Advertisement

Archives of Pharmacal Research

, Volume 40, Issue 6, pp 760–771 | Cite as

Phytoceramide ameliorates ß-amyloid protein-induced memory impairment and neuronal death in mice

  • Ji Yeon Jang
  • Hong Kyu Lee
  • Hwan-Su Yoo
  • Yeon Hee SeongEmail author
Research Article

Abstract

The present study was performed to investigate the protective effect of phytoceramide against ß-amyloid protein (Aβ) (25–35)-induced memory impairment and its underlying mechanisms in mice. Memory impairment in mice was induced by intracerebroventricular injection of 15 nmol Aβ (25–35) and measured by the passive avoidance test and Morris water maze test. Chronic administration of phytoceramide (10, 25 and 50 mg/kg, p.o.) resulted in significantly less Aβ (25–35)-induced memory loss and hippocampal neuronal death in treated mice compared to controls. The decrease of glutathione level and increase of lipid peroxidation in brain tissue following injection of Aβ (25–35) was reduced by phytoceramide. Alteration of apoptosis-related proteins, increase of inflammatory factors, and phosphorylation of mitogen activated proteins kinases (MAPKs) in Aβ (25–35)-administered mice hippocampus were inhibited by phytoceramide. Phosphatidylinositol 3′-kinase (PI3K)/Akt pathway and phosphorylation of cyclic AMP response element-binding protein (CREB) were suppressed, while phosphorylation of tau (p-tau) was increased in Aß (25–35)-treated mice brain; these effects were significantly inhibited by administration of phytoceramide. These results suggest that phytoceramide has a possible therapeutic role in managing cognitive impairment associated with Alzheimer’s disease. The underlying mechanism might involve inhibition of p-tau formation via anti-apoptosis and anti-inflammation activity and promotion of PI3K/Akt/CREB signaling process.

Keywords

Phytoceramide Alzheimer’s disease β-amyloid protein (25–35) Memory impairment Neuroprotection 

