Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways
Tomoko Nishimura, Tamaki Ishima, Masaomi Iyo, Kenji Hashimoto, Tomoko Nishimura, Tamaki Ishima, Masaomi Iyo, Kenji Hashimoto
Abstract
Background: Selective 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 findings: The 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 (IP(3)) 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 IP(3) receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-gamma), 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.
Conclusion: These findings suggest that stimulation of sigma-1 receptors and subsequent interaction with IP(3) receptors, PLC-gamma, 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.
Conflict of interest statement
Competing Interests: Dr. Kenji Hashimoto reports receiving the speaker fees from Solvay, Meiji Seika, Asteras, Eli Lilly, Janssen, Pfizer, and Otsuka. Dr. Masaomi Iyo reports receiving the speaker fees from Janssen, Meiji Seika., Dainippon-Sumitomo, GlaxoSmithKline, Novartis, Eli Lilly, Pfizer, and Otsuka. Ms. Tomoko Nishimura and Ms. Tamaki Ishima report no competing interests.
Figures
![Figure 1. Effects of NGF on neurite…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g001.jpg)
![Figure 2. Effects of three SSRIs (fluvoxamine,…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g002.jpg)
![Figure 3. Effects of three sigma-1 receptor…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g003.jpg)
![Figure 4. Representative photographs of MAP-2 immunocytochemistry…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g004.jpg)
![Figure 5. Effects of the IP3 receptor…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g005.jpg)
Figure 6. Effects of the specific inhibitors…
Figure 6. Effects of the specific inhibitors of PLC-γ, PI3K, p38MAPK, and JNK on potentiation…
Figure 7. Effects of the specific inhibitors…
Figure 7. Effects of the specific inhibitors of Ras, Raf, MEK1/2, and MAPK on potentiation…
Figure 8. Proposed mechanism for potentiation of…
Figure 8. Proposed mechanism for potentiation of NGF-induced neurite outgrowth by sigma-1 receptor agonists.
NGF…
- Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: a possible role of IP₃ receptors.Minase T, Ishima T, Itoh K, Hashimoto K. Minase T, et al. Eur J Pharmacol. 2010 Dec 1;648(1-3):67-73. doi: 10.1016/j.ejphar.2010.09.007. Epub 2010 Sep 18. Eur J Pharmacol. 2010. PMID: 20854802
- Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells.Ishima T, Fujita Y, Hashimoto K. Ishima T, et al. Eur J Pharmacol. 2014 Mar 15;727:167-73. doi: 10.1016/j.ejphar.2014.01.064. Epub 2014 Feb 5. Eur J Pharmacol. 2014. PMID: 24508523
- Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 cells via a mechanism involving the sigma-1 receptor.Matsushima Y, Terada K, Kamei C, Sugimoto Y. Matsushima Y, et al. Eur J Pharmacol. 2019 Jun 15;853:129-135. doi: 10.1016/j.ejphar.2019.03.032. Epub 2019 Mar 19. Eur J Pharmacol. 2019. PMID: 30902656
- Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship.Hashimoto K. Hashimoto K. Cent Nerv Syst Agents Med Chem. 2009 Sep;9(3):197-204. doi: 10.2174/1871524910909030197. Cent Nerv Syst Agents Med Chem. 2009. PMID: 20021354 Review.
- Sigma-1 Receptor Agonists and Their Clinical Implications in Neuropsychiatric Disorders.Albayrak Y, Hashimoto K. Albayrak Y, et al. Adv Exp Med Biol. 2017;964:153-161. doi: 10.1007/978-3-319-50174-1_11. Adv Exp Med Biol. 2017. PMID: 28315270 Review.
- Overview of the potential use of fluvoxamine for COVID-19 and long COVID.Hashimoto K. Hashimoto K. Discov Ment Health. 2023;3(1):9. doi: 10.1007/s44192-023-00036-3. Epub 2023 Mar 21. Discov Ment Health. 2023. PMID: 36968793 Free PMC article. Review.
