Fluvoxamine alleviates ER stress via induction of sigma-1 receptor.
Open accessAbstract
We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell's responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig-1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv-induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress.
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Up-regulation of Sig-1R suppresses apoptosis caused by ER stress.
“More interestingly the induction of Sig-1R can repress cell death signaling: up-regulation of Sig-1R suppresses the apoptosis caused by ER stress (Omi et al., 2014).”
From The therapeutic potentials of Ayahuasca: possible effects against various diseases of civilization (2016) · cites this paper as Omi et al., 2014
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Cites
Control of inositol 1,4,5-trisphosphate-induced Ca2+ release by cytosolic Ca2+
Bootman, M. D., Missiaen, L., Parys, J. B., SMEDT, H. D., & Casteels, R. (1995) · Biochemical Journal · doi:10.1042/bj3060445 · Cited by 5,120 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β
Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B. A., & Yuan, J. (2000) · Nature · doi:10.1038/47513 · Cited by 3,262 · see citing works
Reinitiation involving upstream ORFs regulates <i>ATF4</i> mRNA translation in mammalian cells
Vattem, K. M., & Wek, R. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400541101 · Cited by 1,696 · see citing works
Nishitoh, H., Matsuzawa, A., Tobiume, K., Saegusa, K., Takeda, K., Inoue, K., Hori, S., Kakizuka, A., & Ichijo, H. (2002) · Genes & Development · doi:10.1101/gad.992302 · Cited by 1,331 · see citing works
Harding, H. P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D. D., & Ron, D. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00264-7 · Cited by 1,217 · see citing works
Lu, P. D., Harding, H. P., & Ron, D. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200408003 · Cited by 1,006 · see citing works
Hara, H., Friedlander, R. M., Gagliardini, V., Ayata, C., Fink, K., Huang, Z., Shimizu‐Sasamata, M., Yuan, J., & Moskowitz, M. A. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.5.2007 · Cited by 835 · see citing works
Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death
Hitomi, J., Katayama, T., Eguchi, Y., Kudo, T., Taniguchi, M., Koyama, Y., Manabe, T., Yamagishi, S., Bandô, Y., Imaizumi, K., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200310015 · Cited by 831 · see citing works
Translational Regulation of Yeast GCN4
Hinnebusch, A. G. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.35.21661 · Cited by 526 · see citing works
Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response
Katayama, T., Imaizumi, K., Sato, N., Miyoshi, K., Kudo, T., Hitomi, J., Morihara, T., Yoneda, T., Gomi, F., Mori, Y., et al. (1999) · Nature Cell Biology · doi:10.1038/70265 · Cited by 521 · see citing works
Imai, Y., Soda, M., Hatakeyama, S., Akagi, T., Hashikawa, T., Nakayama, K. I., & Takahashi, R. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00583-x · Cited by 473 · see citing works
Hara, H., Huang, P. L., Panahian, N., Fishman, M. C., & Moskowitz, M. A. (1996) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199607000-00010 · Cited by 410 · see citing works
Regulating ankyrin dynamics: Roles of sigma-1 receptors
Hayashi, T., & Su, T. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.491 · Cited by 331 · see citing works
Martindale, J. J., Fernandez, R., Thuerauf, D. J., Whittaker, R., Gude, N. A., Sussman, M. A., & Glembotski, C. C. (2006) · Circulation Research · doi:10.1161/01.res.0000220643.65941.8d · Cited by 323 · see citing works
HAYASHI, T., Maurice, T., & Su, T. (2000) · PubMed · Cited by 296 · see citing works
Hayashi, T., & Su, T. (2004) · CNS Drugs · doi:10.2165/00023210-200418050-00001 · Cited by 295 · see citing works
The unfolded protein response: an intracellular signalling pathway with many surprising features
Sidrauski, C. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)01267-7 · Cited by 273 · see citing works
Interactions of selective serotonin reuptake inhibitors with subtypes of σ receptors in rat brain
Narita, N., Hashimoto, K., Tomitaka, S.-I., & Minabe, Y. (1996) · European Journal of Pharmacology · doi:10.1016/0014-2999(96)00254-3 · Cited by 254 · see citing works
A molecular chaperone inducer protects neurons from ER stress
Kudo, T., Kanemoto, S., Hara, H., Morimoto, N., Morihara, T., Kimura, R., Tabira, T., Imaizumi, K., & Takeda, M. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402276 · Cited by 250 · see citing works
Cerebral ischemia and the unfolded protein response
DeGracia, D. J., & Montie, H. L. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02703.x · Cited by 224 · see citing works
Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders
