Published November 24, 2025
| Version v1
Journal article
Open
Oxidative stress in neurodegeneration: in vitro models for investigating cellular damage and neuroprotective strategies
Authors/Creators
- 1. Medical University of Sofia, Sofia, Bulgaria
Description
Neurodegenerative disorders such as Parkinson's disease (PD) are driven by complex and multifactorial mechanisms, among which oxidative stress plays a central pathogenic role. A sustained imbalance between reactive oxygen species (ROS) production and antioxidant defenses contributes to mitochondrial dysfunction, lipid peroxidation, and dopaminergic neuronal loss. This review focuses on oxidative stress-induced neurodegeneration and explores how in vitro models can be effectively used to study the cellular consequences of oxidative damage. Particular emphasis is placed on toxin-based models, including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+), as well as cellular systems such as immortalized cell lines, primary neurons, and induced pluripotent stem cell (iPSC)-derived neurons. The applicability, advantages, and limitations of each model are discussed in the context of mimicking PD-related oxidative damage and screening for neuroprotective strategies. Ultimately, this review underscores the importance of selecting appropriate in vitro models for dissecting oxidative stress pathways and advancing neuroprotective research in PD.
Files
PHAR_article_175265.pdf
Files
(1.1 MB)
| Name | Size | Download all |
|---|---|---|
|
md5:3e182f4e9585bd3176bd1fab5715b1d9
|
930.1 kB | Preview Download |
|
md5:f30c9cd31c11049431ea75863d0e4a6b
|
146.0 kB | Preview Download |
Additional details
References
- Ablain J, Leiva M, Peres L, Fonsart J, Anthony E, De Thé H (2013) Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies. Journal of Experimental Medicine 210: 647–653. https://doi.org/10.1084/jem.20122337
- Agholme L, Lindström T, Kågedal K, Marcusson J, Hallbeck M (2010) An in vitro model for neuroscience: differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons. Journal of Alzheimer's Disease 20: 1069–1082. https://doi.org/10.3233/JAD-2010-091363
- Alexander GE (2004) Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Dialogues in Clinical Neuroscience 6: 259–280. https://doi.org/10.31887/DCNS.2004.6.3/galexander
- Barrera G, Pizzimenti S, Daga M, Dianzani C, Arcaro A, Cetrangolo GP, Giordano G, Cucci MA, Graf M, Gentile F (2018) Lipid peroxidation-derived aldehydes, 4-hydroxynonenal and malondialdehyde in aging-related disorders. Antioxidants 7: 102. https://doi.org/10.3390/antiox7080102
- Barzilai A, Yamamoto K-I (2004) DNA damage responses to oxidative stress. DNA Repair 3: 1109–1115. https://doi.org/10.1016/j.dnarep.2004.03.002
- Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organization Journal 5: 9–19. https://doi.org/10.1097/WOX.0b013e3182439613
- Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8: 57–69. https://doi.org/10.1038/nrn2038
- Booth HDE, Hirst WD, Wade-Martins R (2017) The role of astrocyte dysfunction in Parkinson's disease pathogenesis. Trends in Neurosciences 40: 358–370. https://doi.org/10.1016/j.tins.2017.04.001
- Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357: 1255–1261. https://doi.org/10.1126/science.aam9080
- Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-hydroxydopamine and 1-methyl-4-phenylpyridinium (MPP+): contribution to oxidative stress and apoptosis. Progress in Neurobiology 65(2): 135–172. https://doi.org/10.1016/S0301-0082(01)00003-X
- Chen Z, Agnew JL, Cohen JD, He P, Shan L, Sheen J, Kunkel BN (2007) Pseudomonas syringae type III effector AvrRpt2 alters Arabidopsis thaliana auxin physiology. Proceedings of the National Academy of Sciences of the United States of America 104: 20131–20136. https://doi.org/10.1073/pnas.0704901104
