Carnosine Protects Against Aβ42-induced Neurotoxicity in Differentiated Rat PC12 Cells
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(1) The present study was designed to investigate whether histamine is involved in the protective effect of carnosine on Aβ42-induced impairment in differentiated PC12 cells. (2) PC12 cells were exposed to Aβ42 (5 μM) for 24 h after carnosine (5 mM) applied for 18 h. Histamine receptor antagonists (diphenhydramine, zolantidine, thioperamide, clobenpropit) or histidine decarboxylase inhibitor (α-fluoromethylhistidine) were added 15 min before carnosine. Cell viability, glutamate release or cell surface expression of NMDA receptor was examined. (3) Aβ42 caused a concentration-dependent reduction of viability in PC12 cells and pretreatment with carnosine ameliorated this impairment. This amelioration was reversed by the H3 receptor antagonists thioperamide and clobenpropit, but not by either the H1 receptor antagonist diphenhydramine or the H2 receptor antagonist zolantidine. Further, α-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, also had no effect. In the presence of Aβ42, carnosine significantly decreased glutamate release and carnosine increased the surface expression of NMDA receptor. (4) These results indicate that the mechanism by which carnosine attenuates Aβ42-induced neurotoxicity is independent of the carnosine–histidine–histamine pathway, but may act through regulation of glutamate release and NMDA receptor trafficking.
KeywordsCarnosine Alzheimer’s disease Histamine Aβ42 NMDA receptor Trafficking Neurotoxicity
This project was supported by grants from the National Natural Science Foundation of China (30725047,30572176 and 30600757) and New Century Excellent Talents Program, Ministry of Education, China (NCET-06-0511) and partly by the Zhejiang Province Healthy Excellent Youth Foundation. We are very grateful to Dr. Iain C. Bruce for reading the manuscript.
- Dai H, Zhang Z, Zhu Y, Shen Y, Hu W, Huang Y, Luo J, Timmerman H, Leurs R, Chen Z (2006) Histamine protects against NMDA-induced necrosis in cultured cortical neurons through H2 receptor/cyclic AMP/protein kinase A and H3 receptor/GABA release pathways. J Neurochem 96(5):1390–1400PubMedCrossRefGoogle Scholar
- