Abstract
BackgroundSelective serotonin reuptake inhibitors (SSRIs) have been widely used and are a major therapeutic advance in psychopharmacology. However, their pharmacology is quite heterogeneous. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC 12 cells. However, the precise cellular and molecular mechanisms underlying potentiation by fluvoxamine are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists.Methods and FindingsThe effects of three SSRIs (fluvoxamine, sertraline, paroxetine) and three sigma-1 receptor agonists (SA4503, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), and dehydroepiandrosterone (DHEA)-sulfate) on NGF-induced neurite outgrowth in PC12 cells were examined. Also examined were the effects of the sigma-1 receptor antagonist NE-100, inositol 1,4,5-triphosphate (IP3) receptor antagonist, and specific inhibitors of signaling pathways in the potentiation of NGF-induced neurite outgrowth by selective sigma-1 receptor agonist SA4503. Fluvoxamine (but not sertraline or paroxetine) and the sigma-1 receptor agonists SA4503, PPBP, and DHEA-sulfate significantly potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. The potentiation by fluvoxamine and the three sigma-1 receptor agonists was blocked by co-administration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptors play a role in blocking the enhancement of NGF-induced neurite outgrowth. Moreover, the potentiation by SA4503 was blocked by co-administration of the IP3 receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-γ), phosphatidylinositol 3-kinase (PI3K), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways blocked the potentiation of NGF-induced neurite outgrowth by SA4503.ConclusionThese findings suggest that stimulation of sigma-1 receptors and subsequent interaction with IP3 receptors, PLC-γ, PI3K, p38MAPK, JNK, and the Ras/Raf/MAPK signaling pathways are involved in the mechanisms of action of sigma-1 receptor agonists such as fluvoxamine and SA4503.
Highlights
Selective serotonin (5-HT; 5-hydroxytryptamine) reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology
These findings suggest that stimulation of sigma-1 receptors and subsequent interaction with IP3 receptors, PLC-c, phosphatidylinositol 3-kinase (PI3K), p38MAPK, Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways are involved in the mechanisms of action of sigma-1 receptor agonists such as fluvoxamine and SA4503
It has been demonstrated that sigma-1 receptor agonists including fluvoxamine could potentiate nerve growth factor (NGF)induced neurite outgrowth in PC12 cells, and that NE-100 blocked the potentiation by sigma-1 receptor agonists, suggesting sigma-1 receptors are involved in neuroplasticity [21]
Summary
Selective serotonin (5-HT; 5-hydroxytryptamine) reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology. It has been demonstrated that sigma-1 receptor agonists including fluvoxamine could potentiate nerve growth factor (NGF)induced neurite outgrowth in PC12 cells, and that NE-100 blocked the potentiation by sigma-1 receptor agonists, suggesting sigma-1 receptors are involved in neuroplasticity [21]. Selective serotonin reuptake inhibitors (SSRIs) have been widely used and are a major therapeutic advance in psychopharmacology. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC 12 cells. We examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists
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