Hayashi, T., Tsai, S., Mori, T., Fujimoto, M., & Su, T. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.560837 · Cited by 206 · see citing works
Katayama, T., Imaizumi, K., Honda, A., Yoneda, T., Kudo, T., Takeda, M., Mori, K., Rozmahel, R. F., Fraser, P., George‐Hyslop, P. S., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104096200 · Cited by 181 · see citing works
Sigma-1 receptor knockout mice display a depressive-like phenotype
Sabino, V., Cottone, P., Parylak, S., Steardo, L., & Zorrilla, E. P. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.11.036 · Cited by 164 · see citing works
The Sigma Receptor: Evolution of the Concept in Neuropsychopharmacology
HAYASHI, T., & Su, T. (2005) · Current Neuropharmacology · doi:10.2174/157015905774322516 · Cited by 154 · see citing works
Hayashi, T., Maurice, T., & Su, T. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)39299-7 · Cited by 152 · see citing works
Selective loss of cerebral cortical Sigma, but not PCP binding sites in schizophrenia
Weissman, A. D., Casanova, M. F., Kleinman, J. E., London, E. D., & Souza, E. B. D. (1991) · Biological Psychiatry · doi:10.1016/0006-3223(91)90209-5 · Cited by 150 · see citing works
Takebayashi, M., Hayashi, T., & Su, T. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.041970 · Cited by 131 · see citing works
The Role of Brain-derived Neurotrophic Factor (BDNF)-induced XBP1 Splicing during Brain Development
Hayashi, A., Kasahara, T., Iwamoto, K., Ishiwata, M., Kametani, M., Kakiuchi, C., Furuichi, T., & Kato, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704300200 · Cited by 121 · see citing works
Ozawa, K., Tsukamoto, Y., Hori, O., Kitao, Y., Yanagi, H., Stern, D., & Ogawa, S. (2001) · PubMed · Cited by 111 · see citing works
Kimball, S. R., Fabian, J. R., Pavitt, G. D., Hinnebusch, A. G., & Jefferson, L. S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.21.12841 · Cited by 105 · see citing works
Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress
Mitsuda, T., Omi, T., Tanimukai, H., Sakagami, Y., Tagami, S., Okochi, M., Kudo, T., & Takeda, M. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.10.113 · Cited by 88 · see citing works
Association between polymorphisms in the type 1 sigma receptor gene and schizophrenia
Ishiguro, H., Ohtsuki, T., Toru, M., Itokawa, M., Aoki, J., Shibuya, H., Kurumaji, A., Okubo, Y., Iwawaki, A., Ota, K., et al. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00797-6 · Cited by 68 · see citing works
Harrison, D. G. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116156 · Cited by 65 · see citing works
ATF4 regulates γ-secretase activity during amino acid imbalance
Mitsuda, T., Hayakawa, Y., Itoh, M., Ohta, K., & Nakagawa, T. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.11.075 · Cited by 47 · see citing works
A Randomized, Double-Blind, Placebo-Controlled Trial of Fluvoxamine in Patients With Schizophrenia
Niitsu, T., Fujisaki, M., Shiina, A., Yoshida, T., Hasegawa, T., Kanahara, N., Hashimoto, T., Shiraishi, T., Fukami, G., Nakazato, M., et al. (2012) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e3182664cfc · Cited by 38 · see citing works
Ishiwata, K., Oda, K., Sakata, M., Kimura, Y., Kawamura, K., Oda, K., Sasaki, T., Naganawa, M., Chihara, K., Okubo, Y., et al. (2006) · Annals of Nuclear Medicine · doi:10.1007/bf03026824 · Cited by 36 · see citing works
Associations of ATF4 gene polymorphisms with schizophrenia in male patients
Qu, M., Tang, F., Wang, L., Yan, H., Han, Y., Yan, J., Yue, W., & Zhang, D. (2007) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30675 · Cited by 22 · see citing works
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- Hayashi T Su TP Sigma-1receptor ligands: potential in the treatment of neuropsychiatric disorders CNS Drugs 2004 18 269 284 15089113
- Hayashi T Su TP The sigma receptor: evolution of the concept in neuropsychopharmacology Curr Neuropharmacol 2005 3 267 280 18369400 PMC2268997
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Reis, G., Moreira-Silva, E. A. D. S., Silva, D. C. M., Thabane, L., Milagres, A. C., Ferreira, T. S., dos Santos, C. V. Q., Campos, V. H. D. S., Nogueira, A. M. R., Almeida, A. P. F. G., et al. (2021) · The Lancet Global Health · doi:10.1016/s2214-109x(21)00448-4 · Cited by 372 · see citing works
The therapeutic potentials of Ayahuasca: possible effects against various diseases of civilization
Frecska, E., Bokor, P., & Winkelman, M. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00035 · Cited by 242 · see citing works
Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease
Lindholm, D., Korhonen, L., Eriksson, O., & Kõks, S. (2017) · Front. Cell Dev. Biol. · doi:10.3389/fcell.2017.00048 · Cited by 198 · see citing works
“Activation of sigma-1 receptors can afford neuroprotection and modulates ER stress pathways in the brain (Hyrskyluoto et al., 2013; Omi et al., 2014).”
