Abstract
Methylglyoxal (MG) is formed during normal metabolism by processes like glycolysis, lipid peroxidation, and threonine catabolism, and its accumulation is associated with various degenerative diseases, such as diabetes and arterial atherogenesis. Furthermore, MG has also been reported to have toxic effects on hippocampal neurons. However, these effects have not been studied in the context of neurogenesis. Here, we report that MG adversely affects hippocampal neurogenesis and induces neural progenitor cell (NPC) death. MG significantly reduced C17.2 NPC proliferation, and high concentration of MG (500 μM) induced cell death and elevated oxidative stress. Further, MG was found to activate the ERK signaling pathway, indicating elevated stress response. To determine the effects of MG in vivo, mice were administrated with vehicle or MG (0.5 or 1 % in drinking water) for 4 weeks. The numbers of BrdU-positive cells in hippocampi were significantly lower in MG-treated mice, indicating impaired neurogenesis, but MG did not induce neuronal damage or glial activations. Interestingly, MG reduced memory retention when administered to mice at 1 % but not at 0.5 %. In addition, the levels of hippocampal BDNF and synaptophysin were significantly lower in the hippocampi of mice treated with MG at 1 %. Collectively, our findings suggest MG could be harmful to NPCs and to hippocampal neurogenesis.
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Abbreviations
- BDNF:
-
Brain-derived neurotropic factor
- BrdU:
-
5-Bromo-2′-deoxyuridine
- DG:
-
Dentate gyrus
- GCL:
-
Granular cell layer
- MG:
-
Methylglyoxal
- NPCs:
-
Neural progenitor cells
References
Adlard PA, Perreau VM, Cotman CW (2005) The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol Aging 26:511–520. doi:10.1016/j.neurobiolaging.2004.05.006
Allaman I, Belanger M, Magistretti PJ (2015) Methylglyoxal, the dark side of glycolysis. Front Neurosci 9:23. doi:10.3389/fnins.2015.00023
Ankrah NA, Appiah-Opong R (1999) Toxicity of low levels of methylglyoxal: depletion of blood glutathione and adverse effect on glucose tolerance in mice. Toxicol Lett 109:61–67
Cameron HA, McKay RD (1999) Restoring production of hippocampal neurons in old age. Nat Neurosci 2:894–897. doi:10.1038/13197
Chang WC, Wu SC, Xu KD, Liao BC, Wu JF, Cheng AS (2015) Scopoletin protects against methylglyoxal-induced hyperglycemia and insulin resistance mediated by suppression of advanced glycation endproducts (AGEs) generation and anti-glycation. Molecules 20:2786–2801. doi:10.3390/molecules20022786
Chen YJ, Huang XB, Li ZX, Yin LL, Chen WQ, Li L (2010) Tenuigenin protects cultured hippocampal neurons against methylglyoxal-induced neurotoxicity. Eur J Pharmacol 645:1–8. doi:10.1016/j.ejphar.2010.06.034
Choi BR, Cho WH, Kim J, Lee HJ, Chung C, Jeon WK, Han JS (2014) Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer’s disease. Exp Mol Med 46:e75. doi:10.1038/emm.2013.147
Christie BR, Cameron HA (2006) Neurogenesis in the adult hippocampus Hippocampus 16:199–207. doi:10.1002/hipo.20151
Creed JA, DiLeonardi AM, Fox DP, Tessler AR, Raghupathi R (2011) Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. J Neurotrauma 28:547–563. doi:10.1089/neu.2010.1729
Crews L et al (2008) Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci 28:4250–4260. doi:10.1523/JNEUROSCI.0066-08.2008
de Arriba SG, Stuchbury G, Yarin J, Burnell J, Loske C, Munch G (2007) Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells—protection by carbonyl scavengers. Neurobiol Aging 28:1044–1050. doi:10.1016/j.neurobiolaging.2006.05.007
Di Loreto S, Caracciolo V, Colafarina S, Sebastiani P, Gasbarri A, Amicarelli F (2004) Methylglyoxal induces oxidative stress-dependent cell injury and up-regulation of interleukin-1beta and nerve growth factor in cultured hippocampal neuronal cells. Brain Res 1006:157–167. doi:10.1016/j.brainres.2004.01.066
Di Loreto S, Zimmitti V, Sebastiani P, Cervelli C, Falone S, Amicarelli F (2008) Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons. Int J Biochem Cell Biol 40:245–257. doi:10.1016/j.biocel.2007.07.019
Duman RS, Malberg J, Nakagawa S (2001) Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 299:401–407
Engstrom A, Wang H, Xia Z (2015) Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases. Toxicol In Vitro 29:1146–1155. doi:10.1016/j.tiv.2015.05.001
