Propofol's Neuroprotective Effect Against Cisplatin-Induced Oxidative Neurotoxicity Via Suppression of the TRPM2 Cation Channel

Year 2024, Volume: 9 Issue: 3, 254 - 262, 16.09.2024

Hacı Ömer Osmanlıoğlu

https://doi.org/10.26453/otjhs.1532340

Abstract

Objective: Cisplatin (CSP) exhibits strong oxidant and apoptotic effects in tumors, but it also causes adverse neurodegenerative effects by stimulating the TRPM2 cation channel. By regulating mitochondrial reactive free oxygen species (ROS) and excessive Ca2+ entry-mediated apoptosis, propofol (PRPF) exhibits antioxidant and neuroprotective properties. However, the action of the TRPM2 in these productions in human SH-SY5Y neuronal cells has not yet been determined. In SH-SY5Y, I investigated the protective effects of PRPF by modifying TRPM2, which affects CSP-induced neuronal mitochondrial function and death.
Materials and Methods: I generated five main groups in the SH-SY5Y as control, PRPF (200 mM for 24h), CSP (25 mM for 24h), CSP + PRPF, and CSP + TRPM2 channel antagonists (25 mM ACA and 100 mM 2APB).
Results: Through TRPM2 stimulation, the incubation with CSP increased the amounts of apoptosis, caspase -3, caspase -9, cell death percentage, ROS, mitochondrial hyperpolarization, TRPM2 current densities, and intracellular free Ca2+. However, the incubation of PRPF through the inhibition of TRPM2 decreased the amounts of these processes.
Conclusions: PRPF treatment via TRPM2 suppression decreased the levels of mitochondrial oxidative stress and neuronal death caused by CSP. One effective therapy option for CSP-induced mitochondrial oxidative neuronal damage is the PRPF.

Keywords

Cisplatin, neuronal injury, oxidative stress, propofol, TRPM2 channel

Ethical Statement

Competing Interests There are no competing interests. Ethical Approve There are no human and animal data available.

Supporting Institution

A company (BSN Health, Analyses, Innov., Consult., Org., Agricul., Trade Ltd., Isparta, Turkiye) provided financial support for this study (Project No: 2023-03). The project is owned by Dr. HÖ Osmanlıoğlu.

Project Number

2023-03

Thanks

Technician Muhammet Şahin (BSN Health, Analyses, Innov., Consult., Org., Agricul., Trade Ltd., Isparta, Turkiye) and technician Fatih Şahin are appreciated by the authors for their help with the LSM-800 laser confocal microscopy analyses, electophysiology, and plate reader.

Propofol’ün, TRPM2 Katyon Kanalını Bastırarak Sisplatin Kaynaklı Oksidatif Nörotoksisiteye Karşı Nöroprotektif Etkisi

Abstract

Amaç: Sisplatin (CPS), TRPM2 kanalını aktive ederek tümör hücrelerinde oksidan ve apoptotik etki meydana getirmesine rağmen bu etkilerin sinir hücrelerindeki yan etkilerinden dolayı CSP kullanımını sınırlandırmaktadır. Propofol (PRPF) mitokondriyal reaktif oksijen türleri (ROS) ve aşırı Ca+2 girişine bağlı apoptozisi düzenleyerek antioksidan ve nöroprotektif etki göstermektedir. Bununla birlikte, PRPF’un TRPM2 kanalını düzenleyerek antioksidan ve anti-apoptotik etki meydana getirebileceği insan SH-SY5Y sinir hücrelerinde henüz araştırılmamıştır. Bu çalışmanın amacı PRPF tedavisinin TRPM2 kanalını düzenleyerek sinir hücre ölüm ve mitokondriyal ROS üretimi üzerindeki etkilerinin SH-SY5Y hücrelerinde araştırılmasıdır.
Materyal ve Metot: SH-SY5Y hücrelerinde 5 ana grup oluşturulmuştur. Bu gruplar: Kontrol, PRPF (200 mM ve 24 saat), CSP (25 mM ve 24 saat), CSP + PRPF ve CSP + TRPM2 kanal blokörleri (25 mM ACA ve 100 mM 2APB).
Bulgular: CSP inkübasyonu, TRPM2 kanalını uyararak apoptosis, kaspaz -3, kaspaz -9, hücre ölümü yüzdesi, ROS, mitokondriyal hiperpolarizasyon, TRPM2 akım yoğunlukları ve hücre içi Ca+2 miktarı artırdı fakat hücre canlılığını azalttı. Bununla birlikte, PRPF, ACA ve 2APB tedavileri sonraları bu değerler normal değerlerine döndüler.
Sonuç: PRPF tedavisi TRPM2 kanalı inhibe ederek CSP neden olduğu mitokondriyal oksidan ve apoptotik etkileri azalttı. PRPF tedavisi, CSP neden olduğu mitokondriyal oksidatif stres ve sinir hücre harabiyetini önlemede potansiyel kaynak olarak gözükmektedir.