BackgroundRoles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases
Weng, T.-Y., Tsai, S., & Su, T. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0380-6 · Cited by 139 · see citing works
Wang, J., Shanmugam, A. K., Markand, S., Zorrilla, E. P., Ganapathy, V., & Smith, S. B. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.04.009 · Cited by 136 · see citing works
The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases
Penke, B., Fülöp, L., Szűcs, M., & Frecska, E. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170529104323 · Cited by 132 · see citing works
“If the Sig-1R mitigates ER stress [71], promotes neuronal survival against oxidative stress [70], and regulates immune processes [168], one may attribute the same role to DMT [169].”
BackgroundNguyen, L., Lucke-Wold, B. P., Mookerjee, S. A., Kaushal, N., & Matsumoto, R. R. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-50174-1_10 · Cited by 119 · see citing works
“As chaperones, sigma-1 receptors participate closely in the degradation of unfolded proteins [82], and multiple studies describe sigma-1 receptor modulation of the UPR [76, 83, 84].”
InfluentialHashimoto, K. (2014) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2014.11.010 · Cited by 107 · see citing works
Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology
Aishwarya, R., Abdullah, C. S., Morshed, M., Remex, N. S., & Bhuiyan, M. S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.705575 · Cited by 106 · see citing works
The acid sphingomyelinase/ceramide system in COVID-19
Kornhuber, J., Hoertel, N., & Gulbins, E. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01309-5 · Cited by 106 · see citing works
“Fluvoxamine is a sigma1 receptor agonist [95, 96].”
Dreser, A., Vollrath, J. T., Sechi, A. S., Johann, S., Roos, A., Yamoah, A., Katona, I., Bohlega, S., Wiemuth, D., Tian, Y., et al. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.88 · Cited by 99 · see citing works
“ATF4 is required for the activation of SigR1 transcription and upregulation of SigR1 suppresses ER stress-mediated cell death, thus considered to be neuroprotective.(43) Consistent with this, Gregianin et al.”
ResultRepurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?
Vela, J. M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.582310 · Cited by 97 · see citing works
Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease
Santos, L. E., & Ferreira, S. T. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.016 · Cited by 92 · see citing works
Hayashi, T. (2015) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12262 · Cited by 87 · see citing works
“Haloperidol possesses a property of the sigma-1 receptor antagonist, whereas fluvoxamine and fluoxetine possess a property of the sigma-1 receptor agonist.(48,49) Sigma-1 receptor agonists have been proven to exert potentiation of neurite outgrowth, myelination, long-term potentiation, and neuroprotection in in vitro…”
BackgroundRole of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS)
Mavlyutov, T. A., Guo, L., Epstein, M. L., & Ruoho, A. E. (2015) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2014.12.013 · Cited by 75 · see citing works
“To date, the S1R has been shown to interact with BIP, PERK, and IRE1 and through these interactions has been proposed, in part, to alleviate ER stress (37,59,60).”
BackgroundAt the Crossing of ER Stress and MAMs: A Key Role of Sigma-1 Receptor?
Delprat, B., Crouzier, L., Su, T., & Maurice, T. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12457-1_28 · Cited by 76 · see citing works
Role of endoplasmic reticulum stress in depression (Review)
Mao, J., Hu, Y., Ruan, L., Ji, Y., & Lou, Z. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10789 · Cited by 74 · see citing works
“Similarly, a previous study by omi et al demonstrated that fluvoxamine‑mediated upregulation of Sig-1r expression promoted neuroprotection by inhibiting er stress-mediated apoptosis and increasing aTF4 translation (65).”
Szabó, Í., Varga, V. É., Dvorácskó, S., Farkas, A. E., Körmöczi, T., Berkecz, R., Kecskés, S., Menyhárt, Á., Frank, R., Hantosi, D., et al. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108612 · Cited by 72 · see citing works
Reis, G., Silva, E. A. D. S. M., Silva, D. C. M., Thabane, L., Milagres, A. C., Ferreira, T. S., dos Santos, C. V. Q., Neto, A. D. D. F., Callegari, E. D., Savassi, L. C. M., et al. (2021) · The Lancet Regional Health - Americas · doi:10.1016/j.lana.2021.100142 · Cited by 64 · see citing works
RetractedPatel, S., Sharma, D., Kalia, K., & Tiwari, V. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.08.025 · Cited by 64 · see citing works
The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy
Omidkhoda, N., Hayes, A. W., Reiter, R. J., & Karimi, G. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104516 · Cited by 61 · see citing works
Sigma-1 receptor: a potential therapeutic target for traumatic brain injury
Shi, M., Chen, F., Chen, Z., Yang, W., Yue, S., Zhang, J., & Chen, X. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.685201 · Cited by 58 · see citing works
Sigma-1 receptor: A potential target for the development of antidepressants
Wang, Y., Xia, C., Jia, H., He, J., Lian, W., Yan, Y., Wang, W., Zhang, W., & Xu, J. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105390 · Cited by 57 · see citing works
Martin, P., Reeder, T., Sourbron, J., de Witte, P. A. M., Gammaitoni, A. R., & Galer, B. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168416 · Cited by 62 · see citing works
Yang, K., Wang, C., & Sun, T. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00528 · Cited by 55 · see citing works
MicroRNA-297 promotes cardiomyocyte hypertrophy via targeting sigma-1 receptor
Bao, Q., Zhao, M., Chen, L., Wang, Y., Wu, S., Wu, W., & Liu, X. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.03.006 · Cited by 50 · see citing works
“receptor (Sig-1R) expression through the PERK pathway [12].”
