Biphasic Neuroprotective and Pro-Inflammatory Synergistic Effects of Red Laser Photobiomodulation Combined with Levodopa in a Rotenone-Induced SH-SY5Y Cell Model of Parkinson's Disease: An in Vitro Study
International Journal of Medical Toxicology and Forensic Medicine,
Vol. 16 (2026),
1 January 2026
,
Page 1-12
https://doi.org/10.22037/ijmtfm.v16.52469
Abstract
Background: Parkinson's disease is a progressive neurodegenerative disorder with no curative therapy. Red laser photobiomodulation (PBM) has emerged as a potential neuroprotective strategy because of its antioxidant and mitochondrial biostimulatory properties. To evaluate the neuroprotective efficacy of individual and combined levodopa and red laser PBM pre-treatment against rotenone-induced neurotoxicity in SH-SY5Y neuroblastoma cells.
Methods: SH-SY5Y cells were pre-treated with levodopa (25, 50, 100 µM), continuous-wave red laser PBM (630–660 nm, 100 mW, 0.5 W/cm²; 10, 20, 40 s), or their combined configurations for 2 h, followed by a 24-hour rotenone (50 µM) challenge. Cell viability (MTT), IL-1β (ELISA), MDA (TBARS), and total antioxidant capacity (TAOC) were quantified.
Results: Rotenone induced cytotoxicity, elevated IL-1β and MDA levels, and depleted TAOC. Individual Levodopa (50 µM) reduced MDA (P < 0.0001) and restored TAOC (P < 0.0001) but failed to rescue viability (P > 0.05). A 20-second red laser exposure (2 J, 10 J/cm²) optimally enhanced cell survival (P = 0.0087), reduced lipid peroxidation (P = 0.0002), and recovered TAOC (P = 0.0004), demonstrating a biphasic dose-response. Specific combined regimens (Triple Pre 1 and 2) triggered a synergistic surge in IL-1β (P < 0.0001), driven by hypermetabolic cross-talk between levodopa auto-oxidation and PBM biostimulation, whereas Triple Pre 3 maintained cytokine homeostasis (P > 0.05 vs. rotenone control).
Conclusion: Red laser PBM provides biphasic, dose-dependent neuroprotection by restoring bioenergetics and antioxidant defenses; however, its combination with levodopa can provoke severe pro-inflammatory synergy, necessitating strict dosimetric thresholding in multimodal Parkinson's interventions.
- Parkinson disease, Photobiomodulation therapy, Levodopa, Rotenone, Neuroblastoma, Interleukin-1beta, Oxidative stress, Neuroprotection
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References
[1] Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood–brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab. 2016;36:1481–507. [DOI: 10.1177/0271678X16655501]
[2] Lama A, Pirozzi C, Avagliano C, Annunziata C, Mollica MP, Calignano A, et al. Nutraceuticals: an integrative approach to starve Parkinson’s disease. Brain Behav Immun Health. 2020;2:100037. [DOI: 10.30476/IJMS.2021.88511.1927]
[3] Awad K, Abushouk AI, AbdelKarim AH, Mohammed M, Negida A, Shalash AS. Bee venom for the treatment of Parkinson’s disease: how far is it possible? Biomed Pharmacother. 2017;91:295–302. [DOI: 10.1016/j.biopha.2017.04.065]
[4] Werner MH, Olanow CW. Parkinson’s disease modification through Abl kinase inhibition: an opportunity. Mov Disord. 2022;37:6–15. [DOI: 10.1093/hmg/ddm159]
