Timing-Dependent Effects of Fluoxetine and 808 nm Photobiomodulation in CORT/H₂O₂-Stressed SH-SY5Y Cells
International Journal of Medical Toxicology and Forensic Medicine,
Vol. 16 (2026),
1 January 2026
,
Page 1-9
https://doi.org/10.22037/ijmtfm.v16.52763
Abstract
Background: Major depressive disorder is associated with glucocorticoid dysregulation, oxidative stress, inflammation, and mitochondrial disturbance. Cellular systems can examine selected components of these processes but do not reproduce the clinical disorder. To examine the timing-dependent effects of fluoxetine and 808 nm photobiomodulation (PBM), alone and together, in CORT/H₂O₂-stressed SH-SY5Y cells.
Methods: SH-SY5Y cells were exposed concurrently to corticosterone and hydrogen peroxide (100 µM each) for 24 h. Fluoxetine (1 µM) and PBM (808 nm, 50 mW, 0.2 cm² beam area, 250 mW/cm², 40 s; calculated nominal fluence 10 J/cm²) were applied before, during, or after stress. Cell viability, malondialdehyde (MDA), reduced glutathione (GSH), and interleukin-6 (IL-6) were assessed. Reported p-values derive from exploratory one-way analyses and do not estimate factorial interactions.
Results: The combined stress condition was associated with lower viability and GSH and higher MDA and IL-6 than the control. In the original exploratory comparisons, co- and post-treatment generally showed more favorable viability and redox outcomes than pretreatment. The combined intervention showed favorable mean responses at several time points, with concurrent treatment showing the broadest redox pattern and post-treatment showing the lowest mean IL-6.
Conclusion: Fluoxetine and PBM were associated with timing-dependent cytoprotective patterns in this cellular stress system. Because factorial interactions were not tested, biochemical endpoints were not documented as cell- or protein-normalized, and the model does not represent major depressive disorder, the findings are hypothesis-generating and do not establish synergy, mechanism, clinical efficacy, or safety.
- Fluoxetine, Photobiomodulation therapy, Oxidative stress, Glutathione, Interleukin-6
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References
[1] Chen X-D, Li F, Zuo H, Zhu F. Trends in Prevalent Cases and Disability-Adjusted Life-Years of Depressive Disorders Worldwide: Findings From the Global Burden of Disease Study From 1990 to 2021. Depress Anxiety 2025;2025:5553491. [DOI: 10.1155/da/5553491]
[2] Ferrari AJ, Santomauro DF, Aali A, Abate YH, Abbafati C, Abbastabar H. GBD 2021 Diseases and Injuries Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 8. Lancet 2024;403:2133–61. [DOI: 0.1016/s0140-6736(24)00757-8]
[3] Perez-Caballero L, Torres-Sanchez S, Romero-López-Alberca C, González-Saiz F, Mico JA, Berrocoso E. Monoaminergic system and depression. Cell Tissue Res 2019;377:107–13. [DOI: 10.1007/s00441-018-2978-8]
[4] Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report. Am J Psychiatry 2006;163:1905–17. [DOI: 10.1176/ajp.2006.163.11.1905]
[5] Lei AA, Phang VWX, Lee YZ, Kow ASF, Tham CL, Ho Y-C, et al. Chronic Stress-Associated Depressive Disorders: The Impact of HPA Axis Dysregulation and Neuroinflammation on the Hippocampus-A Mini Review. Int J Mol Sci 2025;26. [DOI: 10.3390/ijms26072940]
[6] McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, et al. Mechanisms of stress in the brain. Nat Neurosci 2015;18:1353–63. [DOI: 10.1038/nn.4086]
[7] Mazereeuw G, Herrmann N, Andreazza AC, Khan MM, Lanctôt KL. A meta-analysis of lipid peroxidation markers in major depression. Neuropsychiatr Dis Treat 2015:2479–91. [DOI: 10.2147/NDT.S89922]
[8] Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 2015;49:206–15. [DOI: 10.1016/j.bbi.2015.06.001]
[9] Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell 2021;184:1299–313. [DOI: 10.1016/j.cell.2021.01.034]
[10] Salehpour F, Mahmoudi J, Kamari F, Sadigh-Eteghad S, Rasta SH, Hamblin MR. Brain photobiomodulation therapy: a narrative review. Mol Neurobiol 2018;55:6601–36. [DOI: 10.1007/s12035-017-0852-4]
[11] Sykiotis GP. Keap1/Nrf2 signaling pathway. Antioxidants 2021;10:828. [DOI: 10.3390/antiox10060828]
[12] Huang Y-Y, Sharma SK, Carroll J, Hamblin MR. Biphasic dose response in low level light therapy–an update. Dose-Response 2011;9:dose-response. [DOI: 10.2203/dose-response.11-009.Hamblin]
[13] Kamiloglu S, Sari G, Ozdal T, Capanoglu E. Guidelines for cell viability assays. Food Front 2020;1:332–49. [DOI: 10.1002/fft2.44]
[14] Hoffmann LF, Martins A, Majolo F, Contini V, Laufer S, Goettert MI. Neural regeneration research model to be explored: SH-SY5Y human neuroblastoma cells. Neural Regen Res 2023;18:1265–6. [DOI: 10.4103/1673-5374.358621]
