Skip to main content
SpringerLink
Log in

DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Hyperglycemia as the major hallmark of diabetic neuropathy severely limited its therapeutic efficiency. Evidences have revealed that selenium (Se) as an essential trace element could effectively reduce the risk of neurological diseases. In the present study, 3,3′-diselenodipropionic acid (DSePA), a derivative of selenocystine, was employed to investigate its protective effect against high glucose-induced neurotoxicity in PC12 cells and evaluate the underlying mechanism. The results suggested that high glucose showed significant cytotoxicity through launching mitochondria-mediated apoptosis in PC12 cells, accompanied by poly (ADP-ribose) polymerase (PARP) cleavage, caspase activation, and mitochondrial dysfunction. Moreover, high glucose also triggered DNA damage and dysregulation of MAPKs and AKT pathways through reactive oxygen species (ROS) overproduction. p53 RNA interference partially suppressed high glucose-induced cytotoxicity and apoptosis, indicating the role of p53 in high glucose-induced signal. However, DSePA pretreatment effectively attenuated high glucose-induced cytotoxicity, inhibited the mitochondrial dysfunction through regulation of Bcl-2 family, and ultimately reversed high glucose-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, PARP cleavage, DNA damage, and ROS accumulation all confirmed its protective effects. Moreover, DSePA markedly alleviated the dysregulation of AKT and MAPKs pathways induced by high glucose. Our findings revealed that the strategy of using DSePA to antagonize high glucose-induced neurotoxicity may be a highly effective strategy in combating high glucose-mediated neurological diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Diogo CV, Suski JM, Lebiedzinska M, Karkucinska-Wieckowska A, Wojtala A, Pronicki M, Duszynski J, Pinton P et al (2013) Cardiac mitochondrial dysfunction during hyperglycemia—the role of oxidative stress and p66Shc signaling. Int J Biochem Cell Biol 45(1):114–122

    Article  CAS  PubMed  Google Scholar 

  2. Rolo AP, Palmeira CM (2006) Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 212(2):167–178

    Article  CAS  PubMed  Google Scholar 

  3. Palmeira CM, Rolo AP, Berthiaume J, Bjork JA, Wallace KB (2007) Hyperglycemia decreases mitochondrial function: the regulatory role of mitochondrial biogenesis. Toxicol Appl Pharmacol 225(2):214–220

    Article  CAS  PubMed  Google Scholar 

  4. Amaral S, Oliveira PJ, Ramalho-Santos J (2008) Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev 4(1):46–54

    Article  CAS  PubMed  Google Scholar 

  5. Wang J, Li G, Wang Z, Zhang X, Yao L, Wang F, Liu S, Yin J et al (2012) High glucose-induced expression of inflammatory cytokines and reactive oxygen species in cultured astrocytes. Neuroscience 202:58–68

    Article  CAS  PubMed  Google Scholar 

  6. van Dam PS, van Asbeck BS, Bravenboer B, van Oirschot JF, Gispen WH, Marx JJ (1998) Nerve function and oxidative stress in diabetic and vitamin E-deficient rats. Free Radic Biol Med 24(1):18–26

    Article  PubMed  Google Scholar 

  7. Singh JN, Jain G, Sharma SS (2013) In vitro hyperglycemia enhances sodium currents in dorsal root ganglion neurons: an effect attenuated by carbamazepine. Neuroscience 232:64–73

    Article  CAS  PubMed  Google Scholar 

  8. Zou Y, Zhao T, Mao G, Zhang M, Zheng D, Feng W, Wang W, Wu X et al (2014) Isolation, purification and characterisation of selenium-containing polysaccharides and proteins in selenium-enriched Radix puerariae. J Sci Food Agric 94(2):349–358

    Article  CAS  PubMed  Google Scholar 

  9. Fan C, Zheng W, Fu X, Li X, Wong YS, Chen T (2014) Strategy to enhance the therapeutic effect of doxorubicin in human hepatocellular carcinoma by selenocystine, a synergistic agent that regulates the ROS-mediated signaling. Oncotarget 5(9):2853–2863

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fan C, Zheng W, Fu X, Li X, Wong YS, Chen T (2014) Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. Cell Death Dis 5:e1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fan C, Chen J, Wang Y, Wong YS, Zhang Y, Zheng W, Cao W, Chen T (2013) Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway. Free Radic Biol Med 65:305–316

    Article  CAS  PubMed  Google Scholar 

  12. Pillai R, Uyehara-Lock JH, Bellinger FP (2014) Selenium and selenoprotein function in brain disorders. IUBMB Life 66(4):229–239