[5] Thomas B, Beal MF. Parkinson’s disease. Hum Mol Genet. 2007;16:R183–94. [DOI: 10.1093/hmg/ddm159]
[6] Titova N, Qamar MA, Chaudhuri KR. The nonmotor features of Parkinson’s disease. Int Rev Neurobiol. 2017;132:33–54. [DOI: 10.1002/jbio.201600327]
[7] Cetin S, Knez D, Gobec S, Kos J, Pišlar A. Cell models for Alzheimer’s and Parkinson’s disease: at the interface of biology and drug discovery. Biomed Pharmacother. 2022;149:112924. [DOI: 10.1007/s10439-011-0454-7]
[8] Presgraves SP, Ahmed T, Borwege S, Joyce JN. Terminally differentiated SH‑SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists. Neurotox Res. 2003;5:579–98. [DOI: 10.5114/fn.2019.89849]
[9] Hong N. Photobiomodulation as a treatment for neurodegenerative disorders: current and future trends. Biomed Eng Lett. 2019;9:359–66. [DOI: 10.1007/s13534-019-00115-x]
[10] Karu TI. Multiple roles of cytochrome c oxidase in mammalian cells under action of red and IR‑A radiation. IUBMB Life. 2010;62:607–10. [DOI: 10.1002/iub.359]
[11] Hamblin MR. Photobiomodulation or low‑level laser therapy. J Biophotonics. 2016;9:1122. [DOI: 10.1002/jbio.201670113]
[12] Han X, Han B, Zhao Y, Li G, Wang T, He J, et al. Rosmarinic acid attenuates rotenone‑induced neurotoxicity in SH‑SY5Y Parkinson’s disease cell model through Abl inhibition. Nutrients. 2022;14:3508. [DOI: 10.3390/nu14173508]
[13] Liu Q, Wu H, Zhang H, Pan Y, Du S, Song W, et al. Heat shock protein is associated with inhibition of inflammatory cytokine production by 630 nm light‑emitting diode irradiation in fibroblast‑like synoviocytes based on RNA sequencing analysis. Photobiomodul Photomed Laser Surg. 2022;40:751–62. [DOI: 10.1089/photob.2022.0041]
[14] Chung H, Dai T, Sharma SK, Huang YY, Carroll JD, Hamblin MR. The nuts and bolts of low‑level laser (light) therapy. Ann Biomed Eng. 2012;40:516–33. [DOI: 10.1007/s10439-011-0454-7]
[15] Li P, Lv H, Zhang B, Duan R, Zhang X, Lin P, et al. Growth differentiation factor 15 protects SH‑SY5Y cells from rotenone‑induced toxicity by suppressing mitochondrial apoptosis. Front Aging Neurosci. 2022;14:869558. [DOI: 10.3389/fnagi.2022.869558]
[16] Pirunkaset E, Boonyarat C, Maneenet J, Khamphukdee C, Daodee S, Monthakantirat O, et al. Effect of diacetylcurcumin manganese complex on rotenone‑induced oxidative stress, mitochondrial dysfunction, and inflammation in the SH‑SY5Y Parkinson’s disease cell model. Molecules. 2024;29:957. [DOI: 10.3390/molecules29050957]
[17] Ibarra‑Gutiérrez MT, Serrano‑García N, Orozco‑Ibarra M. Rotenone‑induced model of Parkinson’s disease: beyond mitochondrial complex I inhibition. Mol Neurobiol. 2023;60:1929–48. [DOI: 10.1007/s12035-022-03193-8]
[18] Hörmann P, Delcambre S, Hanke J, Geffers R, Leist M, Hiller K. Impairment of neuronal mitochondrial function by L‑DOPA in the absence of oxygen‑dependent auto‑oxidation and oxidative cell damage. Cell Death Discov. 2021;7:151. [DOI: 10.1038/s41420-021-00547-4]
[19] Asanuma M, Miyazaki I, Ogawa N. Dopamine‑ or L‑DOPA‑induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease. Neurotox Res. 2003;5:165–76. [DOI: 10.1007/BF03033137]
[20] Huang YY, Chen ACH, Carroll JD, Hamblin MR. Biphasic dose response in low level light therapy. Dose Response. 2009;7:358–83. [DOI: 10.2203/dose-response.09-027.Hamblin]