Notes

Acknowledgements

This work was supported by National Research Foundation of Korea Grant funded by the Korean Government (2012-0014760).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. Bal-Price A, Brown GC (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21:6480–6491PubMedGoogle Scholar
  2. Brazil DP, Park J, Hemmings BA (2002) PKB binding proteins. Getting in on the Akt. Cell 111:293–303PubMedGoogle Scholar
  3. Brenner AJ, Harris ED (1995) A quantitative test for copper using bicinchoninic acid. Anal Biochem 226:80–84CrossRefPubMedGoogle Scholar
  4. Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32:1050–1060CrossRefPubMedGoogle Scholar
  5. Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445CrossRefPubMedGoogle Scholar
  6. Cecchi C, Fiorillo C, Baglioni S, Pensalfini A, Bagnoli S, Nacmias B, Sorbi S, Nosi D, Relini A, Liguri G (2007) Increased susceptibility to amyloid toxicity in familial Alzheimer’s fibroblasts. Neurobiol Aging 28:863–876CrossRefPubMedGoogle Scholar
  7. Chen Y, Ginis I, Hallenbeck JM (2001) The protective effect of ceramide in immature rat brain hypoxia-ischemia involves up-regulation of bcl-2 and reduction of TUNEL-positive cells. J Cereb Blood Flow Metab 21:34–40CrossRefPubMedGoogle Scholar
  8. Cho SO, Ban JY, Kim JY, Jeong HY, Lee IS, Song KS, Bae K, Seong YH (2009) Aralia cordata protects against amyloid beta protein (25-35)-induced neurotoxicity in cultured neurons and has antidementia activities in mice. J Pharmacol Sci 111:22–32CrossRefPubMedGoogle Scholar
  9. Choi YB, Kim YI, Lee KS, Kim BS, Kim DJ (2004) Protective effect of epigallocatechin gallate on brain damage after transient middle cerebral artery occlusion in rats. Brain Res 1019:47–54CrossRefPubMedGoogle Scholar
  10. Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, Slack RS (2002) Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 158:507–517CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dasgupta S, Kong J, Bieberich E (2013) Phytoceramide in vertebrate tissues: one step chromatography separation for molecular characterization of ceramide species. PLoS ONE 8:e80841CrossRefPubMedPubMedCentralGoogle Scholar
  12. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an n-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601CrossRefPubMedGoogle Scholar
  13. Du K, Montminy M (1998) CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273:32377–32379CrossRefPubMedGoogle Scholar
  14. Ellman GL, Burkhalter A, Ladou J (1961) A fluorometric method for the determination of hippuric acid. J Lab Clin Med 57:813–818PubMedGoogle Scholar
  15. Elyaman W, Terro F, Suen KC, Yardin C, Chang RC, Hugon J (2002) BAD and Bcl-2 regulation are early events linking neuronal endoplasmic reticulum stress to mitochondria-mediated apoptosis. Brain Res Mol Brain Res 109:233–238CrossRefPubMedGoogle Scholar
  16. Ferreiro E, Baldeiras I, Ferreira IL, Costa RO, Rego AC, Pereira CF, Oliveira CR (2012) Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer’s disease: from pathogenesis to biomarkers. Int J Cell Biol 2012:735206CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ferrer I, Blanco R, Carmona M, Puig B (2001) Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies. J Neural Transm 108:1397–1415CrossRefPubMedGoogle Scholar
  18. Ferrer I, Friguls B, Dalfo E, Justicia C, Planas AM (2003) Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat. Neuropathol Appl Neurobiol 29:472–481CrossRefPubMedGoogle Scholar
  19. Furuya K, Ginis I, Takeda H, Chen Y, Hallenbeck JM (2001) Cell permeable exogenous ceramide reduces infarct size in spontaneously hypertensive rats supporting in vitro studies that have implicated ceramide in induction of tolerance to ischemia. J Cereb Blood Flow Metab 21:226–232CrossRefPubMedGoogle Scholar
  20. Gault CR, Obeid LM, Hannun YA (2010) An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 688:1–23CrossRefPubMedPubMedCentralGoogle Scholar
  21. Goodman Y, Mattson MP (1996) Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid beta-peptide toxicity. J Neurochem 66:869–872CrossRefPubMedGoogle Scholar
  22. He FQ, Qiu BY, Zhang XH, Li TK, Xie Q, Cui DJ, Huang XL, Gan HT (2011) Tetrandrine attenuates spatial memory impairment and hippocampal neuroinflammation via inhibiting NF-kappaB activation in a rat model of Alzheimer’s disease induced by amyloid-beta(1-42). Brain Res 1384:89–96CrossRefPubMedGoogle Scholar
  23. Ito A, Horigome K (1995) Ceramide prevents neuronal programmed cell death induced by nerve growth factor deprivation. J Neurochem 65:463–466CrossRefPubMedGoogle Scholar