Epp JR, Chow C, Galea LA (2013) Hippocampus-dependent learning influences hippocampal neurogenesis. Front Neurosci 7:57. doi:10.3389/fnins.2013.00057
Figarola JL, Singhal J, Rahbar S, Awasthi S, Singhal SS (2014) LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells. Apoptosis 19:776–788. doi:10.1007/s10495-014-0974-3
Fujioka K, Shibamoto T (2004) Formation of genotoxic dicarbonyl compounds in dietary oils upon oxidation. Lipids 39:481–486
Golej J, Hoeger H, Radner W, Unfried G, Lubec G (1998) Oral administration of methylglyoxal leads to kidney collagen accumulation in the mouse. Life Sci 63:801–807
Gomes da Silva S et al (2012) Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats. Hippocampus 22:347–358. doi:10.1002/hipo.20903
Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 95:3168–3171
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999a) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260–265. doi:10.1038/6365
Gould E, Tanapat P, Hastings NB, Shors TJ (1999b) Neurogenesis in adulthood: a possible role in learning. Trends Cogn Sci 3:186–192
Heimfarth L, Loureiro SO, Pierozan P, de Lima BO, Reis KP, Torres EB, Pessoa-Pureur R (2013) Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases. Metab Brain Dis 28:429–438. doi:10.1007/s11011-013-9379-1
Huang SM, Chuang HC, Wu CH, Yen GC (2008) Cytoprotective effects of phenolic acids on methylglyoxal-induced apoptosis in Neuro-2A cells. Mol Nutr Food Res 52:940–949. doi:10.1002/mnfr.200700360
Huang X, Wang F, Chen W, Chen Y, Wang N, von Maltzan K (2012) Possible link between the cognitive dysfunction associated with diabetes mellitus and the neurotoxicity of methylglyoxal. Brain Res 1469:82–91. doi:10.1016/j.brainres.2012.06.011
Jie P et al (2015) Activation of transient receptor potential vanilloid 4 induces apoptosis in hippocampus through downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways. Cell Death Dis 6:e1775. doi:10.1038/cddis.2015.146
Kikuchi S, Shinpo K, Moriwaka F, Makita Z, Miyata T, Tashiro K (1999) Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases. J Neurosci Res 57:280–289. doi:10.1002/(SICI)1097-4547(19990715)57:2<280:AID-JNR14>3.0.CO;2-U
Kim SJ et al (2008) Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem 283:14497–14505. doi:10.1074/jbc.M708373200
Kohl Z et al (2012) Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model. Eur J Neurosci 35:10–19. doi:10.1111/j.1460-9568.2011.07933.x
Kong KH et al (2010) Capsaicin impairs proliferation of neural progenitor cells and hippocampal neurogenesis in young mice. J Toxicol Environ Health A 73:1490–1501. doi:10.1080/15287394.2010.511572
Kuhla B, Luth HJ, Haferburg D, Boeck K, Arendt T, Munch G (2005) Methylglyoxal, glyoxal, and their detoxification in Alzheimer’s disease. Ann N Y Acad Sci 1043:211–216. doi:10.1196/annals.1333.026
Kuhla B, Boeck K, Schmidt A, Ogunlade V, Arendt T, Munch G, Luth HJ (2007) Age- and stage-dependent glyoxalase I expression and its activity in normal and Alzheimer’s disease brains. Neurobiol Aging 28:29–41. doi:10.1016/j.neurobiolaging.2005.11.007
Learish RD, Bruss MD, Haak-Frendscho M (2000) Inhibition of mitogen-activated protein kinase kinase blocks proliferation of neural progenitor cells. Brain Res Dev Brain Res 122:97–109
Lee J, Duan W, Mattson MP (2002a) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375
Lee J, Seroogy KB, Mattson MP (2002b) Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J Neurochem 80:539–547
Li XH et al (2012) Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation. Neuromol Med 14:338–348. doi:10.1007/s12017-012-8191-0
Lu Y, Christian K, Lu B (2008) BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 89:312–323. doi:10.1016/j.nlm.2007.08.018
Ma T, Gong K, Yan Y, Zhang L, Tang P, Zhang X, Gong Y (2013) Huperzine A promotes hippocampal neurogenesis in vitro and in vivo. Brain Res 1506:35–43. doi:10.1016/j.brainres.2013.02.026
Mirochnic S, Wolf S, Staufenbiel M, Kempermann G (2009) Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease. Hippocampus 19:1008–1018. doi:10.1002/hipo.20560
Mu Y, Gage FH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6:85. doi:10.1186/1750-1326-6-85
Murray PS, Holmes PV (2011) An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus. Int J Pept 2011:654085. doi:10.1155/2011/654085
