Advertisement

Metabolic Brain Disease

, Volume 34, Issue 1, pp 79–85 | Cite as

Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses

  • Sohaila Erfani
  • Ali Moghimi
  • Nahid AboutalebEmail author
  • Mehdi Khaksari
Original Article
  • 121 Downloads

Abstract

Nesfatin-1 is a novel peptide with anorexigenic and anti-hyperglycemic properties. According to previous studies, this multi-functional peptide protects dopaminergic cells against neurotoxicity via anti-apoptotic effects. In addition, Nesfatin-1 protects myocardial tissue after myocardial infarction via anti-inflammatory and anti-apoptotic mechanisms. In this study, we investigated the neuroprotective effects of nesfatin-1 against cerebral ischemia reperfusion injury in the CA1 area of hippocampus in rats. 56 male Wistar rats (240-270 g) were randomly selected and allocated into four groups: (1) sham, (2) nesfatin-1, (3) ischemia/reperfusion, (4) ischemia/reperfusion+nesfatin-1. Cerebral ischemia induced by the occlusion of the common carotid arteries for 20 min was followed by reperfusion. Saline as a vehicle and nesfatin-1 (20 μg/kg) were injected intraperitoneally (IP) at the start of cerebral reperfusion. Apoptotic and necrotic cell death was detected by TUNEL and Nissl staining. Malondialdehyde (MDA) and antioxidant enzymes (GSH and SOD) levels were measured by the ELISA method. The results showed that cerebral ischemia increased the apoptotic and necrotic cell death in the CA1 area of hippocampus, while, treatment with nesfatin-1significantly reduced apoptotic and necrotic cell death. Moreover, the MDA levels of the hippocampus in ischemic rats were higher, whereas in nesfatin-1-treated rats the MDA levels were decreased. Furthermore, the SOD and GSH levels in the ischemic rats were decreased, whilst in ischemic rats treated with nesfatin-1, the SOD and GSH levels were increased. This study for the first time found that nesfatin-1 treatment improves CA1 hippocampus injuries after cerebral ischemia through preventing neuronal cell death and enhancement of antioxidant defenses.

Keywords

Nesfatin-1 Apoptosis Necrosis Brain ischemia Hippocampus 

Notes

Acknowledgements

This study was supported by the grant No.95-03-130-29617from Iran University of Medical Sciences.

