Phytoceramide ameliorates ß-amyloid protein-induced memory impairment and neuronal death in mice
- 359 Downloads
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.
KeywordsPhytoceramide Alzheimer’s disease β-amyloid protein (25–35) Memory impairment Neuroprotection
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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