-
- Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry. 2004;65(suppl 4):5–10. - PubMed
-
- Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders–I. Basic pharmacology. J Psychopharmacol. 1998;12(3 Suppl B):S5–20. - PubMed
-
- Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders–II. Efficacy and quality of life. J Psychopharmacol. 1998;12(3 Suppl B):S21–54. - PubMed
-
- Stahl SM. Not so selective serotonin selective reuptake inhibitors. J Clin Psychiatry. 1998;59:343–344. - PubMed
-
- Stahl SM. Using secondary binding properties to select a not so selective serotonin selective reuptake inhibitor. J Clin Psychiatry. 1998;59:642–643. - PubMed
- Research Support, Non-U.S. Gov't
- Animals
- Cells, Cultured
- Fluvoxamine / pharmacology*
- Immunohistochemistry
- Inositol 1,4,5-Trisphosphate Receptors / metabolism*
- MAP Kinase Signaling System
- Nerve Growth Factor / pharmacology*
- Neurites / physiology*
- Piperazines / pharmacology
- Rats
- Receptor, trkA / metabolism
- Receptors, sigma / agonists
- Receptors, sigma / metabolism*
- Selective Serotonin Reuptake Inhibitors / pharmacology*
- Signal Transduction*
- Inositol 1,4,5-Trisphosphate Receptors
- Piperazines
- Receptors, sigma
- Serotonin Uptake Inhibitors
- sigma-1 receptor
- Nerve Growth Factor
- SA 4503
- Receptor, trkA
- Fluvoxamine
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 6. Effects of the specific inhibitors…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g006.jpg)
Figure 7. Effects of the specific inhibitors…
Figure 7. Effects of the specific inhibitors of Ras, Raf, MEK1/2, and MAPK on potentiation…
Figure 8. Proposed mechanism for potentiation of…
Figure 8. Proposed mechanism for potentiation of NGF-induced neurite outgrowth by sigma-1 receptor agonists.
NGF…
- Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: a possible role of IP₃ receptors.Minase T, Ishima T, Itoh K, Hashimoto K. Minase T, et al. Eur J Pharmacol. 2010 Dec 1;648(1-3):67-73. doi: 10.1016/j.ejphar.2010.09.007. Epub 2010 Sep 18. Eur J Pharmacol. 2010. PMID: 20854802
- Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells.Ishima T, Fujita Y, Hashimoto K. Ishima T, et al. Eur J Pharmacol. 2014 Mar 15;727:167-73. doi: 10.1016/j.ejphar.2014.01.064. Epub 2014 Feb 5. Eur J Pharmacol. 2014. PMID: 24508523
- Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 cells via a mechanism involving the sigma-1 receptor.Matsushima Y, Terada K, Kamei C, Sugimoto Y. Matsushima Y, et al. Eur J Pharmacol. 2019 Jun 15;853:129-135. doi: 10.1016/j.ejphar.2019.03.032. Epub 2019 Mar 19. Eur J Pharmacol. 2019. PMID: 30902656
- Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship.Hashimoto K. Hashimoto K. Cent Nerv Syst Agents Med Chem. 2009 Sep;9(3):197-204. doi: 10.2174/1871524910909030197. Cent Nerv Syst Agents Med Chem. 2009. PMID: 20021354 Review.
- Sigma-1 Receptor Agonists and Their Clinical Implications in Neuropsychiatric Disorders.Albayrak Y, Hashimoto K. Albayrak Y, et al. Adv Exp Med Biol. 2017;964:153-161. doi: 10.1007/978-3-319-50174-1_11. Adv Exp Med Biol. 2017. PMID: 28315270 Review.
- Overview of the potential use of fluvoxamine for COVID-19 and long COVID.Hashimoto K. Hashimoto K. Discov Ment Health. 2023;3(1):9. doi: 10.1007/s44192-023-00036-3. Epub 2023 Mar 21. Discov Ment Health. 2023. PMID: 36968793 Free PMC article. Review.