- Chinta SJ, Andersen JK (2008) Redox imbalance in Parkinson's disease. Biochimica et Biophysica Acta – General Subjects 1780(11): 1362–1367. https://doi.org/10.1016/j.bbagen.2008.02.005
- Croft CL, Futch HS, Moore BD, Golde TE (2019) Organotypic brain slice cultures to model neurodegenerative proteinopathies. Molecular Neurodegeneration 14: 45. https://doi.org/10.1186/s13024-019-0346-0
- Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39: 889–909. https://doi.org/10.1016/S0896-6273(03)00568-3
- Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. Journal of Neurochemistry 52: 1830–1836. https://doi.org/10.1111/j.1471-4159.1989.tb07264.x
- Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149: 1060–1072. https://doi.org/10.1016/j.cell.2012.03.042
- Do Van B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Pétrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian J-C (2016) Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiology of Disease 94: 169–178. https://doi.org/10.1016/j.nbd.2016.05.011
- Dringen R (2000) Metabolism and functions of glutathione in brain. Progress in Neurobiology 62: 649–671. https://doi.org/10.1016/S0301-0082(99)00060-X
- Duan W, Guo Z, Jiang H, Karuppagounder SS, Jing S, Xu K, Andrabi SA, Milne GL, Venkateshappa C, Keene CD, Lo DC, Ichijo H, Ratan RR, Johnson GV, Davey GP, Andersen JK (2002) Paracrine signaling between neurons and astrocytes mediated by p53 and nitric oxide in the pathogenesis of Parkinson's disease. Journal of Neuroscience 22(15): 7052–7060.
- Floor E, Wetzel MG (1998) Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. Journal of Neurochemistry 70: 268–275. https://doi.org/10.1046/j.1471-4159.1998.70010268.x
- Fomenko DE, Gladyshev VN (2012) Comparative genomics of thiol oxidoreductases reveals widespread and essential functions of thiol-based redox control of cellular processes. Antioxidants & Redox Signaling 16: 193–201. https://doi.org/10.1089/ars.2011.3980
- Freshney RI (2001) Culture of Animal Cells: A Manual of Basic Technique. 5th edn. Wiley-Liss, New York.
- Gaki GS, Papavassiliou AG (2014) Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease. NeuroMolecular Medicine 16: 217–230. https://doi.org/10.1007/s12017-014-8294-x
- Gao H-M, Hong J-S (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends in Immunology 29: 357–365. https://doi.org/10.1016/j.it.2008.05.002
- Gaschler MM, Stockwell BR (2017) Lipid peroxidation in cell death. Biochemical and Biophysical Research Communications 482: 419–425. https://doi.org/10.1016/j.bbrc.2016.10.086
- Godic A, Poljšak B, Adamic M, Dahmane R (2014) The role of antioxidants in skin cancer prevention and treatment. Oxidative Medicine and Cellular Longevity 2014: 860479. https://doi.org/10.1155/2014/860479
- González-González C, Mediavilla MD, Sánchez-Barceló EJ (2018) Melatonin: a neuroprotective agent in neurodegenerative diseases. Current Neuropharmacology 16(9): 1274–1285. https://doi.org/10.2174/1570159X15666171204122051
- Hunsucker SA, Mitchell BS, Spychala J (2005) The 5'-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacology & Therapeutics 107: 1–30. https://doi.org/10.1016/j.pharmthera.2005.01.003
- Josephy PD (2010) The role of glutathione S-transferases: functions, polymorphisms, and detoxification. Drug Metabolism Reviews 42(2): 272–289. https://doi.org/10.3109/03602530903207440
- Kalkman HO, Loetscher E (2003) Neuroprotective strategies in Parkinson's disease: an overview of experimental models and clinical perspectives. Neurotoxicity Research 5(1–2): 103–114. https://doi.org/10.1007/BF03033147
