The protective effect of N-acetylcysteine on hippocampal ferroptosis in an experimental obesity model

Year 2023, Volume: 15 Issue: 2, 1137 - 1146, 29.09.2023

Kiymet Kubra Tüfekci , Musa Tatar

https://doi.org/10.37212/jcnos.1358141

Abstract

Ferroptosis is a non-apoptotic cell death closely related to a metabolic pathway involving iron overload, imbalanced glutathione metabolism, oxidative stress and lipid peroxidation damage. Obesity is closely associated with these imbalances. In this study, we aimed to investigate the effect of hippocampal ferroptosis in an obesity model and the potential role of N-acetylcysteine (NAC) against ferroptosis. A high-fat (60%) dietary pattern was used to establish an obesity model for 15 weeks. NAC was administered to NAC and Obese+NAC (ObNAC) groups by oral gavage at a dose of 150 mg/kg for 3 weeks. Glutathione peroxidase 4 (GPX4) and the cystine transporter solute carrier family 7- member 11 (SLC7A11) expression levels were investigated immunohistochemically to detect ferroptosis in hippocampal tissues. In the statistical analysis, H-scores of GPX4 and SLC7A11 in the hippocampus sections of the Ob group were significantly lower than in the control, NAC and ObNAC groups (p<0.01). On the other hand, NAC treatment significantly attenuated hippocampal ferroptosis by maintaining both GPX4 and SLC7A11 expression levels in the ObNAC group. These findings imply that ferroptosis may be essential in the hippocampus, an area of the brain critical for memory, learning, and emotional reactions in obese individuals. In addition, NAC, a promoter of GSH biosynthesis, may attenuate hippocampal ferroptosis in obesity by inhibiting the downregulation of GPX4 and SLC7A11 expression signaling.