References

  1. Aboutaleb N, Shamsaei N, Khaksari M, Erfani S, Rajabi H, Nikbakht F (2015) Pre-ischemic exercise reduces apoptosis in hippocampal CA3 cells after cerebral ischemia by modulation of the Bax/Bcl-2 proteins ratio and prevention of caspase-3 activation. J Physiol Sci 65:435–443CrossRefGoogle Scholar
  2. Aboutaleb N, Shamsaei N, Rajabi H, Khaksari M, Erfani S, Nikbakht F, Motamedi P, Shahbazi A (2016) Protection of hippocampal CA1 neurons against ischemia/reperfusion injury by exercise preconditioning via modulation of Bax/Bcl-2 ratio and prevention of caspase-3 activation. Basic and clinical neuroscience 7:21PubMedPubMedCentralGoogle Scholar
  3. Arvin B, Neville LF, Barone FC, Feuerstein GZ (1996) The role of inflammation and cytokines in brain injury. Neurosci Biobehav Rev 20:445–452CrossRefGoogle Scholar
  4. Chen S-D, Yang D-I, Lin T-K, Shaw F-Z, Liou C-W, Chuang Y-C (2011) Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci 12:7199–7215CrossRefGoogle Scholar
  5. Chen Y-F, Wu K-J, Huang W-S, Hsieh Y-W, Wang Y-W, Tsai H-Y, Lee M-M (2016) Neuroprotection of Gueichih-Fuling-wan on cerebral ischemia/reperfusion injury in streptozotocin-induced hyperglycemic rats via the inhibition of the cellular apoptosis pathway and neuroinflammation. BioMedicine 6:21CrossRefGoogle Scholar
  6. Coimbra-Costa D, Alva N, Duran M, Carbonell T, Rama R (2017) Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol 12:216–225CrossRefGoogle Scholar
  7. Doyle KP, Simon RP, Stenzel-Poore MP (2008) Mechanisms of ischemic brain damage. Neuropharmacology 55:310–318CrossRefGoogle Scholar
  8. Erfani S, Aboutaleb N, Oryan S, Shamsaei N, Khaksari M, Kalalian-Moghaddam H, Nikbakht F (2015a) Visfatin inhibits apoptosis and necrosis of hippocampus CA3 cells following transient global ischemia/reperfusion in rats. Int J Pept Res Ther 21:223–228CrossRefGoogle Scholar
  9. Erfani S, Khaksari M, Oryan S, Shamsaei N, Aboutaleb N, Nikbakht F, Jamali-Raeufy N, Gorjipour F (2015b) Visfatin reduces hippocampal CA1 cells death and improves learning and memory deficits after transient global ischemia/reperfusion. Neuropeptides 49:63–68CrossRefGoogle Scholar
  10. Foo K, Brismar H, Broberger C (2008) Distribution and neuropeptide coexistence of nucleobindin-2 mRNA/nesfatin-like immunoreactivity in the rat CNS. Neuroscience 156:563–579CrossRefGoogle Scholar
  11. Granger DN, Kvietys PR (2015) Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox Biol 6:524–551CrossRefGoogle Scholar
  12. Hetman M, Gozdz A (2004) Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. FEBS J 271:2050–2055Google Scholar
  13. Hu G-Q, Du X, Li Y-J, Gao X-Q, Chen B-Q, Yu L (2017) Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis: nicotiflorin and JAK2/STAT3 pathway. Neural Regen Res 12:96–102CrossRefGoogle Scholar
  14. Jiang G, Wang M, Wang L, Chen H, Chen Z, Guo J, Weng X, Liu X (2015) The protective effect of nesfatin-1 against renal ischemia–reperfusion injury in rats. Ren Fail 37:882–889CrossRefGoogle Scholar
  15. Khaksari M, Mehrjerdi FZ, Rezvani ME, Safari F, Mirgalili A, Niknazar S (2017) The role of erythropoietin in remote renal preconditioning on hippocampus ischemia/reperfusion injury. J Physiol Sci 67:163–171CrossRefGoogle Scholar
  16. Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15CrossRefGoogle Scholar
  17. Li Z, Gao L, Tang H, Yin Y, Xiang X, Li Y, Zhao J, Mulholland M, Zhang W (2013) Peripheral effects of nesfatin-1 on glucose homeostasis. PLoS One 8:e71513CrossRefGoogle Scholar
  18. Northington FJ, Chavez-Valdez R, Martin LJ (2011) Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol 69:743–758CrossRefGoogle Scholar
  19. Oh S, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K (2006) Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature 443:709–712CrossRefGoogle Scholar
  20. ÖzsavcÍ D, Erşahin M, Şener A, Özakpinar ÖB, Toklu HZ, Akakín D, Şener G, Yeğen BÇ (2011) The novel function of Nesfatin-1 as an anti-inflammatory and Antiapoptotic peptide in subarachnoid hemorrhage–induced oxidative brain damage in rats. Neurosurgery 68:1699–1708CrossRefGoogle Scholar