Keywords

Oksidatif stres, propofol, sinir hasarı, sisplatin, TRPM2 kanalı

Project Number

2023-03

References

• Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem. 1992; 59(5):1609-23. doi:10.1111/j.1471-4159.1992.tb10990.x
• Nazıroğlu M. New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res. 2007;32(11):1990-2001. doi:10.1007/s11064-007-9386-x
• Osmanlıoğlu HÖ, Yıldırım MK, Akyuva Y, Yıldızhan K, Nazıroğlu M. Morphine induces apoptosis, inflammation, and mitochondrial oxidative stress via activation of TRPM2 channel and nitric oxide signalling pathways in the hippocampus. Mol Neurobiol. 2020;57(8):3376-3389. doi:10.1007/s12035-020-01975-6
• Yıldızhan K, Nazıroğlu M. NMDA Receptor Activation Stimulates Hypoxia-Induced TRPM2 Channel Activation, Mitochondrial Oxidative Stress, and Apoptosis in Neuronal Cell Line: Modular Role of Memantine. Brain Res. 2023; 1803:148232. doi:10.1016/j.brainres.2023.148232 
• Nazıroğlu M, Lückhoff A. Effects of antioxidants on calcium influx through TRPM2 channels in transfected cells activated by hydrogen peroxide. J Neurol Sci. 2008;270(1-2):152-158. doi:10.1016/j.jns.2008.03.003
• Osmanlıoğlu HÖ, Nazıroğlu M. Resveratrol Modulates Diabetes-Induced Neuropathic Pain, Apoptosis, and Oxidative Neurotoxicity in Mice Through TRPV4 Channel Inhibition. Mol Neurobiol. 2024. doi:10.1007/s12035-024-04311-4
• Osmanlıoğlu HÖ. Ketamine attenuates hypoxia-induced cell death and oxidative toxicity via inhibition of the TRPM2 channel in neuronal cells. J Cell Neurosci Oxid Stress 2022;14(3):1095-1104. doi:10.37212/jcnos.1325007.
• Gonullu E, Dagistan G, Erkin Y, Erdogan MA, Erbas O. Demonstration of the protective effect of propofol in rat model of cisplatin-induced neuropathy. Bratisl Lek Listy. 2023;124(1):64-69. doi:10.4149/BLL_2023_010
• Krarup-Hansen A, Helweg-Larsen S, Schmalbruch H, Rørth M, Krarup C. Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain. 2007;130(Pt 4):1076-1088. doi:10.1093/brain/awl356
• Wang X, Zhou Y, Wang D, et al. Cisplatin-induced ototoxicity: From signaling network to therapeutic targets. Biomed Pharmacother. 2023;157:114045. doi:10.1016/j.biopha.2022.114045
• Ertilav K, Nazıroğlu M. Honey bee venom melittin increases the oxidant activity of cisplatin and kills human glioblastoma cells by stimulating the TRPM2 channel. Toxicon. 2023;222:106993. doi:10.1016/j.toxicon.2022.106993  
• He H, Ge J, Yi S, et al. Ginkgolide A downregulates transient receptor potential (melastatin) 2 to protect cisplatin-induced acute kidney injury in rats through the TWEAK/Fn14 pathway: Ginkgolide A improve acute renal injury. Hum Exp Toxicol. 2023;42:9603271231200868. doi:10.1177/09603271231200868.
• Yu B, Jin L, Yao X, et al. TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy. Theranostics. 2023;13(13):4356-4375. doi:10.7150/thno.84655
• Özkaya D, Nazıroğlu M. Curcumin diminishes cisplatin-induced apoptosis and mitochondrial oxidative stress through inhibition of TRPM2 channel signaling pathway in mouse optic nerve. J Recept Signal Transduct Res. 2020;40(2):97-108. doi:10.1080/10799893.2020.1720240
• Boisset S, Steghens JP, Favetta P, Terreux R, Guitton J. Relative antioxidant capacities of propofol and its main metabolites. Arch Toxicol. 2004;78(11):635-642. doi:10.1007/s00204-004-0585-9
• Zhang Y, Zuo Y, Li B, Xie J, Ma Z, Thirupathi A, et al. Propofol prevents oxidative stress and apoptosis by regulating iron homeostasis and targeting JAK/STAT3 signaling in SH-SY5Y cells. Brain Res Bull. 2019;153:191-201. doi:10.1016/j.brainresbull.2019.08.018