[21] Sharma SK, Kharkwal GB, Sajo M, Huang YY, De Taboada L, McCarthy T, et al. Dose response effects of 810 nm laser light on mouse primary cortical neurons. Lasers Surg Med. 2011;43:851–9. [DOI: 10.1002/lsm.21100]
[22] Chang SY, Lee MY, Chung PS, Kim S, Choi B, Suh MW, et al. Enhanced mitochondrial membrane potential and ATP synthesis by photobiomodulation increases viability of the auditory cell line after gentamicin‑induced intrinsic apoptosis. Sci Rep. 2019;9:19248. [DOI: 10.1038/s41598-019-55711-9]
[23] Shen Q, Guo H, Yan Y. Photobiomodulation for neurodegenerative diseases: a scoping review. Int J Mol Sci. 2024;25. [DOI: 10.3390/ijms25031625]
[24] Salehpour F, Farajdokht F, Erfani M, Sadigh‑Eteghad S, Shotorbani SS, Hamblin MR, et al. Transcranial near‑infrared photobiomodulation attenuates memory impairment and hippocampal oxidative stress in sleep‑deprived mice. Brain Res. 2018;1682:36–43. [DOI: 10.1016/j.brainres.2017.12.040]
[25] Rossato RC, Salles GR, Albuquerque AL, Porcionatto MA, Granato AEC, Ulrich H, et al. Photobiomodulation by LED 660 nm and taurine against H₂O₂ oxidative stress in SH‑SY5Y cells. Lasers Med Sci. 2025;40:211. [DOI: 10.1007/s10103-025-04467-y]
[26] Li X, Wang XK, Zhu ZJ, Liang ZW, Li PH, Ma YG, et al. Photobiomodulation provides neuroprotection through regulating mitochondrial fission imbalance in the subacute phase of spinal cord injury. Neural Regen Res. 2023;18:2005–10. [DOI: 10.4103/1673-5374.366491]
[27] Hamblin MR. Mechanisms and applications of the anti‑inflammatory effects of photobiomodulation. AIMS Biophys. 2017;4:337–61. [DOI: 10.3934/biophy.2017.3.337]
[28] Dos Santos Cardoso F, Mansur FCB, Araújo BHS, Gonzalez‑Lima F, Gomes da Silva S. Photobiomodulation improves the inflammatory response and intracellular signaling proteins linked to vascular function and cell survival in the brain of aged rats. Mol Neurobiol. 2022;59:420–8. [DOI: 10.1007/s12035-021-02606-4]
[29] Emdadul Haque M, Asanuma M, Higashi Y, Miyazaki I, Tanaka K, Ogawa N. Apoptosis‑inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. Biochim Biophys Acta. 2003;1619:39–52. [DOI: 10.1016/s0304-4165(02)00440-3]
[30] Pike AF, Longhena F, Faustini G, van Eik JM, Gombert I, Herrebout MAC, et al. Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson’s disease. J Neuroinflammation. 2022;19:50. [DOI: 10.1186/s12974-022-02410-4]
[31] Lee E, Hwang I, Park S, Hong S, Hwang B, Cho Y, et al. MPTP‑driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ. 2019;26:213–28. [DOI: 10.1038/s41418-018-0124-5]
[32] Farazi N, Salehi‑Pourmehr H, Farajdokht F, Mahmoudi J, Sadigh‑Eteghad S. Photobiomodulation combination therapy as a new insight in neurological disorders: a comprehensive systematic review. BMC Neurol. 2024;24:101. [DOI: 10.1186/s12883-024-03593-4]
[33] Matt SM, Nolan R, Manikandan S, Agarwal Y, Channer B, Oteju O, et al. Dopamine‑driven increase in IL‑1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV. J Neuroinflammation. 2025;22:91. [DOI: 10.1186/s12974-025-03403-9]
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