Nakayama K, Nakayama M, Terawaki H, Murata Y, Sato T, Kohno M, Ito S (2009) Carbonated soft drinks and carbonyl stress burden. J Toxicol Sci 34:699–702
Ogawa S et al (2010) Methylglyoxal is a predictor in type 2 diabetic patients of intima-media thickening and elevation of blood pressure. Hypertension 56:471–476. doi:10.1161/HYPERTENSIONAHA.110.156786
Oh SB, Park HR, Jang YJ, Choi SY, Son TG, Lee J (2013) Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by gamma-ray radiation. Br J Pharmacol 168:421–431. doi:10.1111/j.1476-5381.2012.02142.x
Park HR, Kong KH, Yu BP, Mattson MP, Lee J (2012) Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis. J Biol Chem 287:42588–42600. doi:10.1074/jbc.M112.406413
Rabbani N, Godfrey L, Xue M, Shaheen F, Geoffrion M, Milne R, Thornalley PJ (2011) Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes. Diabetes 60:1973–1980. doi:10.2337/db11-0085
Schmitt U, Tanimoto N, Seeliger M, Schaeffel F, Leube RE (2009) Detection of behavioral alterations and learning deficits in mice lacking synaptophysin. Neuroscience 162:234–243. doi:10.1016/j.neuroscience.2009.04.046
Seo K, Ki SH, Shin SM (2014) Methylglyoxal induces mitochondrial dysfunction and cell death in liver. Toxicol Res 30:193–198. doi:10.5487/TR.2014.30.3.193
Simpson JM, Gil-Mohapel J, Pouladi MA, Ghilan M, Xie Y, Hayden MR, Christie BR (2011) Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease. Neurobiol Dis 41:249–260. doi:10.1016/j.nbd.2010.09.012
Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68:33–51
Son S, Kim KT, Cho DC, Kim HJ, Sung JK, Bae JS (2014) Curcumin stimulates proliferation of spinal cord neural progenitor cells via a mitogen-activated protein kinase signaling pathway. J Korean Neurosurg Soc 56:1–4. doi:10.3340/jkns.2014.56.1.1
Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Munch G (2011) Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol Aging 32:763–777. doi:10.1016/j.neurobiolaging.2009.04.016
Tan D, Wang Y, Lo CY, Ho CT (2008a) Methylglyoxal: its presence and potential scavengers. Asia Pac J Clin Nutr 17 Suppl 1:261–264
Tan D, Wang Y, Lo CY, Sang S, Ho CT (2008b) Methylglyoxal: its presence in beverages and potential scavengers. Ann N Y Acad Sci 1126:72–75. doi:10.1196/annals.1433.027
Tsao HK, Chiu PH, Sun SH (2013) PKC-dependent ERK phosphorylation is essential for P2X7 receptor-mediated neuronal differentiation of neural progenitor cells. Cell Death Dis 4:e751. doi:10.1038/cddis.2013.274
Vadodaria KC, Brakebusch C, Suter U, Jessberger S (2013) Stage-specific functions of the small Rho GTPases Cdc42 and Rac1 for adult hippocampal neurogenesis. J Neurosci 33:1179–1189. doi:10.1523/JNEUROSCI.2103-12.2013
Vlassara H, Palace MR (2002) Diabetes and advanced glycation endproducts. J Intern Med 251:87–101
Wang J, Chang T (2010) Methylglyoxal content in drinking coffee as a cytotoxic factor. J Food Sci 75:H167–H171. doi:10.1111/j.1750-3841.2010.01658.x
Watanabe K et al (2014) Methylglyoxal (MG) and cerebro-renal interaction: does long-term orally administered MG cause cognitive impairment in normal Sprague-Dawley rats? Toxins (Basel) 6:254–269. doi:10.3390/toxins6010254
Wu CW et al (2008) Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J Appl Physiol 105:1585–1594. doi:10.1152/japplphysiol.90775.2008
Xie B, Lin F, Peng L, Ullah K, Wu H, Qing H, Deng Y (2014) Methylglyoxal increases dopamine level and leads to oxidative stress in SH-SY5Y cells. Acta Biochim Biophys Sin 46:950–956. doi:10.1093/abbs/gmu094
Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660. doi:10.1016/j.cell.2008.01.033
Zhou WJ, Gui QF, Wu Y, Yang YM (2015) Tanshinone IIA protects against methylglyoxal-induced injury in human brain microvascular endothelial cells Int J. Clin Exp Med 8:1985–1992
Acknowledgments
This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP) (Grant Nos. 2009-0083538 and NRF-2013R1A2A2A01067388).
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Chun, H.J., Lee, Y., Kim, A.H. et al. Methylglyoxal Causes Cell Death in Neural Progenitor Cells and Impairs Adult Hippocampal Neurogenesis. Neurotox Res 29, 419–431 (2016). https://doi.org/10.1007/s12640-015-9588-y
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DOI: https://doi.org/10.1007/s12640-015-9588-y