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DOI: 10.1055/a-1158-9248
Sulforaphane and Vitamin E Protect From Glucotoxic Neurodegeneration and Lifespan Reduction In C. Elegans

Abstract
Caenorhabditis elegans is an established model organism in neurodegeneration and aging research. Oxidative stress and formation of advanced glycation endproducts (AGEs), as they occur under hyperglycemic conditions in diabetes mellitus, contribute to neuronal damage and lifespan reduction. Sulforaphane (SFN) is an indirect antioxidant, alpha-tocopherol (vitamin E) is a direct antioxidant that acts as a free radical scavenger. Aim of this study is to investigate the protective effects of SFN and vitamin E against glucotoxic damages to the neuronal system and lifespan in C. elegans. Culture conditions that mimic clinical hyperglycemia increased the formation of reactive oxygen species (ROS) (p<0.001) and the accumulation of methylglyoxal-derived advanced glycation endproducts (MG-derived AGEs) (p<0.01) with subsequent neuronal damage and neuronal dysfunction, ultimately leading to a significant shortening of lifespan (p<0.01). Treatment with both, 20 µmol/l SFN and 200 µg/ml vitamin E, completely prevented the increase in ROS and MG-derived AGEs, abolished the glucotoxic effects on neuronal structure and function, and preserved lifespan, resulting in a life expectancy similar to untreated controls. These data emphasize the relevance of indirect and direct antioxidants as potential therapeutic options for the prevention of glucotoxic pathologies.
Publication History
Received: 04 December 2019
Received: 31 March 2020
Accepted: 15 April 2020
Article published online:
05 June 2020
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References
- 1 Lee SJ, Murphy CT, Kenyon C. Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 2009; 10: 379-391.
- 2 Mendler M, Schlotterer A, Morcos M. et al. Understanding diabetic polyneuropathy and longevity: What can we learn from the nematode Caenorhabditis elegans?. Exp Clin Endocrinol Diabetes 2012; 120: 182-183.
- 3 Schlotterer A, Kukudov G, Bozorgmehr F. et al. C. elegans as model for the study of high glucose- mediated life span reduction. Diabetes 2009; 58: 2450-2456.
- 4 Schulz TJ, Zarse K, Voigt A. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 2007; 6: 280-293.
- 5 Alexander AG, Marfil V, Li C. Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Front Genet 2014; 5: 279.
- 6 Wolkow CA, Kimura KD, Lee MS. et al. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 2000; 290: 147-150
- 7 Morcos M, Du X, Pfisterer F. et al. Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans. Aging Cell 2008; 7: 260-269
- 8 Thornalley PJ. Glyoxalase I--structure, function and a critical role in the enzymatic defence against glycation. Biochem Soc Trans 2003; 31: 1343-1348
- 9 Bierhaus A, Fleming T, Stoyanov S. et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 2012; 18: 926-933.
- 10 Fleming T, Cuny J, Nawroth G. et al. Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates?. Diabetologia 2012; 55: 1151-1155.
- 11 Fleming TH, Humpert PM, Nawroth PP. et al. Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: A mini-review. Gerontology 2011; 57: 435-443.
- 12 Schlotterer A, Hamann A, Kukudov G. et al. Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans. Aging Cell 2010; 9: 420-432.
- 13 Vander Jagt DL. Methylglyoxal, diabetes mellitus and diabetic complications. Drug Metabol Drug Interact 2008; 23: 93-124.
- 14 Rose P, Huang Q, Ong CN. et al. Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol 2005; 209: 105-113.
- 15 Briones-Herrera A, Eugenio-Perez D, Reyes-Ocampo JG. et al. New highlights on the health-improving effects of sulforaphane. Food Funct 2018; 9: 2589-2606.
- 16 Negi G, Kumar A, Sharma SS. Nrf2 and NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 2011; 8: 294-304.
- 17 Cui W, Bai Y, Miao X. et al. Prevention of diabetic nephropathy by sulforaphane: possible role of Nrf2 upregulation and activation. Oxid Med Cell Longev 2012; 2012: 821936
- 18 Kubo E, Chhunchha B, Singh P. et al. Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress. Sci Rep 2017; 7: 14130
- 19 Tullet JMA, Green JW, Au C. et al. The SKN-1/Nrf2 transcription factor can protect against oxidative stress and increase lifespan in C. elegans by distinct mechanisms. Aging Cell 2017; 16: 1191-1194
- 20 Thakkar N. Sulforaphane Improves Oxidative Stress Response in Caenorhabditis elegans via SKN-1. International Science and Engineering Fair. 2019 Phoenix, AZ, USA
- 21 Harrington LA, Harley CB. Effect of vitamin E on lifespan and reproduction in Caenorhabditis elegans. Mech Ageing Dev 1988; 43: 71-78
- 22 Kamal-Eldin A, Appelqvist LA. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 1996; 31: 671-701.