[15] Lopes FM, Schröder R, da Frota Júnior MLC, Zanotto-Filho A, Müller CB, Pires AS, et al. Comparison between proliferative and neuron-like SH-SY5Y cells as an in vitro model for Parkinson disease studies. Brain Res 2010;1337:85–94. [DOI: 10.1016/j.brainres.2010.03.102]
[16] Yang R, Wei L, Fu Q-Q, Wang H, You H, Yu H-R. Sod3 ameliorates h2o2-induced oxidative damage in sh-sy5y cells by inhibiting the mitochondrial pathway. Neurochem Res 2016;41:1818–30. [DOI: 10.1007/s11064-016-1897-x]
[17] Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Lett 2018;592:692–702. [DOI: 10.1002/1873-3468.12964]
[18] Huang B, Liu J, Fu S, Zhang Y, Li Y, He D, et al. α-Cyperone attenuates H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells via activation of Nrf2. Front Pharmacol 2020;11:281. [DOI: 10.3389/fphar.2020.00281]
[19] Perlikowska R, Długosz-Pokorska A, Domowicz M, Grabowicz S, Stasiołek M, Zakłos-Szyda M. Reduction in SH-SY5Y Cell Stress Induced by Corticosterone and Attenuation of the Inflammatory Response in RAW 264.7 Cells Using Endomorphin Analogs. Biomedicines 2025;13:1774. [DOI: 10.3389/fphar.2020.00281]
[20] Mundalil Vasu M, Anitha A, Takahashi T, Thanseem I, Iwata K, Asakawa T, et al. Fluoxetine increases the expression of miR-572 and miR-663a in human neuroblastoma cell lines. PLoS One 2016;11:e0164425. [DOI: 10.1371/journal.pone.0164425]
[21] Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S. Roles of PI3K/AKT/GSK3/mTOR pathway in cell signaling of mental illnesses. Depress Res Treat 2012;2012:752563. [DOI: 10.1155/2012/752563]
[22] Shu X, Sun Y, Sun X, Zhou Y, Bian Y, Shu Z, et al. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell Death Dis 2019;10:577. [DOI: 10.1038/s41419-019-1813-9]
[23] Hamblin MR. Mechanisms and mitochondrial redox signaling in photobiomodulation. Photochem Photobiol 2018;94:199–212. [DOI: 10.1111/php.12864]
[24] Hamblin MR. Shining light on the head: Photobiomodulation for brain disorders. BBA Clin 2016;6:113–24. [DOI: 10.1016/j.bbacli.2016.09.002]
[25] Tian M, Yang M, Li Z, Wang Y, Chen W, Yang L, et al. Fluoxetine suppresses inflammatory reaction in microglia under OGD/R challenge via modulation of NF-κB signaling. Biosci Rep 2019;39:BSR20181584. [DOI: 10.1042/BSR20181584]
[26] Takenaka Y, Tanaka R, Kitabatake K, Kuramochi K, Aoki S, Tsukimoto M. Profiling differential effects of 5 selective serotonin reuptake inhibitors on TLRs-dependent and-independent IL-6 production in immune cells identifies fluoxetine as preferred anti-inflammatory drug candidate. Front Pharmacol 2022;13:874375. [DOI: 10.3389/fphar.2022.874375]
[27] Roy S, Ansari MA, Choudhary K, Singh S. NLRP3 inflammasome in depression: A review. Int Immunopharmacol 2023;117:109916. [DOI: 10.1016/j.intimp.2023.109916]
[28] Feng Y, Yang L, Ma X, Huang Z, Zong X, Citadin CT, et al. Photobiomodulation treatment inhibits neurotoxic astrocytic polarization and protects neurons in in vitro and in vivo stroke models. Neurochem Int 2023;162:105464. [DOI: 10.1016/j.neuint.2022.105464]
[29] Aoyama K. Glutathione in the Brain. Int J Mol Sci 2021;22:5010. [DOI: 10.3390/ijms22095010]
[30] Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 2013;34:167–77. [DOI: 10.1016/j.tips.2013.01.001]
[31] Caruso G, Grasso M, Fidilio A, Torrisi SA, Musso N, Geraci F, et al. Antioxidant activity of fluoxetine and vortioxetine in a non-transgenic animal model of alzheimer’s disease. Front Pharmacol 2021;12:809541. [DOI: 10.3389/fphar.2021.809541]
[32] García-García ML, Tovilla-Zárate CA, Villar-Soto M, Juárez-Rojop IE, González-Castro TB, Genis-Mendoza AD, et al. Fluoxetine modulates the pro-inflammatory process of IL-6, IL-1β and TNF-α levels in individuals with depression: a systematic review and meta-analysis. Psychiatry Res 2022;307:114317. [DOI: 10.1016/j.psychres.2021.114317]
[33] Cassano P, Petrie SR, Mischoulon D, Cusin C, Katnani H, Yeung A, et al. Transcranial photobiomodulation for the treatment of major depressive disorder. The ELATED-2 pilot trial. Photomed Laser Surg 2018;36:634–46. [DOI: 10.1089/pho.2018.4490]
[34] Montazeri K, Farhadi M, Fekrazad R, Chaibakhsh S, Mahmoudian S. Photobiomodulation therapy in mood disorders: a systematic review. Lasers Med Sci 2022;37:3343–51. [DOI: 10.1007/s10103-022-03641-w]
[35] Edinoff AN, Akuly HA, Hanna TA, Ochoa CO, Patti SJ, Ghaffar YA, et al. Selective serotonin reuptake inhibitors and adverse effects: a narrative review. Neurol Int 2021;13:387–401. [DOI: 10.3390/neurolint13030038]
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