Skip to main content
SpringerLink
Log in

Protective Actions of Ghrelin on Global Cerebral Ischemia-Induced Memory Deficits

  • Published:
Neurophysiology Aims and scope

In our study, we investigated transient global cerebral ischemia (TGCI)-induced changes in spatial memory and motor activity together with apoptotic, oxidant, and NO/NOS signaling parameters in rats and the effects of treatment of animals with ghrelin. The TGCI-induced deficiencies of spatial memory and motor activity in the Y-maze and open field tests were attenuated by ghrelin treatment. Furthermore, ghrelin administration lowered the levels of caspase-3 and iNOS elevated by TGCI in the hippocampus. Thus, we conclude that ghrelin exerts a neuroprotective action against hippocampal TGCI injury via influencing apoptotic, oxidant, and/or NO/NOS pathways. If the underlying mechanisms of action of this agent are fully clarified, ghrelin might be a candidate drug for treatment of TGCI-induced memory impairments.

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

Similar content being viewed by others

References

  1. A. Peskine, C. Picq, and P. Pradat-Diehl, “Cerebral anoxia and disability,” Brain Injury, 18, No. 12, 1243-1254 (2004).

    Article  PubMed  Google Scholar 

  2. Y. D. Cheng, L. Al-Khoury, and J. A. Zivin, “Neuroprotection for ischemic stroke: two decades of success and failure,” NeuroRx, 1, No. 1, 36-45 (2004).

    Article  PubMed Central  PubMed  Google Scholar 

  3. J. L. Cummings, U. Tomiyasu, S. Read, et al., “Amnesia with hippocampal lesions after cardiopulmonary arrest,” Neurology, 34, No. 5, 679-681 (1984).

    Article  CAS  PubMed  Google Scholar 

  4. S. Zola-Morgan, L. R. Squire, and D. G. Amaral, “Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus,” J. Neurosci., 6, No. 10, 2950-2967 (1986).

    CAS  PubMed  Google Scholar 

  5. C. K. Petito, E. Feldmann, W. A. Pulsinelli, et al., “Delayed hippocampal damage in humans following cardiorespiratory arrest,” Neurology, 37, No. 8, 1281-1286 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. W. A. Pulsinelli, J. B. Brierley, and F. Plum, “Temporal profile of neuronal damage in a model of transient forebrain ischemia,” Ann. Neurol., 11, No. 5, 491-498 (1982).

    Article  CAS  PubMed  Google Scholar 

  7. “Recommendations for standards regarding preclinical neuroprotective and restorative drug development,” Stroke, 30, No. 12, 2752-2758 (1999).

  8. I. Szabo and A. S. Tarnawski, “Apoptosis in the gastric mucosa: molecular mechanisms, basic and clinical implications,” J. Physiol. Pharmacol., 51, No. 1, 3-15 (2000).

    CAS  PubMed  Google Scholar 

  9. J. Chandra, A. Samali, and S. Orrenius, “Triggering and modulation of apoptosis by oxidative stress,” Free Radical Biol. Med., 29, Nos. 3/4, 323-333 (2000).

    Article  CAS  Google Scholar 

  10. I. Bohm and H. Schild, “Apoptosis: the complex scenario for a silent cell death,” Mol. Imag. Biol., 5, No. 1, 2-14 (2003).

    Article  Google Scholar 

  11. G. M. Cohen, “Caspases: the executioners of apoptosis,” Biochem. J., 326, Part. 1, 1-16 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  12. A. Rami, S. Jansen, I. Giesser, and J. Winckler, “Postischemic activation of caspase-3 in the rat hippocampus: evidence of an axonal and dendritic localization,” Neurochem. Int., 43, No. 3, 211-223 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. M. Kaste, “Current therapeutic options for brain ischemia,” Neurology, 49, No. 5, Suppl. 4, S56-S59 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. M. A. Moro, A. Cardenas, O. Hurtado, et al., “Role of nitric oxide after brain ischaemia,” Cell Calcium, 36, Nos. 3/4, 265-275 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. L. J. Ignarro, G. M. Buga, K. S. Wood, et al., “Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide,” Proc. Natl. Acad. Sci. USA, 84, No. 24, 9265-9269 (1987).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. S. Moncada and J. P. Bolanos, “Nitric oxide, cell bioenergetics and neurodegeneration,” J. Neurochem., 97, No. 6, 1676-1689 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. N. Panahian, T. Yoshida, P. L. Huang, et al., “Attenuated hippocampal damage after global cerebral ischemia in mice mutant in neuronal nitric oxide synthase,” Neuroscience, 72, No. 2, 343-354 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. C. Iadecola, “Bright and dark sides of nitric oxide in ischemic brain injury,” Trends Neurosci., 20, No. 3, 132-139 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. A. F. Samdani, T. M. Dawson, and V. L. Dawson, “Nitric oxide synthase in models of focal ischemia,” Stroke, 28, No. 6, 1283-1288 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. N. Adachi, B. Lei, M. Soutani, and T. Arai, “Different roles of neuronal and endothelial nitric oxide synthases on ischemic nitric oxide production in gerbil striatum,” Neurosci. Lett., 288, No. 2, 151-154 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. E. El Eter, A. Al Tuwaijiri, H. Hagar, and M. Arafa, “In vivo and in vitro antioxidant activity of ghrelin: Attenuation of gastric ischemic injury in the rat,” J. Gastroenterol. Hepatol., 22, No. 11, 1791-1799 (2007).