- 23 Porta EA, Joun NS, Nitta RT. Effects of the type of dietary fat at two levels of vitamin E in Wistar male rats during development and aging. I. Life span, serum biochemical parameters and pathological changes. Mech Ageing Dev 1980; 13: 1-39
- 24 Driver C, Georgeou A. Variable effects of vitamin E on Drosophila longevity. Biogerontology 2003; 4: 91-95.
- 25 Rajanandh MG, Kosey S, Prathiksha G. Assessment of antioxidant supplementation on the neuropathic pain score and quality of life in diabetic neuropathy patients – a randomized controlled study. Pharmacol Rep 2014; 66: 44-48.
- 26 Altun-Gultekin Z, Andachi Y, Tsalik EL. et al. A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans. Development 2001; 128: 1951-1969
- 27 Kohl K, Fleming T, Acunman K. et al. Plate-based Large-scale Cultivation of Caenorhabditis elegans: Sample Preparation for the Study of Metabolic Alterations in Diabetes. J Vis Exp. 2018
- 28 Liu P, Wang W, Tang J. et al. Antioxidant effects of sulforaphane in human HepG2 cells and immortalised hepatocytes. Food Chem Toxicol 2019; 128: 129-136.
- 29 Li Y, Li Y, Wu Q. et al. High concentration of vitamin E decreases thermosensation and thermotaxis learning and the underlying mechanisms in the nematode Caenorhabditis elegans. PLoS One 2013; 8: e71180.
- 30 Schlotterer A, Greten HJ, Remppis BA. et al. Neuroprotection and antioxidative effects of Sijunzi Tang Decoction in the nematode Caenorhabditis elegans. Eur J Integr Med 2016; 8: 526-532.
- 31 Abramoff MD, Magelhaes PJ, Ram SJ. Image Processing with ImageJ. Biophotonics Int 2004; 11: 36-42
- 32 Schlotterer A, Pfisterer F, Kukudov G. et al. Neuronal damage and shortening of lifespan in C. elegans by peritoneal dialysis fluid: Protection by glyoxalase-1. Biomed Rep 2018; 8: 540-546.
- 33 Wongchai K, Schlotterer A, Lin J. et al. Protective effects of liraglutide and linagliptin in C. elegans as a new model for glucose-induced neurodegeneration. Horm Metab Res 2016; 48: 70-75.
- 34 Brownlee M. The pathological implications of protein glycation. Clin Invest Med 1995; 18: 275-281
- 35 Nowotny K, Jung T, Hohn A. et al. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5: 194-222.
- 36 Yoon HY, Kang NI, Lee HK. et al. Sulforaphane protects kidneys against ischemia-reperfusion injury through induction of the Nrf2-dependent phase 2 enzyme. Biochem Pharmacol 2008; 75: 2214-2223
- 37 Klomparens EA, Ding Y. The neuroprotective mechanisms and effects of sulforaphane. Brain Circ 2019; 5: 74-83
- 38 Galli F, Azzi A, Birringer M. et al. Vitamin E: Emerging aspects and new directions. Free Radic Biol Med 2017; 102: 16-36
- 39 Mendler M, Riedinger C, Schlotterer A. et al. Reduction in ins-7 gene expression in non-neuronal cells of high glucose exposed Caenorhabditis elegans protects from reactive metabolites, preserves neuronal structure and head motility, and prolongs lifespan. J Diabetes Complications 2017; 31: 304-310.
- 40 Lavigne JP, Audibert S, Molinari N. et al. Influence of a high-glucose diet on the sensitivity of Caenorhabditis elegans towards Escherichia coli and Staphylococcus aureus strains. Microbes Infect 2013; 15: 540-549
- 41 Mendler M, Schlotterer A, Ibrahim Y. et al. daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans. Diabetologia 2015; 58: 393-401.
- 42 Riedinger C, Mendler M, Schlotterer A. et al. High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans. J Biol Chem 2018; 293: 4845-4859
- 43 Garcia AM, Ladage ML, Dumesnil DR. et al. Glucose induces sensitivity to oxygen deprivation and modulates insulin/IGF-1 signaling and lipid biosynthesis in Caenorhabditis elegans. Genetics 2015; 200: 167-184
- 44 Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med 2011; 51: 327-336
- 45 Yang W, Hekimi S. A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 2010; 8: e1000556
- 46 Owusu-Ansah E, Song W, Perrimon N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 2013; 155: 699-712
- 47 Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders - A step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 1066-1077.