatment with the ERK-specific inhibitor of U0126 inhibits NGF-induced and aripiprazole-enhanced neurite outgrowth (Harada et al 2001;Pellegrino and Stork 2006;Eriksson et al 2007;Ravni et al 2008;Chung et al 2010;Mullenbrock et al 2011;Ishima et al 2012;Kudo et al 2013). Similarly, artemisinin and its derivatives induce neurite outgrowth of PC12 cells in an ERK/CREB dependent manner (Sarina et al 2013).…”