  21. Price TO, Samson WK, Niehoff ML, Banks WA (2007) Permeability of the blood–brain barrier to a novel satiety molecule nesfatin-1. Peptides 28:2372–2381CrossRefGoogle Scholar
  22. Shamsaei N, Khaksari M, Erfani S, Rajabi H, Aboutaleb N (2015) Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia. Neural Regen Res 10:1245CrossRefGoogle Scholar
  23. Shen X-L, Song N, Du X-X, Li Y, Xie J-X, Jiang H (2017) Nesfatin-1 protects dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the C-Raf–ERK1/2-dependent anti-apoptotic pathway. Sci Rep 7Google Scholar
  24. Solmaz A, Bahadir E, Gülçiçek OB, Yiğitbaş H, Çelik A, Karagöz A, Özsavcı D, Şirvancı S, Yeğen BÇ (2016) Nesfatin-1 improves oxidative skin injury in normoglycemic or hyperglycemic rats. Peptides 78:1–10CrossRefGoogle Scholar
  25. Su Y, Zhang J, Tang Y, Bi F, Liu J-N (2010) The novel function of nesfatin-1: anti-hyperglycemia. Biochem Biophys Res Commun 391:1039–1042CrossRefGoogle Scholar
  26. Tan Z, Xu H, Shen X, Jiang H (2015) Nesfatin-1 antagonized rotenone-induced neurotoxicity in MES23. 5 dopaminergic cells. Peptides 69:109–114CrossRefGoogle Scholar
  27. Tang C-H, Fu X-J, Xu X-L, Wei X-J, Pan H-S (2012) The anti-inflammatory and anti-apoptotic effects of nesfatin-1 in the traumatic rat brain. Peptides 36:39–45CrossRefGoogle Scholar
  28. Tasatargil A, Kuscu N, Dalaklioglu S, Adiguzel D, Celik-Ozenci C, Ozdem S, Barutcigil A, Ozdem S (2017) Cardioprotective effect of nesfatin-1 against isoproterenol-induced myocardial infarction in rats: role of the Akt/gsk-3β pathway. Peptides 95:1–9CrossRefGoogle Scholar
  29. Thundimadathil J (2012) Cancer treatment using peptides: current therapies and future prospects. J Amino Acids 2012:1–13CrossRefGoogle Scholar
  30. Wang L, Du F, Wang X (2008) TNF-α induces two distinct caspase-8 activation pathways. Cell 133:693–703CrossRefGoogle Scholar
  31. White BC, Sullivan JM, Degracia DJ, O’Neil BJ, Neumar RW, Grossman LI, Rafols JA, Krause GS (2000) Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 179:1–33CrossRefGoogle Scholar
  32. Wicha P, Tocharus J, Janyou A, Jittiwat J, Changtam C, Suksamrarn A, Tocharus C (2017) Hexahydrocurcumin protects against cerebral ischemia/reperfusion injury, attenuates inflammation, and improves antioxidant defenses in a rat stroke model. PLoS One 12:e0189211CrossRefGoogle Scholar
  33. Xiao Y-F, Jie M-M, Li B-S, Hu C-J, Xie R, Tang B, Yang S-M (2015) Peptide-based treatment: a promising cancer therapy. J Immunol Res 2015:1–13CrossRefGoogle Scholar
  34. Zegers D, Beckers S, Mertens IL, Van Gaal LF, Van Hul W (2011) Association between polymorphisms of the Nesfatin gene, NUCB2, and obesity in men. Mol Genet Metab 103:282–286CrossRefGoogle Scholar
  35. Zhang A-Q, Li X-L, Jiang C-Y, Lin L, Shi R-H, Chen J-D, Oomura Y (2010) Expression of nesfatin-1/NUCB2 in rodent digestive system. World J Gastroenterol: WJG 16:1735–1741CrossRefGoogle Scholar
  36. Zhao TZ, Ding Q, Hu J, He SM, Shi F, Ma LT (2016) GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. Brain and behavior 6:e00449CrossRefGoogle Scholar
  37. Zhu Y-M, Wang C-C, Chen L, Qian L-B, Ma L-L, Yu J, Zhu M-H, Wen C-Y, Yu L-N, Yan M (2013) Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res 1494:1–8CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sohaila Erfani
    • 1
  • Ali Moghimi
    • 2
  • Nahid Aboutaleb
    • 3
    • 4
    Email author
  • Mehdi Khaksari
    • 5
  1. 1.Department of Biology, Faculty of ScienceFerdowsi University of MashhadMashhadIran
  2. 2.Rayan Center for Neuroscience and Behavior, Department of Biology, Faculty of ScienceFerdowsi University of MashhadMashhadIran
  3. 3.Physiology Research Center, Faculty of MedicineIran University of Medical SciencesTehranIran
  4. 4.Department of Physiology, Faculty of MedicineIran University of Medical SciencesTehranIran
  5. 5.Addiction Research CenterShahroud University of Medical SciencesShahroudIran

Personalised recommendations