    Article  PubMed  Google Scholar 

  22. M. Kojima, H. Hosoda, Y. Date, et al., “Ghrelin is a growth-hormone-releasing acylated peptide from stomach,” Nature, 402, No. 6762, 656-660 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. N. Nagaya, M. Uematsu, M. Kojima, et al., “Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure,” Circulation, 104, No. 12, 1430-1435 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. E. Ghigo, F. Broglio, E. Arvat, et al., “Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor,” Clin. Endocrinol. (Oxf.), 62, No. 1, 1-17 (2005).

    Article  CAS  Google Scholar 

  25. M. Kojima and K. Kangawa, “Ghrelin: structure and function,” Physiol. Rev., 85, No. 2, 495-522 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. J. F. Davis, D. L. Choi, D. J. Clegg, and S. C. Benoit, “Signaling through the ghrelin receptor modulates hippocampal function and meal anticipation in mice,” Physiol. Behav., 103, No. 1, 39-43 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. J. N. Cuellar and M. Isokawa, “Ghrelin-induced activation of cAMP signal transduction and its negative regulation by endocannabinoids in the hippocampus,” Neuropharmacology, 60, No. 6, 842-851 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. S. Hwang, M. Moon, S. Kim, et al., “Neuroprotective effect of ghrelin is associated with decreased expression of prostate apoptosis response-4,” Endocrinol. J., 56, No. 4, 609-617 (2009).

    CAS  Google Scholar 

  29. H. Chung, E. Kim, D. H. Lee, et al., “Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygenglucose deprivation,” Endocrinology, 148, No. 1, 148-159 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Y. Liu, L. Chen, X. Xu, et al., “Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2,” BMC Physiol., 9, 17 (2009).

    Article  PubMed Central  PubMed  Google Scholar 

  31. W. A. Pulsinelli and J. B. Brierley, “A new model of bilateral hemispheric ischemia in the unanesthetized rat,” Stroke, 10, No. 3, 267-272 (1979).

    Article  CAS  PubMed  Google Scholar 

  32. O. Cheng, R. P. Ostrowski, B. Wu, et al., “Cyclooxygenase-2 mediates hyperbaric oxygen preconditioning in the rat model of transient global cerebral ischemia,” Stroke, 42, No. 2, 484-490 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. W. R. Hawley, E. M. Grissom, and G. P. Dohanich, “The relationships between trait anxiety, place recognition memory, and learning strategy,” Behav. Brain Res., 216, No. 2, 525-530 (2011).

    Article  PubMed  Google Scholar 

  34. J. Zhao, Y. Zhao, W. Zheng, et al., “Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats,” Brain Res., 1229, 224-232 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. G. A. Donnan, M. Fisher, M. Macleod, and S. M. Davis, “Stroke,” Lancet, 371, No. 9624, 1612-1623 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. W. T. Longstreth Jr. and S. S. Dikmen, “Outcomes after cardiac arrest,” Ann. Emerg. Med., 22, No. 1, 64-69 (1993).

    Article  PubMed  Google Scholar 

  37. P. S. Lagali, C. P. Corcoran, and D. J. Picketts, “Hippocampus development and function: role of epigenetic factors and implications for cognitive disease,” Clin. Genet., 78, No. 4, 321-333 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. S. Diano, S. A. Farr, S. C. Benoit, et al., “Ghrelin controls hippocampal spine synapse density and memory performance,” Nat. Neurosci., 9, No. 3, 381-388 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. M. Jászberényi, E. Bujdosó, Z. Bagosi, and G. Telegdy, “Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin,” Horm. Behav., 50, No. 2, 266-273 (2006).

    Article  PubMed  Google Scholar 

  40. Y. Liu, P. S. Wang, D. Xie, et al., “Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion,” Chin. J. Physiol., 49, No. 5, 244-250 (2006).