- Kuhlow CJ, Krady JK, Basu A, Levison SW (2003) Astrocytic ceruloplasmin expression, which is induced by IL-1β and by traumatic brain injury, increases in the absence of the IL-1 type 1 receptor. Glia 44: 76–84. https://doi.org/10.1002/glia.10273
- Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung W-S, Peterson TC, Wilton D-K, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481–487. https://doi.org/10.1038/nature21029
- Lobo V, Patil A, Phatak A, Chandra N (2010) Free radicals, antioxidants and functional foods: impact on human health. Pharmacognosy Reviews 4(8): 118–126. https://pubmed.ncbi.nlm.nih.gov/22228951/
- Lopes FM, Schröder R, da Frota MLC, Zanotto-Filho A, Müller CB, Pires AS, Meurer RT, Colpo GD, Gelain DP, Kapczinski F, Moreira JCF, Fernandes MDC, Klamt F (2010) Comparison between proliferative and neuron-like SH-SY5Y cells as an in vitro model for Parkinson disease studies. Brain Research 1337: 85–94. https://doi.org/10.1016/j.brainres.2010.03.102
- Malagelada C, Greene LA (2008) PC12 cells as a model for oxidative stress and neuroprotection: focus on signaling pathways and apoptosis. Methods in Molecular Biology 399: 251–264. https://doi.org/10.1007/978-1-59745-504-6_17
- Meister A, Anderson ME (1983) Glutathione. Annual Review of Biochemistry 52: 711–760. https://doi.org/10.1146/annurev.bi.52.070183.003431
- Migliore L, Coppedè F (2009) Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 674: 73–84. https://doi.org/10.1016/j.mrgentox.2008.09.013
- Niki E, Yoshida Y, Saito Y, Noguchi N (2005) Lipid peroxidation: mechanisms, inhibition, and biological effects. Biochemical and Biophysical Research Communications 338: 668–676. https://doi.org/10.1016/j.bbrc.2005.08.072
- Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. Journal of Neuroscience 19(6): 1959–1964. https://doi.org/10.1523/JNEUROSCI.19-06-01959.1999
- Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68: 1820–1825. https://doi.org/10.1212/01.wnl.0000262033.01945.9a
- Özcan A, Ogun M (2015) Biochemistry of reactive oxygen and nitrogen species. InTechOpen. https://doi.org/10.5772/61193
- Perry TL, Godin DV, Hansen S (1982) Parkinson's disease: a disorder due to nigral glutathione deficiency? Neuroscience Letters 33: 305–310. https://doi.org/10.1016/0304-3940(82)90390-1
- Pisoschi AM, Pop A (2015) The role of antioxidants in the chemistry of oxidative stress: a review. European Journal of Medicinal Chemistry 97: 55–74. https://doi.org/10.1016/j.ejmech.2015.04.040
- Reiter R, Rosales-Corral S, Tan D-X, Acuna-Castroviejo D, Qin L, Yang S-F, Xu K (2017) Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. International Journal of Molecular Sciences 18: 843. https://doi.org/10.3390/ijms18040843
- Rhodes SL, Buchanan DD, Ahmed I, Taylor KD, Loriot M-A, Sinsheimer JS, Bronstein JM, Elbaz A, Mellick GD, Rotter JI, Ritz B (2014) Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin. Neurobiology of Disease 62: 172–178. https://doi.org/10.1016/j.nbd.2013.09.019
- Rui Q, Ni H, Li D, Gao R, Chen G (2018) The role of LRRK2 in neurodegeneration of Parkinson disease. Current Neuropharmacology 16: 1348–1357. https://doi.org/10.2174/1570159X16666180222165418
- Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson's disease. Journal of Neurochemistry 54: 823–827. https://doi.org/10.1111/j.1471-4159.1990.tb02325.x
- Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase-dependent and AIF-mediated cell death. Cell Metabolism 8: 237–248. https://doi.org/10.1016/j.cmet.2008.07.005
- Shu Y, Su Q, Liao S, Lu T, Li R, Sun X, Qiu W, Yang Y, Hu X, Lu Z (2017) Low serum vitamin D levels and anti-N-methyl-D-aspartate receptor encephalitis: a case–control study. Neurochemistry International 102: 89–94. https://doi.org/10.1016/j.neuint.2016.11.002