BackgroundZhao, X., Zhu, L., Liu, D., Chi, T., Ji, X., Liu, P., Yang, X., Tian, X., & Zou, L. (2018) · APOPTOSIS · doi:10.1007/s10495-018-1495-2 · Cited by 50 · see citing works
Cao, Z., Xiao, Q., Dai, X., Zhou, Z., Jiang, R., Cheng, Y., Yang, X., Guo, H., Wang, J., Xi, Z., et al. (2017) · Cell Death and Disease · doi:10.1038/s41419-017-0017-4 · Cited by 50 · see citing works
Cheng, D., Lei, Z., Chu, K., Lam, O. J. H., Chiang, C. Y., & Zhang, Z.-J. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01462-3 · Cited by 46 · see citing works
“These results were consistent with other previous studies, which found that the agonist of Sig-1r increased the expression of Sig-1r protein and mRNA [42, 43].”
ResultHappy, M., Dejoie, J., Zajac, C. K., Cortez, B., Chakraborty, K., Aderemi, J., & Sauane, M. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.12.029 · Cited by 41 · see citing works
Role of σ1 Receptors in Learning and Memory and Alzheimer’s Disease-Type Dementia
Maurice, T., & Goguadze, N. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-50174-1_15 · Cited by 42 · see citing works
Mavlyutov, T. A., Duellman, T., Kim, H. T., Epstein, M. L., Leese, C., Davletov, B. A., & Yang, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.06.030 · Cited by 41 · see citing works
“Upregulation of the S1R transcript via the pERK/ eIF2α-ATF4 pathway during ER stress has been reported (Mitsuda et al., 2011), and the selective serotonin uptake inhibitor fluvoxamine also upregulates the S1R transcript through direct activation of ATF4 without involving pERK (Omi et al., 2014).”
BackgroundLee, P.-T., Liévens, J.-C., Wang, S., Chuang, J., Khalil, B., Wu, H.-E., Chang, W., Maurice, T., & Su, T. (2020) · Nature Communications · doi:10.1038/s41467-020-19396-3 · Cited by 39 · see citing works
Abelaira, H. M., Réus, G. Z., Ignácio, Z. M., dos Santos, M. A. D., de Moura, A. B., Matos, D., Demo, J. P., da Silva, J. B., Michels, M., Abatti, M., et al. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.12.002 · Cited by 43 · see citing works
“However, other study demonstrated that fluvoxamine, a SSRI, did not alter the PERK levels (Omi et al., 2014).”
ResultChaperone Sigma1R and Antidepressant Effect
Воронин, М. В., Vakhitova, Y. V., & Середенин, С. Б. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197088 · Cited by 40 · see citing works
Rodríguez, L. R., Lapeña-Luzón, T., Benetó, N., Beltran-Beltran, V., Pallardó, F. V., González‐Cabo, P., & Navarro, J. A. (2022) · Antioxidants · doi:10.3390/antiox11010165 · Cited by 39 · see citing works
Munguía-Galaviz, F. J., Miranda‐Díaz, A. G., Cárdenas-Sosa, M. A., & Echavarría, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031997 · Cited by 39 · see citing works
“ATF4 is a transcription factor able to interact with the SIGMAR1 gene in manners that are PERKdependent, in response to ER stress, or PERK-independent, upon fluvoxamine binding to Sig-1R [104].”
BackgroundShi, M., Liu, L., Min, X., Mi, L., Chai, Y., Chen, F., Wang, J., Yue, S., Zhang, J., Deng, Q., et al. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11092348 · Cited by 37 · see citing works
Loss of Sigma‐1 Receptor Chaperone Promotes Astrocytosis and Enhances the Nrf2 Antioxidant Defense
Weng, T.-Y., Hung, D. T., Su, T., & Tsai, S. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/4582135 · Cited by 37 · see citing works
“The Sig-1R can attenuate the ER stress [59]; therefore, we speculate that the cellular stress caused by the MG132 may lead to partial induction of Sig-1R expressions.”
