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Apelin-13 Protects PC12 Cells from Corticosterone-Induced Apoptosis Through PI3K and ERKs Activation

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Abstract

It is widely accepted that environmental stress is a risk factor for mental disorders. Glucocorticoid hormones play a vital role in the regulation of physiological response to stress. High concentrations of corticosterone can induce cellular damage in PC12 cells, which possess typical neuronal features. Apelin and its receptor APJ are widely distributed in the central nervous system including limbic structures involved in stress responses. Previous studies have suggested that apelin has a neuroprotective function. However, the effect of apelin on corticosterone-induced neuronal damage remains to be elucidated. In the present study, we explored the potential protective activity of apelin-13 in PC12 cells treated with corticosterone and its underling mechanisms. The viability of the cells, the apoptosis of the cells, the level of phosphorylation of Akt (p-Akt) and extracellular signal-regulated kinases (p-ERKs) and cleaved caspase-3 expression were detected by MTT, Hoechst staining and flow cytometer assays and Western blotting. Results showed that corticosterone induced cells viability loss, cell apoptosis, down-regulation of p-Akt and p-ERKs and up-regulation of cleaved caspase-3. The effects induced by corticosterone were attenuated by apelin-13 pretreatment. Furthermore, apelin-13-mediated anti-viability loss, antiapoptosis and caspase-3 suppression activities were blocked by specific inhibitors of phosphatidylinositol 3-kinase (PI3K) (LY294002) and ERKs (PD98059). The data suggest that apelin-13 protects PC12 cells from corticosterone-induced apoptosis through activating PI3K/Akt and ERKs signaling pathways.

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References

  1. Miller S, Dell’Osso B, Ketter TA (2014) The prevalence and burden of bipolar depression. J Affect Disord 169(Suppl 1):S3–11

    Article  PubMed  Google Scholar 

  2. Du X, Pang TY (2015) Is dysregulation of the HPA-axis a core pathophysiology mediating Co-Morbid depression in neurodegenerative diseases? Front Psychiatry 6:32

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5:374–381

    Article  CAS  PubMed  Google Scholar 

  4. Kino T (2015) Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders. Front Physiol 6:230

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, Kitada C, Honda S, Kurokawa T, Onda H, Nishimura O, Fujino M (2000) Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem 275:21061–21067

    Article  CAS  PubMed  Google Scholar 

  6. Cheng B, Chen J, Bai B, Xin Q (2012) Neuroprotection of apelin and its signaling pathway. Peptides 37:171–173

    Article  CAS  PubMed  Google Scholar 

  7. O’Carroll AM, Lolait SJ, Harris LE, Pope GR (2013) The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J Endocrinol 219:R13–35

    Article  PubMed  Google Scholar 

  8. Kagiyama S, Fukuhara M, Matsumura K, Lin Y, Fujii K, Iida M (2005) Central and peripheral cardiovascular actions of apelin in conscious rats. Regul Pept 125:55–59

    Article  CAS  PubMed  Google Scholar 

  9. Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M, Bloom S (2002) The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochem Biophys Res Commun 291:1208–1212

    Article  CAS  PubMed  Google Scholar 

  10. O’Carroll AM, Don AL, Lolait SJ (2003) APJ receptor mRNA expression in the rat hypothalamic paraventricular nucleus: regulation by stress and glucocorticoids. J Neuroendocrinol 15:1095–1101

    Article  PubMed  Google Scholar 

  11. Wei L, Hou X, Tatemoto K (2005) Regulation of apelin mRNA expression by insulin and glucocorticoids in mouse 3T3-L1 adipocytes. Regul Pept 132:27–32

    Article  CAS  PubMed  Google Scholar 

  12. Newson MJ, Pope GR, Roberts EM, Lolait SJ, O’Carroll AM (2013) Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic-pituitary-adrenal axis response to acute stress. J Endocrinol 216:99–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morsink MC, Joels M, Sarabdjitsingh RA, Meijer OC, De Kloet ER, Datson NA (2006) The dynamic pattern of glucocorticoid receptor-mediated transcriptional responses in neuronal PC12 cells. J Neurochem 99:1282–1298

    Article  CAS  PubMed  Google Scholar 

  14. Westerink RH, Ewing AG (2008) The PC12 cell as model for neurosecretion. Acta Physiol (Oxf) 192:273–285

    Article  CAS  Google Scholar 

  15. Jiang Y, Li Z, Liu Y, Liu X, Chang Q, Liao Y, Pan R (2015) Neuroprotective effect of water extract of Panax ginseng on corticosterone-induced apoptosis in PC12 cells and its underlying molecule mechanisms. J Ethnopharmacol 159:102–112