• Hama-Tomioka K, Kinoshita H, Nakahata K, et al. Roles of neuronal nitric oxide synthase, oxidative stress, and propofol in N-methyl-D-aspartate-induced dilatation of cerebral arterioles. Br J Anaesth. 2012;108(1):21-29. doi:10.1093/bja/aer368  
• Ghezzi F, Monni L, Corsini S, Rauti R, Nistri A. Propofol Protects Rat Hypoglossal Motoneurons in an In Vitro Model of Excitotoxicity by Boosting GABAergic Inhibition and Reducing Oxidative Stress. Neuroscience. 2017;367:15-33. doi:10.1016/j.neuroscience.2017.10.019
• Kozinn J, Mao L, Arora A, Yang L, Fibuch EE, Wang JQ. Inhibition of glutamatergic activation of extracellular signal-regulated protein kinases in hippocampal neurons by the intravenous anesthetic propofol. Anesthesiology. 2006;105(6):1182-91. doi:10.1097/00000542-200612000-00018
• Chen K, Yu J, Wang Q, Wu L, et al. The timing of propofol administration affects the effectiveness of remote ischemic preconditioning induced cardioprotection in rats. J Cell Biochem. 2020 Nov;121(11):4535-4541. doi:10.1002/jcb.29671
• Qi J, Wu Q, Zhu X, et al. Propofol attenuates the adhesion of tumor and endothelial cells through inhibiting glycolysis in human umbilical vein endothelial cells. Acta Biochim Biophys Sin (Shanghai). 2019;51(11):1114-1122. doi:10.1093/abbs/gmz105
• Ji W, Cui C, Zhang Z, Liang J. Paradoxic effects of propofol on visceral pain induced by various TRPV1 agonists. Exp Ther Med. 2013;5(4):1259-1263. doi:10.3892/etm.2013.950 
• Chen XH, Zhou X, Yang XY, et al. Propofol Protects Against H2O2-Induced Oxidative Injury in Differentiated PC12 Cells via Inhibition of Ca(2+)-Dependent NADPH Oxidase. Cell Mol Neurobiol. 2016;36(4):541-551. doi:10.1007/s10571-015-0235-1
• Vaglienti MV, Subirada PV, Barcelona PF, Bonacci G, Sanchez MC. Quantification of Reactive Oxygen Species Using 2',7'-Dichlorofluorescein Diacetate Probe and Flow-Cytometry in Müller Glial Cells. J Vis Exp. 2022;(183). doi:10.3791/63337
• Daldal H, Nazıroğlu M. Selenium and resveratrol attenuated diabetes mellitus-mediated oxidative retinopathy and apoptosis via the modulation of TRPM2 activity in mice. Biol Trace Elem Res. 2022;200(5):2283-2297. doi:10.1007/s12011-022-03203-9
• Han B, Liu Y, Zhang Q, Liang L. Propofol decreases cisplatin resistance of non-small cell lung cancer by inducing GPX4-mediated ferroptosis through the miR-744-5p/miR-615-3p axis. J Proteomics. 2023;274:104777. doi:10.1016/j.jprot.2022.104777
• Xu Z, Lu Y, Wang J, Ding X, Chen J, Miao C. The protective effect of propofol against TNF-α-induced apoptosis was mediated via inhibiting iNOS/NO production and maintaining intracellular Ca2+ homeostasis in mouse hippocampal HT22 cells. Biomed Pharmacother. 2017;91:664-672. doi:10.1016/j.biopha.2017.04.110
• Zhao L, Zhuang J, Wang Y, et al. Propofol Ameliorates H9c2 Cells Apoptosis Induced by Oxygen Glucose Deprivation and Reperfusion Injury via Inhibiting High Levels of Mitochondrial Fusion and Fission. Front Pharmacol. 2019;10:61. doi:10.3389/fphar.2019.00061
• Zhang Q, Cai S, Guo L, Zhao G. Propofol induces mitochondrial-associated protein LRPPRC and protects mitochondria against hypoxia in cardiac cells. PLoS One. 2020;15(9):e0238857. doi:10.1371/journal.pone.0238857
• Xiao W, Chen S, Chen J, Huang J. Dexmedetomidine alleviates propofol-induced neural injury in developing rats. Int J Dev Neurosci. 2023;83(7):631-640. doi:10.1002/jdn.10291