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Reis, G., Silva, E. A. D. S. M., Silva, D. C. M., Thabane, L., Campos, V. H. D. S., Ferreira, T. S., dos Santos, C. V. Q., Nogueira, A. M. R., Almeida, A. P. F. G., Savassi, L. C. M., et al. (2023) · Annals of Internal Medicine · doi:10.7326/m22-3305 · Cited by 36 · see citing works
The pain of pain: Challenges of animal behavior models
Barrett, J. E. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.11.046 · Cited by 33 · see citing works
Yang, L., Zheng, L., Wan, Y., Chen, Z., Li, P., & Wang, Y. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00696 · Cited by 33 · see citing works
“Another SSRIs drug study showed fluvoxamine could reduce the incidence of cerebral ischemia via alleviating the ERS by decreasing the levels of CHOP, cleaved caspase4, and cleaved caspase3 (24).”
BackgroundRetractedMorihara, R., Yamashita, T., Liu, X., Nakano, Y., Fukui, Y., Sato, K., Ohta, Y., Hishikawa, N., Shang, J., & Abe, K. (2018) · Journal of Neuroscience Research · doi:10.1002/jnr.24270 · Cited by 32 · see citing works
“, 2011) (Omi et al., 2014), the expression of Sig-1R protein in vivo following treatment with Sig-1R agonists has not been reported.”
BackgroundBogár, F., Fülöp, L., & Penke, B. (2022) · Biomolecules · doi:10.3390/biom12030363 · Cited by 27 · see citing works
Crouzier, L., Denus, M., Richard, É. M., Tavernier, A., Diez, C., Cubedo, N., Maurice, T., & Delprat, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011049 · Cited by 25 · see citing works
Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection
Воронин, М. В., Абрамова, Е. В., Verbovaya, E. R., Vakhitova, Y. V., & Середенин, С. Б. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010823 · Cited by 27 · see citing works
“It has been shown that the effects of fluvoxamine may be related with both Sigma1R chaperone function activation [267], and its ability to enhance Sigmar1 expression [433].”
BackgroundDelint‐Ramírez, I., García‐Oscos, F., Segev, A., & Kourrich, S. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0092-7 · Cited by 23 · see citing works
Li, Z., Ran, Q., Qu, C., Hu, S., Cui, S., Zhou, Y., Shen, B., & Yang, B. (2025) · Biology Direct · doi:10.1186/s13062-025-00617-y · Cited by 24 · see citing works
“After an extensive literature search, we found that flu-voxamine (Flv) is a potent sigma-1 receptor inducer that effectively activates the sigma-1 receptor [17].”
Fujii, C., Zorumski, C. F., & Izumi, Y. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.391334 · Cited by 25 · see citing works
“Several studies have shown that S1R signaling plays a critical role in controlling ER stress (Omi et al., 2014; Morihara et al., 2018; Zhao et al., 2019).”
The Sigma-1 Receptor–A Therapeutic Target for the Treatment of ALS?
Mavlyutov, T. A., Baker, E. M., Losenegger, T. M., Kim, J. R., Torres, B., Epstein, M. L., & Ruoho, A. E. (2017) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-50174-1_17 · Cited by 24 · see citing works
Izumi, Y., Reiersen, A. M., Lenze, E. J., Mennerick, S. J., & Zorumski, C. F. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02343-3 · Cited by 22 · see citing works
Yang, J.-Z., Zhang, K.-K., Shen, H.-W., Liu, Y., Li, X., Chen, L., Liu, J.-L., Li, J.-H., Zhao, D., Wang, Q., et al. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1255971 · Cited by 21 · see citing works
Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway
Almási, N., Török, S., Dvorácskó, S., Tömböly, C., Csonka, Á., Baráth, Z., Murlasits, Z., Valkusz, Z., Pósa, A., Varga, C., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114046 · Cited by 20 · see citing works
“It has also been shown that FLV can induce activating transcription factor-4 (ATF-4) mediated expression of σ1R and exerts the alleviation of ER stress, thus contributing to neuroprotection [39].”
BackgroundHosoi, T., & Ozawa, K. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00059 · Cited by 19 · see citing works
“Fluvoxamine has affinity for the sigma-1 receptor (Sig-1R) (39), which is an ER protein involved in ER stress (40).”
BackgroundAlmási, N., Török, S., Valkusz, Z., Tajti, M., Csonka, Á., Murlasits, Z., Pósa, A., Varga, C., & Kupai, K. (2020) · Antioxidants · doi:10.3390/antiox9111081 · Cited by 19 · see citing works
“Currently, as an agonist, fluvoxamine (FLV, an antidepressant) [24] and cutamesine dihydrochloride (SA4503) are widely applied [25], while BD1063 [26] and NE-100 are frequently used as σ1R antagonists [21].”
BackgroundCellular Response to Unfolded Proteins in Depression
Kowalczyk, M., Kowalczyk, E., Kwiatkowski, P. A., Łopusiewicz, Ł., Talarowska, M. E., & Sienkiewicz, M. (2021) · Life · doi:10.3390/life11121376 · Cited by 19 · see citing works
“showed that fluvoxamine-mediated upregulation of Sig-1R promoted neuroprotection by inhibiting ER-induced apoptosis [73].”