    Article  CAS  PubMed  Google Scholar 

  16. Li ZY, Jiang YM, Liu YM, Guo Z, Shen SN, Liu XM, Pan RL (2014) Saikosaponin D acts against corticosterone-induced apoptosis via regulation of mitochondrial GR translocation and a GR-dependent pathway. Prog Neuropsychopharmacol Biol Psychiatry 53:80–89

    Article  CAS  PubMed  Google Scholar 

  17. Tang XQ, Feng JQ, Chen J, Chen PX, Zhi JL, Cui Y, Guo RX, Yu HM (2005) Protection of oxidative preconditioning against apoptosis induced by H2O2 in PC12 cells: mechanisms via MMP, ROS, and Bcl-2. Brain Res 1057:57–64

    Article  CAS  PubMed  Google Scholar 

  18. Khan M, Maryam A, Qazi JI, Ma T (2015) Targeting apoptosis and multiple signaling pathways with Icariside II in cancer cells. Int J Biol Sci 11:1100–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Brück W, Jellinger K, Lassmann H (1999) Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. Am J Pathol 155:1459–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang H, Zhou X, Huang J, Mu N, Guo Z, Wen Q, Wang R, Chen S, Feng ZP, Zheng W (2013) The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells. Psychopharmacology 228:129–141

    Article  CAS  PubMed  Google Scholar 

  21. Zhao J, Peng L, Zheng W, Wang R, Zhang L, Yang J, Chen H (2015) Chemically bonding of amantadine with gardenamide a enhances the neuroprotective effects against corticosterone-induced insults in PC12 Cells. Int J Mol Sci 16:22795–22810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khaksari M, Aboutaleb N, Nasirinezhad F, Vakili A, Madjd Z (2012) Apelin-13 protects the brain against ischemic reperfusion injury and cerebral edema in a transient model of focal cerebral ischemia. J Mol Neurosci 48:201–208

    Article  CAS  PubMed  Google Scholar 

  23. Yang Y, Lv SY, Lyu SK, Wu D, Chen Q (2015) The protective effect of apelin on ischemia/reperfusion injury. Peptides 63:43–46

    Article  CAS  PubMed  Google Scholar 

  24. Bao HJ, Zhang L, Han WC, Dai DK (2015) Apelin-13 attenuates traumatic brain injury-induced damage by suppressing autophagy. Neurochem Res 40:89–97

    Article  CAS  PubMed  Google Scholar 

  25. Xin Q, Cheng B, Pan Y, Liu H, Yang C, Chen J, Bai B (2015) Neuroprotective effects of apelin-13 on experimental ischemic stroke through suppression of inflammation. Peptides 63:55–62

    Article  CAS  PubMed  Google Scholar 

  26. Kasai A, Kinjo T, Ishihara R, Sakai I, Ishimaru Y, Yoshioka Y, Yamamuro A, Ishige K, Ito Y, Maeda S (2011) Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis. PLoS ONE 6:e23968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cook DR, Gleichman AJ, Cross SA, Doshi S, Ho W, Jordan-Sciutto KL, Lynch DR, Kolson DL (2011) NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury. J Neurochem 118:1113–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. O’Donnell LA, Agrawal A, Sabnekar P, Dichter MA, Lynch DR, Kolson DL (2007) Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury. J Neurochem 102:1905–1917

    Article  PubMed  Google Scholar 

  29. Zeng XJ, Yu SP, Zhang L, Wei L (2010) Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons. Exp Cell Res 316:1773–1783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Finsterwald C, Alberini CM (2014) Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies. Neurobiol Learn Mem 112:17–29

    Article  CAS  PubMed  Google Scholar 

  31. Jiang BP, Liu YM, Le L, Li ZY, Si JY, Liu XM, Chang Q, Pan RL (2014) Cajaninstilbene acid prevents corticosterone-induced apoptosis in PC12 cells by inhibiting the mitochondrial apoptotic pathway. Cell Physiol Biochem 34:1015–1026

    Article  CAS  PubMed  Google Scholar 

  32. Li YF, Liu YQ, Huang WC, Luo ZP (2003) Cytoprotective effect is one of common action pathways for antidepressants. Acta Pharmacol Sin 24:996–1000