Keywords

ferroptosis, GPX4, hippocampus, brain

References

• Alim I, Caulfield JT, Chen Y, Swarup V, Geschwind DH, Ivanova E, Seravalli J, Ai Y, Sansing LH, Ste Marie EJ, Hondal RJ, Mukherjee S, Cave JW, Sagdullaev BT, Karuppagounder SS, Ratan RR. (2019). Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell. 177(5):1262-1279 e1225. https://doi.org/10.1016/j.cell.2019.03.032.
• Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. (2002). The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci. 22(20):9134-9141. https://doi.org/10.1523/JNEUROSCI.22-20-09134.2002.
• Chen J, Wang Y, Wu J, Yang J, Li M, Chen Q. (2020). The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease. Front Mol Neurosci. 13110. https://doi.org/10.3389/fnmol.2020.00110.
• Chen L, Hambright WS, Na R, Ran Q. (2015). Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis. J Biol Chem. 290(47):28097-28106. https://doi.org/10.1074/jbc.M115.680090. Chen X, Li J, Kang R, Klionsky DJ, Tang D. (2021). Ferroptosis: machinery and regulation. Autophagy. 17(9):2054-2081. https://doi.org/10.1080/15548627.2020.1810918.
• Cobley JN, Fiorello ML, Bailey DM. (2018). 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 15490-503. https://doi.org/10.1016/j.redox.2018.01.008.
• Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, 3rd, Stockwell BR. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 149(5):1060-1072. https://doi.org/10.1016/j.cell.2012.03.042.
• Dludla PV, Mazibuko-Mbeje SE, Nyambuya TM, Mxinwa V, Tiano L, Marcheggiani F, Cirilli I, Louw J, Nkambule BB. (2019). The beneficial effects of N-acetyl cysteine (NAC) against obesity associated complications: A systematic review of pre-clinical studies. Pharmacol Res. 146104332. https://doi.org/10.1016/j.phrs.2019.104332.
• Fang J, Yuan Q, Du Z, Zhang Q, Yang L, Wang M, Yang W, Yuan C, Yu J, Wu G, Hu J. (2023). Overexpression of GPX4 attenuates cognitive dysfunction through inhibiting hippocampus ferroptosis and neuroinflammation after traumatic brain injury. Free Radic Biol Med. 20468-81. https://doi.org/10.1016/j.freeradbiomed.2023.04.014.
• Geng Z, Guo Z, Guo R, Ye R, Zhu W, Yan B. (2021). Ferroptosis and traumatic brain injury. Brain Res Bull. 172212-219. https://doi.org/10.1016/j.brainresbull.2021.04.023.
• Gong Y, Wang N, Liu N, Dong H. (2019). Lipid Peroxidation and GPX4 Inhibition Are Common Causes for Myofibroblast Differentiation and Ferroptosis. DNA Cell Biol. 38(7):725-733. https://doi.org/10.1089/dna.2018.4541.
• Gonzalez-Dominguez A, Visiedo-Garcia FM, Dominguez-Riscart J, Gonzalez-Dominguez R, Mateos RM, Lechuga-Sancho AM. (2020). Iron Metabolism in Obesity and Metabolic Syndrome. Int J Mol Sci. 21(15). https://doi.org/10.3390/ijms21155529.
• Gout PW, Buckley AR, Simms CR, Bruchovsky N. (2001). Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia. 15(10):1633-1640. https://doi.org/10.1038/sj.leu.2402238.
• Guan X, Li X, Yang X, Yan J, Shi P, Ba L, Cao Y, Wang P. (2019). The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. Life Sci. 235116795. https://doi.org/10.1016/j.lfs.2019.116795.
• Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. (2017). Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 128-17. https://doi.org/10.1016/j.redox.2017.01.021.
• Hart AM, Terenghi G, Kellerth JO, Wiberg M. (2004). Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury. Neuroscience. 125(1):91-101. https://doi.org/10.1016/j.neuroscience.2003.12.040.
• He LP, Zhou ZX, Li CP. (2023). Narrative review of ferroptosis in obesity. J Cell Mol Med. 27(7):920-926. https://doi.org/10.1111/jcmm.17701.
• Karuppagounder SS, Alin L, Chen Y, Brand D, Bourassa MW, Dietrich K, Wilkinson CM, Nadeau CA, Kumar A, Perry S, Pinto JT, Darley-Usmar V, Sanchez S, Milne GL, Pratico D, Holman TR, Carmichael ST, Coppola G, Colbourne F, Ratan RR. (2018). N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E(2) to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice. Ann Neurol. 84(6):854-872. https://doi.org/10.1002/ana.25356.
• Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G. (2020). Ferroptosis: past, present and future. Cell Death Dis. 11(2):88. https://doi.org/10.1038/s41419-020-2298-2.
• Li J, Jia B, Cheng Y, Song Y, Li Q, Luo C. (2022a). Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders. Oxid Med Cell Longev. 20223999083. https://doi.org/10.1155/2022/3999083.