BackgroundMAM-mediated mitophagy and endoplasmic reticulum stress: the hidden regulators of ischemic stroke
Jia, Z., Li, H., Xu, K., Li, R., Yang, S., Chen, L., Zhang, Q., Li, S., & Sun, X. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1470144 · Cited by 19 · see citing works
Fluvoxamine alleviates paclitaxel-induced neurotoxicity
Tanimukai, H., & Kudo, T. (2015) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2015.09.014 · Cited by 18 · see citing works
“Although, we only performed a cellular model and focused on the Px induced ER stress related neurotoxicity in the present study, our previous animal study has demonstrated that Flv treatment suppressed cerebral infarction size in mice after focal cerebral ischemia [26].”
BackgroundResultInfluentialLin, C., Wu, H.-E., Weng, E. F.-J., Wu, H.-C., Su, T., & Wang, S. (2024) · Molecular Neurobiology · doi:10.1007/s12035-023-03885-9 · Cited by 17 · see citing works
Martin, P., Maurice, T., Gammaitoni, A. R., Farfel, G. M., Boyd, B., & Galer, B. S. (2022) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2021.108526 · Cited by 17 · see citing works
EFFECTS OF STRESS IN PREGNANCY ON PRENATAL ATTACHMENT, AND CONTRIBUTING FACTORS
Şanlı, Y., & Akbağ, N. N. A. (2022) · Psychiatria Danubina · doi:10.24869/psyd.2022.25 · Cited by 16 · see citing works
Peeking into Sigma-1 Receptor Functions Through the Retina
Mavlyutov, T. A., & Guo, L. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-50174-1_19 · Cited by 16 · see citing works
“, S1R interacts with and stabilizes ER stress sensor IRE1 [29, 33, 34].”
BackgroundJiang, L., Cui, J., Zhang, C., Xie, J., Zhang, S., Fu, D., & Duo, W. (2020) · Aging · doi:10.18632/aging.103166 · Cited by 15 · see citing works
Effects of Escitalopram on Endoplasmic Reticulum Stress and Oxidative Stress Induced by Tunicamycin
Yang, L., Chen, Z., Li, J., Ding, P., & Wang, Y. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.737509 · Cited by 15 · see citing works
Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids
Izumi, Y., Reiersen, A. M., Lenze, E. J., Mennerick, S. J., & Zorumski, C. F. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03185-3 · Cited by 14 · see citing works
Repurposing Sigma-1 Receptor-Targeting Drugs for Therapeutic Advances in Neurodegenerative Disorders
Eskandari, K., Bélanger, S.-M., Lachance, V., & Kourrich, S. (2025) · Pharmaceuticals · doi:10.3390/ph18050700 · Cited by 14 · see citing works
“, highlighting once more the importance of S1R in fluvoxamine’s mechanism of action [125].”
Haloperidol Affects Plasticity of Differentiated NG-108 Cells Through σ1R/IP3R1 Complex
Kubíčková, J., Lencesova, L., Csáderová, L., Stračina, T., Hudecová, S., Babula, P., Rozborilova, E., Novàkovâ, M., & Križanová, O. (2017) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0524-y · Cited by 13 · see citing works
The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders
Srinivasan, V., Korhonen, L., & Lindholm, D. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.554548 · Cited by 13 · see citing works
“Park et al. (2012) Olanzapine SH-SY5Y human neuroblastoma cells.”
ResultFernández, J. J., Marin, A., Rosales, R., Penrice-Randal, R., Mlcochova, P., Alvarez, Y., Villalón-Letelier, F., Yildiz, S., Pérez, E. R., Rathnasinghe, R., et al. (2024) · Biochimica et Biophysica Acta - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167193 · Cited by 11 · see citing works
Davis, M. P. (2024) · Palliative Care and Social Practice · doi:10.1177/26323524241266603 · Cited by 11 · see citing works
Aboras, S. I., Megahed, A. A., El‐Yazbi, F. A., & Maher, H. M. (2024) · BMC Chemistry · doi:10.1186/s13065-024-01147-w · Cited by 9 · see citing works
“1A [16].”
Mitochondrial Movement and Number Deficits in Embryonic Cortical Neurons from 3xTg-AD Mice
Cavendish, J. Z., Sarkar, S. N., Colantonio, M. A., Quintana, D. D., Ahmed, N., White, B. A., Engler-Chiurazzi, E. B., & Simpkins, J. W. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190143 · Cited by 9 · see citing works
“The relationship of reduced mitochondrial number and movement to ER stress should also be examined, as ER stress markers are increased in 3xTg-AD mice as early as 2 months of age [40]. σ 1 R attenuate ER stress [41] and could potentially exert their mitochondrial effects through this pathway.”