    Article  CAS  PubMed  Google Scholar 

  13. Ozbal S, Erbil G, Kocdor H, Tugyan K, Pekcetin C, Ozogul C (2008) The effects of selenium against cerebral ischemia-reperfusion injury in rats. Neurosci Lett 438(3):265–269

    Article  PubMed  Google Scholar 

  14. Bellinger FP, Raman AV, Reeves MA, Berry MJ (2009) Regulation and function of selenoproteins in human disease. Biochem J 422(1):11–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kunwar A, Bag PP, Chattopadhyay S, Jain VK, Priyadarsini KI (2011) Anti-apoptotic, anti-inflammatory, and immunomodulatory activities of 3,3′-diselenodipropionic acid in mice exposed to whole body gamma-radiation. Arch Toxicol 85(11):1395–1405

    Article  CAS  PubMed  Google Scholar 

  16. Kunwar A, Bansal P, Kumar SJ, Bag PP, Paul P, Reddy ND, Kumbhare LB, Jain VK et al (2010) In vivo radioprotection studies of 3,3′-diselenodipropionic acid, a selenocystine derivative. Free Radic Biol Med 48(3):399–410

    Article  CAS  PubMed  Google Scholar 

  17. Cao W, Li X, Zheng S, Zheng W, Wong YS, Chen T (2014) Selenocysteine derivative overcomes TRAIL resistance in melanoma cells: evidence for ROS-dependent synergism and signaling crosstalk. Oncotarget 5(17):7431–7445

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yagami T, Yamamoto Y, Koma H (2014) The role of secretory phospholipase A(2) in the central nervous system and neurological diseases. Mol Neurobiol 49(2):863–876

    Article  CAS  PubMed  Google Scholar 

  19. Cho SW, Park JS, Heo HJ, Park SW, Song S, Kim I, Han YM, Yamashita JK et al (2014) Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells. J Am Heart Assoc 3(2):e000693

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bove J, Martinez-Vicente M, Dehay B, Perier C, Recasens A, Bombrun A, Antonsson B, Vila M (2014) BAX channel activity mediates lysosomal disruption linked to Parkinson disease. Autophagy 10(5):889–900

    Article  CAS  PubMed  Google Scholar 

  21. Gomez-Crisostomo NP, Lopez-Marure R, Zapata E, Zazueta C, Martinez-Abundis E (2013) Bax induces cytochrome c release by multiple mechanisms in mitochondria from MCF7 cells. J Bioenerg Biomembr 45(5):441–448

    Article  CAS  PubMed  Google Scholar 

  22. Simonishvili S, Jain MR, Li H, Levison SW, Wood TL (2013) Identification of Bax-interacting proteins in oligodendrocyte progenitors during glutamate excitotoxicity and perinatal hypoxia-ischemia. ASN Neuro 5(5):e00131

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liu MH, Yuan C, He J, Tan TP, Wu SJ, Fu HY, Liu J, Yu S et al (2014) Resveratrol protects PC12 cells from high glucose-induced neurotoxicity via PI3K/Akt/FoxO3a pathway. Cell Mol Neurobiol 35:513–522

    Article  CAS  PubMed  Google Scholar 

  24. Chen T, Wong YS (2008) Selenocystine induces apoptosis of A375 human melanoma cells by activating ROS-mediated mitochondrial pathway and p53 phosphorylation. Cell Mol Life Sci 65(17):2763–2775

    Article  CAS  PubMed  Google Scholar 

  25. Park JH, Lee SW, Yang SW, Yoo HM, Park JM, Seong MW, Ka SH, Oh KH et al (2014) Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage. Nat Commun 5:5483

    Article  PubMed  Google Scholar 

  26. Coulpier M, Anders J, Ibanez CF (2002) Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. J Biol Chem 277(3):1991–1999

    Article  CAS  PubMed  Google Scholar 

  27. Pitts MW, Byrns CN, Ogawa-Wong AN, Kremer P, Berry MJ (2014) Selenoproteins in nervous system development and function. Biol Trace Elem Res 161(3):231–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bellinger FP, He QP, Bellinger MT, Lin Y, Raman AV, White LR, Berry MJ (2008) Association of selenoprotein p with Alzheimer’s pathology in human cortex. J Alzheimers Dis 15(3):465–472

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shahar A, Patel KV, Semba RD, Bandinelli S, Shahar DR, Ferrucci L, Guralnik JM (2010) Plasma selenium is positively related to performance in neurological tasks assessing coordination and motor speed. Mov Disord 25(12):1909–1915