• Li J, Kang R, Tang D. (2021). Monitoring autophagy-dependent ferroptosis. Methods Cell Biol. 165163-176. https://doi.org/10.1016/bs.mcb.2020.10.012.
• Li Q, Liao J, Chen W, Zhang K, Li H, Ma F, Zhang H, Han Q, Guo J, Li Y, Hu L, Pan J, Tang Z. (2022b). NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway. Free Radic Biol Med. 187158-170. https://doi.org/10.1016/j.freeradbiomed.2022.05.024.
• Liu T, Jiang L, Tavana O, Gu W. (2019). The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11. Cancer Res. 79(8):1913-1924. https://doi.org/10.1158/0008-5472.CAN-18-3037.
• Numata M, Morinaga S, Watanabe T, Tamagawa H, Yamamoto N, Shiozawa M, Nakamura Y, Kameda Y, Okawa S, Rino Y, Akaike M, Masuda M, Miyagi Y. (2013). The clinical significance of SWI/SNF complex in pancreatic cancer. Int J Oncol. 42(2):403-410. https://doi.org/10.3892/ijo.2012.1723.
• Park HR, Park M, Choi J, Park KY, Chung HY, Lee J. (2010). A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 482(3):235-239. https://doi.org/10.1016/j.neulet.2010.07.046.
• Rui T, Wang H, Li Q, Cheng Y, Gao Y, Fang X, Ma X, Chen G, Gao C, Gu Z, Song S, Zhang J, Wang C, Wang Z, Wang T, Zhang M, Min J, Chen X, Tao L, Wang F, Luo C. (2021). Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis. J Pineal Res. 70(2):e12704. https://doi.org/10.1111/jpi.12704.
• Schriever SC, Zimprich A, Pfuhlmann K, Baumann P, Giesert F, Klaus V, Kabra DG, Hafen U, Romanov A, Tschop MH, Wurst W, Conrad M, Holter SM, Vogt Weisenhorn D, Pfluger PT. (2017). Alterations in neuronal control of body weight and anxiety behavior by glutathione peroxidase 4 deficiency. Neuroscience. 357241-254. https://doi.org/10.1016/j.neuroscience.2017.05.050.
• Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, Xu S, Gao Y, Chen X, Sui X, Li G. (2020). The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 127110108. https://doi.org/10.1016/j.biopha.2020.110108.
• Tatar M, Tufekci KK, Uslu S, Oner J. (2023). Expression of ADAMTS 1-4-8 and placental growth factor in ovary and oviduct during pregnancy in the first trimester. Anat Histol Embryol. 52(4):619-626. https://doi.org/10.1111/ahe.12922.
• Thilaganathan B. (2017). Placental syndromes: getting to the heart of the matter. Ultrasound Obstet Gynecol. 49(1):7-9. https://doi.org/10.1002/uog.17378.
• Tozuka Y, Wada E, Wada K. (2009). Diet-induced obesity in female mice leads to peroxidized lipid accumulations and impairment of hippocampal neurogenesis during the early life of their offspring. FASEB J. 23(6):1920-1934. https://doi.org/10.1096/fj.08-124784.
• Tufekci KK, Bakirhan EG, Terzi F. (2023). A Maternal High-Fat Diet Causes Anxiety-Related Behaviors by Altering Neuropeptide Y1 Receptor and Hippocampal Volumes in Rat Offspring: the Potential Effect of N-Acetylcysteine. Mol Neurobiol. 60(3):1499-1514. https://doi.org/10.1007/s12035-022-03158-x.
• Wang X, Wang Z, Cao J, Dong Y, Chen Y. (2021). Ferroptosis Mechanisms Involved in Hippocampal-Related Diseases. Int J Mol Sci. 22(18). https://doi.org/10.3390/ijms22189902.
• Wu C, Zhao W, Yu J, Li S, Lin L, Chen X. (2018). Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells. Sci Rep. 8(1):574. https://doi.org/10.1038/s41598-017-18935-1.
• Xu S, He Y, Lin L, Chen P, Chen M, Zhang S. (2021). The emerging role of ferroptosis in intestinal disease. Cell Death Dis. 12(4):289. https://doi.org/10.1038/s41419-021-03559-1.
• Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell. 156(1-2):317-331. https://doi.org/10.1016/j.cell.2013.12.010.
• Yao X, Zhang Y, Hao J, Duan HQ, Zhao CX, Sun C, Li B, Fan BY, Wang X, Li WX, Fu XH, Hu Y, Liu C, Kong XH, Feng SQ. (2019). Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res. 14(3):532-541. https://doi.org/10.4103/1673-5374.245480.
• Yu Y, Yan Y, Niu F, Wang Y, Chen X, Su G, Liu Y, Zhao X, Qian L, Liu P, Xiong Y. (2021). Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov. 7(1):193. https://doi.org/10.1038/s41420-021-00579-w.
• Zhang S, Sun Z, Jiang X, Lu Z, Ding L, Li C, Tian X, Wang Q. (2022). Ferroptosis increases obesity: Crosstalk between adipocytes and the neuroimmune system. Front Immunol. 131049936. https://doi.org/10.3389/fimmu.2022.1049936.
• Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. (2020). Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 6689-100. https://doi.org/10.1016/j.semcancer.2019.03.002.