Chiba, T., Maeda, T., Kimura, S., Morimoto, Y., Sanbe, A., UEDA, H. M. D., & Kudo, K. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.09.038 · Cited by 9 · see citing works
Peng, L., Wang, K., Wu, L., Yao, L., Shen, B., & Li, J. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103131 · Cited by 12 · see citing works
Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model
Mills, F. P., Reis, G., Wilson, L. A., Thorlund, K., Forrest, J. I., Guo, C. M., Boulware, D. R., Mills, E. J., & _, _. (2022) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.22-0106 · Cited by 8 · see citing works
Psychiatric Diagnoses and Medications in Wolfram Syndrome
Reiersen, A. M., Noel, J., Doty, T., Sinkre, R. A., Narayanan, A., & Hershey, T. G. (2022) · Scandinavian Journal of Child and Adolescent Psychiatry and Psychology · doi:10.2478/sjcapp-2022-0017 · Cited by 7 · see citing works
Tran, M. N., Medveczki, T., Besztercei, B., Török, G., Szabo, A. J., Gasull, X., Kovács, I., Fekete, A., & Hodrea, J. (2023) · Life · doi:10.3390/life13071581 · Cited by 7 · see citing works
Kawashima, Y., Ezawa, T., Yamamura, M., Harada, T., Noguchi, T., & Imai, N. (2015) · Tetrahedron Letters · doi:10.1016/j.tetlet.2015.12.113 · Cited by 7 · see citing works
Sigma‑1 receptor overexpression promotes proliferation and ameliorates cell apoptosis in β‑cells
Ke, M., Lin, F., Wang, H., He, G., Feng, J., Song, L., Xu, Y., & Liu, J. (2022) · Molecular Medicine Reports · doi:10.3892/mmr.2022.12686 · Cited by 7 · see citing works
付茹婷, Fang, L., Liu, J., Liu, Y., Wang, Y., Kong, D., & Guo, J. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107248 · Cited by 8 · see citing works
Sigma-1 Receptor Agonist Fluvoxamine Ameliorates Fibrotic Response of Trabecular Meshwork Cells
Hodrea, J., Tran, M. N., Besztercei, B., Medveczki, T., Szabo, A. J., Őrfi, L., Kovács, I., & Fekete, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411646 · Cited by 6 · see citing works
Ezawa, T., Kawashima, Y., Noguchi, T., Jung, S., & Imai, N. (2017) · Tetrahedron Asymmetry · doi:10.1016/j.tetasy.2016.12.010 · Cited by 6 · see citing works
Al‐Maamari, A., Sultan, M., Zhang, T., Qaed, E., Wu, S., Qiao, R., Duan, Y., Ding, S., Liu, G., & Su, S. (2025) · Cardiovascular Toxicology · doi:10.1007/s12012-025-09975-5 · Cited by 5 · see citing works
“2 Schematic overview showing the changes and the effects of S1R ablation in different systems of mice of dysfunctional mitochondria; culminating in cardiac contractile dysfunction is caused by abnormal mitochondrial structure as well as adverse cardiac remodeling [91].”
Ahmed, M. K., Abdou, K., Ibrahim, W. W., Mohamed, A. F., & El-Boghdady, N. A. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06940-6 · Cited by 4 · see citing works
“( Hashimoto et al. 2007; Nishimura et al. 2008; Niitsu et al. 2012; Sugimoto et al. 2012; Omi et - Mice treated with MK-801exhibited significant impairments in spatial working memory (Y-maze) and passive avoidance learning, modeling schizophrenia-like cognitive deficits.”
Munguía-Galaviz, F. J., Miranda‐Díaz, A. G., Gutiérrez-Mercado, Y. K., Ku-Centurion, M., González-González, R., Buen, E. P., & Echavarría, R. (2024) · Biomedicines · doi:10.3390/biomedicines12081908 · Cited by 4 · see citing works
“Sigmar1 ligands influence its expression in various cells and tissues, and elevated Sig-mar1 levels could be partly responsible for the changes observed in the kidneys and hearts of UUO mice associated with CRS4 development [23–25].”
BackgroundTreatment with fluvoxamine in nonhospitalized coronavirus disease 2019 patients
Ibrahim, M. A., & Shehta, M. (2023) · Egyptian Journal of Chest Diseases and Tuberculosis · doi:10.4103/ecdt.ecdt_38_22 · Cited by 4 · see citing works
Association and Interaction of Epstein–Barr Virus with SARS-CoV-2 Infection—A Review
Mahajan, S., Mahajan, S., & Patgiri, S. (2025) · Viruses · doi:10.3390/v17070903 · Cited by 3 · see citing works
“Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) and a σ -1 receptor (S1R) agonist [32] that inhibits acid sphingomyelinase (ASM) activity and the formation of the ceramide-enriched membrane domain.”
Yang, S., Zhang, M., Wei, J., Yu, L., Li, H., Rong, S., Chen, L., Zhao, T., 詹俊鲲, Wang, X., et al. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04084-z · Cited by 3 · see citing works
“ATF4 plays a dual role in bone metabolism, promoting osteogenesis while inhibiting osteoclastogenesis [45], and has been identified as a key upstream transcription factor regulating SigmaR1 [46, 47].”