-
- Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry. 2004;65(suppl 4):5–10. - PubMed
-
- Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders–I. Basic pharmacology. J Psychopharmacol. 1998;12(3 Suppl B):S5–20. - PubMed
-
- Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders–II. Efficacy and quality of life. J Psychopharmacol. 1998;12(3 Suppl B):S21–54. - PubMed
-
- Stahl SM. Not so selective serotonin selective reuptake inhibitors. J Clin Psychiatry. 1998;59:343–344. - PubMed
-
- Stahl SM. Using secondary binding properties to select a not so selective serotonin selective reuptake inhibitor. J Clin Psychiatry. 1998;59:642–643. - PubMed
- Research Support, Non-U.S. Gov't
- Animals
- Cells, Cultured
- Fluvoxamine / pharmacology*
- Immunohistochemistry
- Inositol 1,4,5-Trisphosphate Receptors / metabolism*
- MAP Kinase Signaling System
- Nerve Growth Factor / pharmacology*
- Neurites / physiology*
- Piperazines / pharmacology
- Rats
- Receptor, trkA / metabolism
- Receptors, sigma / agonists
- Receptors, sigma / metabolism*
- Selective Serotonin Reuptake Inhibitors / pharmacology*
- Signal Transduction*
- Inositol 1,4,5-Trisphosphate Receptors
- Piperazines
- Receptors, sigma
- Serotonin Uptake Inhibitors
- sigma-1 receptor
- Nerve Growth Factor
- SA 4503
- Receptor, trkA
- Fluvoxamine
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 7. Effects of the specific inhibitors…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g007.jpg)
Figure 8. Proposed mechanism for potentiation of…
Figure 8. Proposed mechanism for potentiation of NGF-induced neurite outgrowth by sigma-1 receptor agonists.
NGF…
![Figure 8. Proposed mechanism for potentiation of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2435603/bin/pone.0002558.g008.jpg)
References
- Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry. 2004;65(suppl 4):5–10.
- Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders–I. Basic pharmacology. J Psychopharmacol. 1998;12(3 Suppl B):S5–20.
- Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders–II. Efficacy and quality of life. J Psychopharmacol. 1998;12(3 Suppl B):S21–54.
- Stahl SM. Not so selective serotonin selective reuptake inhibitors. J Clin Psychiatry. 1998;59:343–344.
- Stahl SM. Using secondary binding properties to select a not so selective serotonin selective reuptake inhibitor. J Clin Psychiatry. 1998;59:642–643.
- Nemeroff CB, Owens MJ. : Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectr. 2004;9(6 Suppl 4):23–31.
- Carrasco JL, Sandner C. Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview. Int J Clin Pract. 2005;59:1428–1434.
- Westenberg HGM, Sandner C. Tolerability and safety of fluvoxamine and other antidepressants. Int J Clin Pract. 2006;60:482–491.
- Hashimoto K, Fujita Y, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors. Neuropsychopharmacology. 2007;32:514–521.
- Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and the sigma-1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Rev. 2001;37:116–132.
- Su TP, Hayashi T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem. 2003;10:2073–2080.
- Hayashi T, Su TP. Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs. 2004;18:269–284.
- Takebayashi M, Hayashi T, Su TP. A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors. Pharmacopsychiatry. 2004;37(Suppl 3):S208–213.
- Bermack JE, Debonnel G. The role of sigma receptors in depression. J Phamacol Sci. 2005;97:317–336.
- Hashimoto K, Ishiwata K. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Curr Pharm Des. 2006;12:3857–3876.
- Monnet FP, Maurice T. The sigma-1 protein as a target for the non-genomic effects of neuro(active)steroids: molecular, physiological, and behavioral aspects. J Pharmacol Sci. 2006;100:93–118.
- Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell. 2007;131:596–610.
- Hayashi T, Su TP. An update on the development of drugs for neuropsychiatric disorders: focusing on the sigma 1 receptor ligand. Expert Opin Ther Targets. 2008;12:45–58.
- Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996;307:117–119.
- Okuyama S, Nakazato A. NE-100: A novel sigma receptor antagonist. CNS Drug Rev. 1996;2:226–237.
- Takebayashi M, Hayashi TP, Su TP. Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants. J Pharmacol Exp Ther. 2002;303:1227–1237.