    CAS  PubMed  Google Scholar 

  33. Mao QQ, Zhong XM, Qiu FM, Li ZY, Huang Z (2012) Protective effects of paeoniflorin against corticosterone-induced neurotoxicity in pc12 cells. Phytother Res 26:969–973

    Article  CAS  PubMed  Google Scholar 

  34. Ogura Y, Sato K, Kawashima K, Kobayashi N, Imura S, Fujino K, Kawaguchi H, Nedachi T (2014) Subtoxic levels of hydrogen peroxide induce brain-derived neurotrophic factor expression to protect PC12 cells. BMC Res Notes 7:840

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zeng J, Li M, Xiao Z, Chen Y, Chang Q, Tian H, Jin H, Liu X (2013) Rapid elevation of calcium concentration in cultured dorsal spinal cord astrocytes by corticosterone. Neurochem Res 38:382–388

    Article  CAS  PubMed  Google Scholar 

  36. Freitas AE, Egea J, Buendia I, Navarro E, Rada P, Cuadrado A, Rodrigues AL, Lopez MG (2015) Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line. Mol Neurobiol 51:1504–1519

    Article  CAS  PubMed  Google Scholar 

  37. Nitta A, Zheng WH, Quirion R (2004) Insulin-like growth factor 1 prevents neuronal cell death induced by corticosterone through activation of the PI3k/Akt pathway. J Neurosci Res 76:98–103

    Article  CAS  PubMed  Google Scholar 

  38. Shibata S, Iinuma M, Soumiya H, Fukumitsu H, Furukawa Y, Furukawa S (2015) A novel 2-decenoic acid thioester ameliorates corticosterone-induced depression- and anxiety-like behaviors and normalizes reduced hippocampal signal transduction in treated mice. Pharmacol Res Perspect 3:e132

    Article  Google Scholar 

  39. Zhou H, Li X, Gao M (2009) Curcumin protects PC12 cells from corticosterone-induced cytotoxicity: possible involvement of the ERK1/2 pathway. Basic Clin Pharmacol Toxicol 104:236–240

    Article  PubMed  Google Scholar 

  40. Masri B, Morin N, Pedebernade L, Knibiehler B, Audigier Y (2006) The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J Biol Chem 281:18317–18326

    Article  CAS  PubMed  Google Scholar 

  41. Qin D, Zheng XX, Jiang YR (2013) Apelin-13 induces proliferation, migration, and collagen I mRNA expression in human RPE cells via PI3K/Akt and MEK/Erk signaling pathways. Mol Vis 19:2227–2236

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Grutter MG (2000) Caspases: key players in programmed cell death. Curr Opin Struct Biol 10:649–655

    Article  CAS  PubMed  Google Scholar 

  43. Lee MK, Kang SJ, Poncz M, Song KJ, Park KS (2007) Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med 39:376–384

    Article  CAS  PubMed  Google Scholar 

  44. Daskalakis NP, De Kloet ER, Yehuda R, Malaspina D, Kranz TM (2015) Early life stress effects on glucocorticoid-BDNF interplay in the hippocampus. Front Mol Neurosci 8:68

    Article  PubMed  PubMed Central  Google Scholar 

  45. Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H (2010) BDNF function and intracellular signaling in neurons. Histol Histopathol 25:237–258

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by National Natural Science Foundation of China (81171281), Science and Technology Project of Hunan Province (2013FJ3133), the Hunan Key Technology R&D Program (2015SF2046-3), the Outstanding Youth Fund of the Department of Education of Hunan Province (15B208), the Natural Science Foundation of Hunan Province (14JJ3104) and the Construct Program of the Key Discipline in Hunan Province.

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Authors and Affiliations

  1. Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Yunjun Zou, Wan Fu & Yaxiong Nie

  2. Department of Anesthesiology, First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Bo Wang

  3. Department of Physiology and Institute of Neuroscience, College of Medicine, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Shouhong Zhou & Shaowen Tian

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  1. Yunjun Zou
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  5. Yaxiong Nie
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Correspondence to Yaxiong Nie or Shaowen Tian.

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The authors declare that they have no conflicts of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors. The current experiment was performed in accordance with the China laws.

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Yunjun Zou and Bo Wang have contributed equally to this work.

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Zou, Y., Wang, B., Fu, W. et al. Apelin-13 Protects PC12 Cells from Corticosterone-Induced Apoptosis Through PI3K and ERKs Activation. Neurochem Res 41, 1635–1644 (2016). https://doi.org/10.1007/s11064-016-1878-0

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  • DOI: https://doi.org/10.1007/s11064-016-1878-0

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