Targeting Neuroinflammation in Depression: The Integrative Role of Sigma‐1 Receptor Modulation
Wang, J., Yang, D., Li, Y., & Ren, P. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70490 · Cited by 3 · see citing works
“…including GRP78/BiP, CHOP, phosphorylated PERK, IRE1, and eIF2α in cellular models, rodent models of depression, and neurodegenerative conditions, highlighting the therapeutic relevance of Sig-1R modulation (Ahmed et al. 2025a; Al-Maamari et al. 2025; Omi et al. 2014; Tanimukai and Kudo 2015).”
The protective effect of DMT against neurodegeneration
Frecska, E., Kovacs, A. I., & Szabó, A. (2025) · International review of neurobiology · doi:10.1016/bs.irn.2025.04.010 · Cited by 3 · see citing works
Karaağaç, M., Ak, M., Kurar, E., Uğuz, F., & Kutlu, S. (2023) · Journal of Clinical Psychiatry · doi:10.5505/kpd.2023.43410 · Cited by 3 · see citing works
Topsakal, Ş., Özmen, Ö., Özcan, K. N., Aşçı, H., İmeci, O. B., Sevük, M. A., & Koşar, P. A. (2025) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.70000 · Cited by 3 · see citing works
CaMK4, a key target for treating pathogenesis of depression?
Yang, Y., Guan, W., & Gu, H. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117429 · Cited by 2 · see citing works
The Potential Use of Dimethyltryptamine against Ischemia-reperfusion Injury of the Brain
Attila, K., Mathe, A., & Frecska, E. (2024) · Journal of Neuroscience and Neurological Disorders · doi:10.29328/journal.jnnd.1001097 · Cited by 2 · see citing works
Fluvoxamine restores TFEB-mediated autophagy through Sigma-1R-controlled POM121 expressionPreprint
Lin, C., Wu, H.-E., Weng, E. F.-J., Su, T., & Wang, S. (2023) · Research Square · doi:10.21203/rs.3.rs-2994070/v1 · Cited by 2 · see citing works
Rodríguez, J. J. F. (2023) · doi:10.35376/10324/61445 · Cited by 2 · see citing works
Borde, P., Abdulla, A., Rajab, E., & Safrany, S. T. (2025) · Cancer Medicine · doi:10.1002/cam4.71376 · Cited by 1 · see citing works
Basic Theory of Pharmacology for Alzheimer’s Disease
Kudo, T. (2016) · Springer eBooks · doi:10.1007/978-3-319-26206-2_1 · Cited by 1 · see citing works
Therapeutic potential of serotonin in ischemic stroke
el-hameed, S. A., Baket, A., El‐Daly, M., Ahmed, A. F., & Heeba, G. H. (2021) · Journal of advanced Biomedical and Pharmaceutical Sciences · doi:10.21608/jabps.2021.88944.1135 · Cited by 1 · see citing works
“Administration of fluoxetine pre or post MCCAO achieved similar reduction in the infarct volume and similar an improvement in neurobehavioral outcomes [52, 53].”
Background免疫系と精神疾患：BDNF と細胞内 Ca2＋シグナリングの関与
義人, 溝., 鍋田, 紘., 今村, 義., Haraguchi, Y., & 晃, 門. (2015) · doi:10.11249/jsbpjjpp.26.1_38
- Authors
- Omi, T., Tanimukai, H., Kanayama, D., Sakagami, Y., Tagami, S., Okochi, M., Morihara, T., Sato, M., Yanagida, K., Kitasyoji, A., Hara, H., Imaizumi, K., Maurice, T., Chevallier, N., Marchal, S., Takeda, M., & Kudo, T.
- Affiliations
- Osaka Prefectural Medical Center (JP)
- The University of Osaka (JP)
- Gifu Pharmaceutical University (JP)
- Hiroshima University (JP)
- Inserm (FR)
- Corresponding author
- Kudo, T
- Venue
- Cell Death & Disease
- Published
- 2014-07-17
- Volume
- 5
- Issue
- 7
- Pages
- e1332-e1332
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4123092
- OpenAlex
- W2093653250
- Cited by
- 113
- References
- 38
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 12 · 2023: 12 · 2022: 9 · 2021: 12 · 2020: 8 · 2019: 6 · 2018: 4 · 2017: 15 · 2016: 5 · 2015: 7 · 2014: 3
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Japan Society for the Promotion of Science (24591709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- fluvoxamine, sigma-1 receptor, endoplasmic reticulum stress, PERK pathway, selective serotonin reuptake inhibitors, neuroblastoma cells, neuronal cell death, focal cerebral ischemia, neuroprotection
- MeSH terms
- Sigma-1 Receptor, Animals, Humans, Male, Neurons, Signal Transduction, Up-Regulation, Fluvoxamine, Apoptosis, Receptors, sigma, Mice, Knockout, Mice, Activating Transcription Factor 4, HEK293 Cells, Endoplasmic Reticulum Stress
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