    Article  PubMed  PubMed Central  Google Scholar 

  30. Mousavi SH, Tayarani NZ, Parsaee H (2010) Protective effect of saffron extract and crocin on reactive oxygen species-mediated high glucose-induced toxicity in PC12 cells. Cell Mol Neurobiol 30(2):185–191

    Article  CAS  PubMed  Google Scholar 

  31. Eslami H, Sharifi AM, Rahimi H, Rahati M (2014) Protective effect of telmisartan against oxidative damage induced by high glucose in neuronal PC12 cell. Neurosci Lett 558:31–36

    Article  CAS  PubMed  Google Scholar 

  32. Yuan J, Huang G, Xiao Z, Lin L, Han T (2013) Overexpression of beta-NGF promotes differentiation of bone marrow mesenchymal stem cells into neurons through regulation of AKT and MAPK pathway. Mol Cell Biochem 383(1-2):201–211

    Article  CAS  PubMed  Google Scholar 

  33. Wu J, Jiang H, Luo S, Zhang M, Zhang Y, Sun F, Huang S, Li H (2013) Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope. Cell Res 23(5):691–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xing S, Zhang J, Dang C, Liu G, Zhang Y, Li J, Fan Y, Pei Z et al (2014) Cerebrolysin reduces amyloid-beta deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction. J Neurol Sci 337(1-2):104–111

    Article  CAS  PubMed  Google Scholar 

  35. Vandegriff KD, Malavalli A, Lohman J, Young MA, Terraneo L, Virgili E, Bianciardi P, Caretti A et al (2014) Impact of acellular hemoglobin-based oxygen carriers on brain apoptosis in rats. Transfusion 54(8):2045–2054

    Article  CAS  PubMed  Google Scholar 

  36. Wu Q, Tang ZH, Peng J, Liao L, Pan LH, Wu CY, Jiang ZS, Wang GX et al (2014) The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer’s disease progression (Review). Biomed Rep 2(2):167–171

    CAS  PubMed  Google Scholar 

  37. Kim SY, Shim MS, Kim KY, Weinreb RN, Wheeler LA, Ju WK (2014) Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis 5:e1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hou Y, Ghosh P, Wan R, Ouyang X, Cheng H, Mattson MP, Cheng A (2014) Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1-42 on neural progenitor cell proliferation. Neurobiol Aging 35(5):975–989

    Article  CAS  PubMed  Google Scholar 

  39. Li DW, Yao M, Dong YH, Tang MN, Chen W, Li GR, Sun BQ (2014) Guanosine exerts neuroprotective effects by reversing mitochondrial dysfunction in a cellular model of Parkinson’s disease. Int J Mol Med 34(5):1358–1364

    CAS  PubMed  Google Scholar 

  40. Li D, Liu M, Tao TQ, Song DD, Liu XH, Shi DZ (2014) Panax quinquefolium saponin attenuates cardiomyocyte apoptosis and opening of the mitochondrial permeability transition pore in a rat model of ischemia/reperfusion. Cell Physiol Biochem 34(4):1413–1426

    Article  CAS  PubMed  Google Scholar 

  41. Gu W, Hou X, Zhou H, Li C (2014) Protective effect of shen-fu injection on neuronal mitochondrial function in a porcine model of prolonged cardiac arrest. Evid Based Complement Alternat Med 2014:523847

    PubMed  PubMed Central  Google Scholar 

  42. Li J, Yu W, Li XT, Qi SH, Li B (2014) The effects of propofol on mitochondrial dysfunction following focal cerebral ischemia-reperfusion in rats. Neuropharmacology 77:358–368

    Article  CAS  PubMed  Google Scholar 

  43. Ge R, Ma WH, Li YL, Li QS (2013) Apoptosis induced neurotoxicity of Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) via mitochondria-mediated pathway in PC12 cells. Toxicol In Vitro 27(1):92–102

    Article  CAS  PubMed  Google Scholar 

  44. Jung SY, Kim DY, Yune TY, Shin DH, Baek SB, Kim CJ (2014) Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the PI3K/Akt pathway in rats. Exp Ther Med 7(3):587–593

    CAS  PubMed  Google Scholar 

  45. Goncalves AC, Barbosa-Ribeiro A, Alves V, Silva T, Sarmento-Ribeiro AB (2013) Selenium compounds induced ROS-dependent apoptosis in myelodysplasia cells. Biol Trace Elem Res 154(3):440–447

    Article  CAS  PubMed  Google Scholar 

  46. Wang Y, Wu Y, Luo K, Liu Y, Zhou M, Yan S, Shi H, Cai Y (2013) The protective effects of selenium on cadmium-induced oxidative stress and apoptosis via mitochondria pathway in mice kidney. Food Chem Toxicol 58:61–67

    Article  CAS  PubMed  Google Scholar 

  47. Sun H, Leng T, Zeng Z, Gao X, Inoue K, Xiong ZG (2013) Role of TRPM7 channels in hyperglycemia-mediated injury of vascular endothelial cells. PLoS One 8(11):e79540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. van Veen S, Sorensen DM, Holemans T, Holen HW, Palmgren MG, Vangheluwe P Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson’s disease and other neurological disorders. Front Mol Neurosci 7:48

  49. Gaspar JM, Martins A, Cruz R, Rodrigues CM, Ambrosio AF, Santiago AR (2013) Tauroursodeoxycholic acid protects retinal neural cells from cell death induced by prolonged exposure to elevated glucose. Neuroscience 253:380–388

    Article  CAS  PubMed  Google Scholar 

  50. Odinokova IV, Sung KF, Mareninova OA, Hermann K, Evtodienko Y, Andreyev A, Gukovsky I, Gukovskaya AS (2009) Mechanisms regulating cytochrome c release in pancreatic mitochondria. Gut 58(3):431–442

    Article  CAS  PubMed  Google Scholar 

  51. Renaud J, Bournival J, Zottig X, Martinoli MG (2014) Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: effect on p53 and GRP75 localization. Neurotox Res 25(1):110–123

    Article  CAS  PubMed  Google Scholar 

  52. Guan L, Huang F, Li Z, Han B, Jiang Q, Ren Y, Yang Y, Xu C (2008) P53 transcription-independent activity mediates selenite-induced acute promyelocytic leukemia NB4 cell apoptosis. BMB Rep 41(10):745–750

    Article  CAS  PubMed  Google Scholar 

  53. Aminzadeh A, Dehpour AR, Safa M, Mirzamohammadi S, Sharifi AM (2014) Investigating the protective effect of lithium against high glucose-induced neurotoxicity in PC12 cells: involvements of ROS, JNK and P38 MAPKs, and apoptotic mitochondria pathway. Cell Mol Neurobiol 34(8):1143–1150

    Article  CAS  PubMed  Google Scholar 

  54. Li Q, Guo HC, Maslov LN, Qiao XW, Zhou JJ, Zhang Y (2014) Mitochondrial permeability transition pore plays a role in the cardioprotection of CB2 receptor against ischemia-reperfusion injury. Can J Physiol Pharmacol 92(3):205–214

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the National Natural Science Foundation of China no. 81471212, 81271275, 81070947, and 30770759 to B.-L. Sun and no. 81301018 to Z.-Y Zhang; and Natural Science Foundation of Shandong no. ZR2012HZ006 to B.-L. Sun, no. ZR2015HQ009 to C.-D. Fan, and no. ZR2015PH003 to X.-Y. Fu.

Conflict of Interest

The authors declare that they have no competing interests.

Author information

Author notes

    Authors and Affiliations

    1. Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China

      Kun Wang, Xiao-ting Fu, Ya-jun Hou, Jie Fang, Shuai Zhang, Ming-feng Yang, Da-wei Li, Lei-lei Mao, Xiao-yi Yang, Cun-dong Fan, Zong-yong Zhang & Bao-liang Sun

    2. Taishan Vocational College of Nursing, Taian, Shandong, 271000, China

      Kun Wang & Jing-yi Sun

    3. School of Basic Medicine, Taishan Medical University, Taian, Shandong, 271000, China

      Xiao-yan Fu

    4. Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China

      Hui Yuan & Bao-liang Sun

    Authors
    1. Kun Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xiao-yan Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Xiao-ting Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ya-jun Hou
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jie Fang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shuai Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ming-feng Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Da-wei Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Lei-lei Mao
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Jing-yi Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Hui Yuan
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Xiao-yi Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Cun-dong Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Zong-yong Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Bao-liang Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Cun-dong Fan, Zong-yong Zhang or Bao-liang Sun.

    Additional information

    Kun Wang and Xiao-yan Fu contributed equally to this work.

    Electronic Supplementary Material

    Below is the link to the electronic supplementary material.

    ESM 1

    (DOC 584 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Wang, K., Fu, Xy., Fu, Xt. et al. DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways. Mol Neurobiol 53, 4363–4374 (2016). https://doi.org/10.1007/s12035-015-9373-1

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9373-1

    Keywords

    Search

    Navigation