- Hashimoto K, Scheffel U, London ED. In vivo labeling of sigma receptors in mouse brain with [3H]4-phenyl-1-(4-phenylbutyl)piperidine. Synapse. 1995;20:85–90.
- Takahashi H, Kirsch JR, Hashimoto K, London ED, Koehler RC, et al. PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats. Stroke. 1995;26:1676–1682.
- Takahashi H, Kirsch JR, Hashimoto K, London ED, Koehler RC, et al. PPBP [4-phenyl-1-(4-phenylbutyl) piperidine] decreases brain injury after transient focal ischemia in rats. Stroke. 1996;27:2120–2123.
- Harukuni I, Bhardwaj A, Shaivitz AB, DeVries AC, London ED, et al. Sigma-1 receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion. Stroke. 2000;31:976–982.
- Goyagi T, Goto S, Bhardwaj A, Dawson VL, Hurn PD, et al. Neuroprotective effect of sigma-1 receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production. Stroke. 2001;32:1613–1620.
- Noda Y, Kamei H, Kamei Y, Nagai T, Nishida M, et al. Neurosteroids ameliorate conditioned fear stress: an association with sigma receptors. Neuropsychopharmacology. 2000;23:276–284.
- Maurice T, Phan VL, Urani A, Guillemain I. Differential involvement of the sigma-1 receptor in the anti-amnesic effect of neuroactive steroids, as demonstrated using an in vivo antisense strategy in the mouse. Br J Pharmacol. 2001;134:1731–1741.
- Matsuno K, Mita S. SA 4503: A novel sigma-1 receptor agonist. CNS Drug Rev. 1998;4:1–24.
- Matsuno K, Senda T, Kobayashi T, Okamoto K, Nakata K, et al. SA4503, a novel cognitive enhancer, with sigma-1 receptor agonistic properties. Behav Brain Res. 1997;83:221–224.
- Gafni J, Munsch JA, Lam TH, Catlin MC, Costa LG, et al. Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor. Neuron. 1997;19:723–733.
- Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 2001;72:609–642.
- Hayashi T, Maurice T, Su TP. Ca2+ signaling via sigma-1 receptors: novel regulatory mechanism affecting intracellular Ca2+ concentration. J Pharmacol Exp Ther. 2000;293:788–798.
- Hayashi T, Su TP. Regulating ankyrin dynamics: Roles of sigma-1 receptors. Proc Natl Acad Sci USA. 2001;98:491–496.
- Urani A, Romieu P, Portales-Casamar E, Roman FJ, Maurice T. The antidepressant-like effect induced by the sigma-1 receptor agonist igmesine involves modulation of intracellular calcium mobilization. Psychopharmacology (Berl) 2002;163:26–35.
- Chao MV. Neurotrophins and their receptors: a convergence point for many signaling pathways. Nature Rev Neurosci. 2003;4:299–309.
- Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nature Rev Cancer. 2007;7:295–308.
- Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001;24:1217–1281.
- Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature. 1989;341:197–205.
- Obermeier A, Bradshaw RA, Seedorf K, Choidas A, Schlessinger J, Ullrich A. Neuronal differentiation signals are controlled by nerve growth factor receptor/Trk binding sites for SHC and PLC-γ. EMBO J. 1994;13:1585–1590.
- Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, et al. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994;12:691–705.
- Kimura K, Hattori S, Kabuyama Y, Shizawa Y, Takayanagi J, et al. Neurite outgrowth of PC12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. J Biol Chem. 1994;269:18961–18967.
- Price RD, Yamaji T, Matsuoka N. FK506 potentiates NGF-induced neurite outgrowth via the Ras/Raf/MAP kinase pathway. Bri J Pharamcol. 2003;140:825–829.
- Price RD, Yamaji T, Yamamoto H, Higashi Y, Hanaoka K, et al. FK1706, a novel non-immunosuppressive immunophilin: neurotrophic activity and mechanism of action. Eur J Pharmacol. 2005;50-:11–19.
- Ishikawa M, Ishiwata K, Ishii K, Kimura Y, Sakata M, et al. High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503. Biol Psychiatry. 2007;62:878–883.
Source: PubMed