  24. Jain V, Baitharu I, Prasad D, Ilavazhagan G (2013) Enriched environment prevents hypobaric hypoxia induced memory impairment and neurodegeneration: role of BDNF/PI3 K/GSK3beta pathway coupled with CREB activation. PLoS ONE 8:e62235CrossRefPubMedPubMedCentralGoogle Scholar
  25. Jang JH, Surh YJ (2005) Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-kappaB signaling pathway. Free Radic Biol Med 38:1604–1613CrossRefPubMedGoogle Scholar
  26. Jin G, Omori N, Li F, Sato K, Nagano I, Manabe Y, Shoji M, Abe K (2002) Activation of cell-survival signal Akt by GDNF in normal rat brain. Brain Res 958:429–433CrossRefPubMedGoogle Scholar
  27. Jin Y, Fan Y, Yan EZ, Liu Z, Zong ZH, Qi ZM (2006) Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus. Acta Pharmacol Sin 27:1309–1316CrossRefPubMedGoogle Scholar
  28. Jung JC, Lee Y, Moon S, Ryu JH, Oh S (2011) Phytoceramide shows neuroprotection and ameliorates scopolamine-induced memory impairment. Molecules 16:9090–9100CrossRefPubMedGoogle Scholar
  29. Karege F, Schwald M, Lambercy C, Murama JJ, Cisse M, Malafosse A (2001) A non-radioactive assay for the cAMP-dependent protein kinase activity in rat brain homogenates and age-related changes in hippocampus and cortex. Brain Res 903:86–93CrossRefPubMedGoogle Scholar
  30. Kashour T, Burton T, Dibrov A, Amara FM (2003) Late Simian virus 40 transcription factor is a target of the phosphoinositide 3-kinase/Akt pathway in anti-apoptotic Alzheimer’s amyloid precursor protein signalling. Biochem J 370:1063–1075CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kaya D, Gursoy-Ozdemir Y, Yemisci M, Tuncer N, Aktan S, Dalkara T (2005) VEGF protects brain against focal ischemia without increasing blood–brain permeability when administered intracerebroventricularly. J Cereb Blood Flow Metab 25:1111–1118CrossRefPubMedGoogle Scholar
  32. Khan MM, Ishrat T, Ahmad A, Hoda MN, Khan MB, Khuwaja G, Srivastava P, Raza SS, Islam F, Ahmad S (2010) Sesamin attenuates behavioral, biochemical and histological alterations induced by reversible middle cerebral artery occlusion in the rats. Chem-Biol Interact 183:255–263CrossRefPubMedGoogle Scholar
  33. Kilic E, Kilic U, Soliz J, Bassetti CL, Gassmann M, Hermann DM (2005) Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. FASEB J 19:2026–2028PubMedGoogle Scholar
  34. Kim HC, Yamada K, Nitta A, Olariu A, Tran MH, Mizuno M, Nakajima A, Nagai T, Kamei H, Jhoo WK, Im DH, Shin EJ, Hjelle OP, Ottersen OP, Park SC, Kato K, Mirault ME, Nabeshima T (2003) Immunocytochemical evidence that amyloid beta (1-42) impairs endogenous antioxidant systems in vivo. Neuroscience 119:399–419CrossRefPubMedGoogle Scholar
  35. Kim JY, Lee HK, Jang JY, Yoo JK, Seong YH (2015) Ilex latifolia prevents amyloid beta protein (25-35)-induced memory impairment by inhibiting apoptosis and tau phosphorylation in mice. J Med Food 18:1317–1326CrossRefPubMedPubMedCentralGoogle Scholar
  36. Krause DL, Muller N (2010) Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis. doi: 10.4061/2010/732806 PubMedPubMedCentralGoogle Scholar
  37. Lee JS, Min DS, Park C, Park CS, Cho NJ (2001) Phytosphingosine and C2-phytoceramide induce cell death and inhibit carbachol-stimulated phospholipase D activation in Chinese hamster ovary cells expressing the Caenorhabditis elegans muscarinic acetylcholine receptor. FEBS Lett 499:82–86CrossRefPubMedGoogle Scholar
  38. Lee Y, Kim J, Jang S, Oh S (2013) Administration of phytoceramide enhances memory and upregulates the expression of pCREB and BDNF in hippocampus of mice. Biomol Ther (Seoul) 21:229–233CrossRefGoogle Scholar
  39. Lee HK, Jang JY, Yoo HS, Seong YH (2015) Neuroprotective effect of phytoceramide against transient focal ischemia-induced brain damage in rats. Arch Pharm Res 38:2241–2250CrossRefPubMedGoogle Scholar
  40. Li J, Ding X, Zhang R, Jiang W, Sun X, Xia Z, Wang X, Wu E, Zhang Y, Hu Y (2015) Harpagoside ameliorates the amyloid-beta-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3 K pathways. Neuroscience 303:103–114CrossRefPubMedGoogle Scholar
  41. Li H, Kang T, Qi B, Kong L, Jiao Y, Cao Y, Zhang J, Yang J (2016) Neuroprotective effects of ginseng protein on PI3 K/Akt signaling pathway in the hippocampus of d-galactose/AlCl3 inducing rats model of Alzheimer’s disease. J Ethnopharmacol 179:162–169CrossRefPubMedGoogle Scholar
  42. Lloret A, Fuchsberger T, Giraldo E, Vina J (2015) Molecular mechanisms linking amyloid beta toxicity and Tau hyperphosphorylation in Alzheimers disease. Free Radic Biol Med 83:186–191CrossRefPubMedGoogle Scholar
  43. Lovell MA, Ehmann WD, Butler SM, Markesbery WR (1995) Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45:1594–1601CrossRefPubMedGoogle Scholar