    CAS  PubMed  Google Scholar 

  41. H. A. Awooda, M. F. Lutfi, G. M. Sharara, and A. M. Saeed, “Role of N-Nitro-L-Arginine-Methylester as anti-oxidant in transient cerebral ischemia and reperfusion in rats,” Exp. Trans. Stroke Med., 5, No. 1, 1 (2013).

    Article  CAS  Google Scholar 

  42. M. Yaman, O. Eser, M. Cosar, et al., “Oral administration of avocado soybean unsaponifiables (ASU) reduces ischemic damage in the rat hippocampus,” Arch. Med. Res., 38, No. 5, 489-494 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. P. H. Chan, “Reactive oxygen radicals in signaling and damage in the ischemic brain,” J. Cerebr. Blood Flow Metab., 21, No. 1, 2-14 (2001).

    Article  CAS  Google Scholar 

  44. K. Zwirska-Korczala, M. Adamczyk-Sowa, P. Sowa, et al., “Role of leptin, ghrelin, angiotensin II and orexins in 3T3 L1 preadipocyte cells proliferation and oxidative metabolism,” J. Physiol. Pharmacol., 58, Suppl. 1, 53-64 (2007).

    Google Scholar 

  45. M. Suematsu, A. Katsuki, Y. Sumida, et al., “Decreased circulating levels of active ghrelin are associated with increased oxidative stress in obese subjects,” Eur. J. Endocrinol., 153, No. 3, 403-407 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. M. A. Moro, A. Almeida, J. P. Bolaños, and I. Lizasoain, “Mitochondrial respiratory chain and free radical generation in stroke,” Free Radical Biol. Med., 39, No. 10, 1291-1304 (2005).

    Article  CAS  Google Scholar 

  47. S. J. Heales, J. P. Bolaños, V. C. Stewart, et al., “Nitric oxide, mitochondria and neurological disease,” Biochim. Biophys. Acta., 1410, No. 2, 215-228 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. B. Lei, N. Adachi, T. Nagaro, et al., “Nitric oxide production in the CA1 field of the gerbil hippocampus after transient forebrain ischemia: effects of 7-nitroindazole and NG-nitro-L-arginine methyl ester,” Stroke, 30, No. 3, 669-677 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. J. S. Stamler, “Redox signaling: nitrosylation and related target interactions of nitric oxide,” Cell, 78, No. 6, 931-936 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. B. Sekhon, C. Sekhon, M. Khan, et al., “N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia,” Brain Res., 971, No. 1, 1-8 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. M. Willmot, C. Gibson, L. Gray, et al., “Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: a systematic review,” Free Radical Biol. Med., 39, No. 3, 412-425 (2005).

    Article  CAS  Google Scholar 

  52. A. Aggarwal, V. Gaur, and A. Kumar, “Nitric oxide mechanism in the protective effect of naringin against post-stroke depression (PSD) in mice,” Life Sci., 86, Nos. 25/26, 928-935 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. S. Murphy and C. L. Gibson, “Nitric oxide, ischaemia and brain inflammation,” Biochem. Soc. Trans., 35, Part 5, 1133-1137 (2007).

    CAS  PubMed  Google Scholar 

  54. M. L. Holtz, S. D. Craddock, and L. C. Pettigrew, “Rapid expression of neuronal and inducible nitric oxide synthases during post-ischemic reperfusion in rat brain,” Brain Res., 898, No. 1, 49-60 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. D. Y. Zhu, Q. Deng, H. H. Yao, et al., “Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice,” Life Sci., 71, No. 17, 1985-1996 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. R. Greco, A. S. Mangione, D. Amantea, et al., “IkappaBalpha expression following transient focal cerebral ischemia is modulated by nitric oxide,” Brain Res., 1372, 145-151 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. V. P. Carlini, M. F. Perez, E. Salde, et al., “Ghrelin induced memory facilitation implicates nitric oxide synthase activation and decrease in the threshold to promote LTP in hippocampal dentate gyrus,” Physiol. Behav., 101, No. 1, 117-123 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. T. Brzozowski, P. C. Konturek, S. J. Konturek, et al., “Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage,” Regulat. Peptides, 120, Nos. 1/3, 39-51 (2004).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical School of the Akdeniz University, Antalya, Turkey

    G. Basaranlar, N. Derin, G. Tanriover & N. Demir

  2. Medical School of the Near East University, North Nicosia, Northern Cyprus

    R. Tan

Authors
  1. G. Basaranlar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Derin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Tanriover
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Derin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Basaranlar, G., Derin, N., Tan, R. et al. Protective Actions of Ghrelin on Global Cerebral Ischemia-Induced Memory Deficits. Neurophysiology 46, 343–351 (2014). https://doi.org/10.1007/s11062-014-9454-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11062-014-9454-1

Keywords

Search

Navigation