- Shulman JM, De Jager PL, Feany MB (2011) Parkinson's disease: genetics and pathogenesis. Annual Review of Pathology: Mechanisms of Disease 6: 193–222. https://doi.org/10.1146/annurev-pathol-011110-130242
- Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Annals of Neurology 36: 348–355. https://doi.org/10.1002/ana.410360305
- Simola N, Morelli M, Carta AR (2007) The 6-hydroxydopamine model of Parkinson's disease. Neurotoxicity Research 11: 151–167. https://doi.org/10.1007/BF03033565
- Simon DK, Tanner CM, Brundin P (2020) Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clinics in Geriatric Medicine 36: 1–12. https://doi.org/10.1016/j.cger.2019.08.002
- Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R (2009) Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136: 964–977. https://doi.org/10.1016/j.cell.2009.02.013
- Stadtman ER, Levine RL (2000) Protein oxidation. Annals of the New York Academy of Sciences 899: 191–208. https://doi.org/10.1111/j.1749-6632.2000.tb06187.x
- Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171: 273–285. https://doi.org/10.1016/j.cell.2017.09.021
- Tatton NA, Maclean-Fraser A, Tatton WG, Perl DP, Warren CO (1998) A fluorescent double-labeling method to detect and confirm apoptotic nuclei in Parkinson's disease. Annals of Neurology 44(Suppl 1): S142–S148. https://pubmed.ncbi.nlm.nih.gov/9749586/
- Tysnes O-B, Storstein A (2017) Epidemiology of Parkinson's disease. Journal of Neural Transmission (Vienna) 124: 901–905. https://doi.org/10.1007/s00702-017-1686-y
- Valadas JS, Batalha VL, Ferreira DG, Gomes R, Coelho JE, Sebastião AM, Diógenes MJ, Lopes LV (2012) Neuroprotection afforded by adenosine A2A receptor blockade is modulated by corticotrophin-releasing factor (CRF) in glutamate-injured cortical neurons. Journal of Neurochemistry 123: 1030–1040. https://doi.org/10.1111/jnc.12050
- Warner TT, Schapira AHV (2003) Genetic and environmental factors in the cause of Parkinson's disease. Annals of Neurology 53(Suppl 3): S16–S23 [discussion S23–S25]. https://doi.org/10.1002/ana.10487
- Xicoy H, Wieringa B, Martens GJM (2017) The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Molecular Neurodegeneration 12: 10. https://doi.org/10.1186/s13024-017-0149-0
- Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America 93: 2696–2701. https://doi.org/10.1073/pnas.93.7.2696
- Zeng XS, Geng WS, Jia JJ, Chen L, Zhang PP (2006) MPTP/MPP+-induced oxidative stress and mitochondrial dysfunction in Parkinson's disease models. Neuroscience Bulletin 22(6): 376–384. https://doi.org/10.1007/s12264-006-0045-3
- Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, Montine TJ (1999) Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. American Journal of Pathology 154: 1423–1429. https://doi.org/10.1016/S0002-9440(10)65396-5
- Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, Faust R, Qian SY, Miller DS, Chignell CF, Wilson B, Jackson-Lewis V, Przedborski S, Joset D, Loike J, Hong J-S, Sulzer D, Zecca L (2011) Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson's disease. Neurotoxicity Research 19: 63–72. https://doi.org/10.1007/s12640-009-9140-z
- Zhang X, Yin Y, Zhang Y (2014) Characterization of the LUHMES human mesencephalic cell line as a dopaminergic neuronal model for Parkinson's disease research. Molecular Neurobiology 49(2): 744–754. https://doi.org/10.1007/s12035-013-8556-9
- Zhou C, Huang Y, Przedborski S (2008) Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance. Annals of the New York Academy of Sciences 1147: 93–104. https://doi.org/10.1196/annals.1427.023