  44. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  45. Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D (2014) Neuroinflammation: the role and consequences. Neurosci Res 79:1–12CrossRefPubMedGoogle Scholar
  46. Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193CrossRefPubMedGoogle Scholar
  47. Miloso M, Scuteri A, Foudah D, Tredici G (2008) MAPKs as mediators of cell fate determination: an approach to neurodegenerative diseases. Curr Med Chem 15:538–548CrossRefPubMedGoogle Scholar
  48. Miranda S, Opazo C, Larrondo LF, Munoz FJ, Ruiz F, Leighton F, Inestrosa NC (2000) The role of oxidative stress in the toxicity induced by amyloid beta-peptide in Alzheimer’s disease. Prog Neurobiol 62:633–648CrossRefPubMedGoogle Scholar
  49. Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM (2007) A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation 4:21CrossRefPubMedPubMedCentralGoogle Scholar
  50. Nakahara S, Yone K, Sakou T, Wada S, Nagamine T, Niiyama T, Ichijo H (1999) Induction of apoptosis signal regulating kinase 1 (ASK1) after spinal cord injury in rats: possible involvement of ASK1-JNK and -p38 pathways in neuronal apoptosis. J Neuropathol Exp Neurol 58:442–450CrossRefPubMedGoogle Scholar
  51. O’Connell C, Gallagher HC, O’Malley A, Bourke M, Regan CM (2000) CREB phosphorylation coincides with transient synapse formation in the rat hippocampal dentate gyrus following avoidance learning. Neural Plast 7:279–289CrossRefPubMedPubMedCentralGoogle Scholar
  52. Pasinetti GM (2002) From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer’s disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia. J Alzheimers Dis 4:435–445CrossRefPubMedGoogle Scholar
  53. Peng Y, Feng SF, Wang Q, Wang HN, Hou WG, Xiong L, Luo ZJ, Tan QR (2010) Hyperbaric oxygen preconditioning ameliorates anxiety-like behavior and cognitive impairments via upregulation of thioredoxin reductases in stressed rats. Prog Neuropsychopharmacol Biol Psychiatry 34:1018–1025CrossRefPubMedGoogle Scholar
  54. Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, Kandel ER (2002) Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34:447–462CrossRefPubMedGoogle Scholar
  55. Posse de Chaves EI (2006) Sphingolipids in apoptosis, survival and regeneration in the nervous system. Biochim Biophys Acta-Biomembr 1758:1995–2015CrossRefGoogle Scholar
  56. Ryder J, Su Y, Ni B (2004) Akt/GSK3beta serine/threonine kinases: evidence for a signalling pathway mediated by familial Alzheimer’s disease mutations. Cell Signal 16:187–200CrossRefPubMedGoogle Scholar
  57. Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116:1–9CrossRefPubMedGoogle Scholar
  58. Sekiya M, Ueda K, Okazaki K, Terashima J, Katou Y, Kikuchi H, Kurata S, Oshima Y (2011) A phytoceramide analog stimulates the production of chemokines through CREB activation in human endothelial cells. Int Immunopharmacol 11:1497–1503CrossRefPubMedGoogle Scholar
  59. Stepanichev MY, Moiseeva YV, Lazareva NA, Onufriev MV, Gulyaeva NV (2003) Single intracerebroventricular administration of amyloid-beta (25-35) peptide induces impairment in short-term rather than long-term memory in rats. Brain Res Bull 61:197–205CrossRefPubMedGoogle Scholar
  60. Su SH, Wang YQ, Wu YF, Wang DP, Lin Q, Hai J (2016) Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3 K/AKT signaling. Behav Brain Res 313:334–344CrossRefPubMedGoogle Scholar
  61. van der Heide LP, Ramakers GM, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79:205–221CrossRefPubMedGoogle Scholar
  62. Waldmeier PC, Tatton WG (2004) Interrupting apoptosis in neurodegenerative disease: potential for effective therapy? Drug Discov Today 9:210–218CrossRefPubMedGoogle Scholar
  63. Wang X, Zheng W, Xie JW, Wang T, Wang SL, Teng WP, Wang ZY (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5:46CrossRefPubMedPubMedCentralGoogle Scholar
  64. Xian YF, Mao QQ, Wu JC, Su ZR, Chen JN, Lai XP, Ip SP, Lin ZX (2014) Isorhynchophylline treatment improves the amyloid-beta-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. J Alzheimers Dis 39:331–346PubMedGoogle Scholar
  65. Yatin SM, Varadarajan S, Link CD, Butterfield DA (1999) In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1-42). Neurobiol Aging 20:325–330 discussion 339–342 CrossRefPubMedGoogle Scholar
  66. Yoshioka T, Kawada K, Shimada T, Mori M (1979) Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol 135:372–376CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2017

Authors and Affiliations

  1. 1.College of Veterinary Medicine and Veterinary Medical CenterChungbuk National UniversityCheongjuRepublic of Korea
  2. 2.College of PharmacyChungbuk National UniversityCheongjuRepublic of Korea

Personalised recommendations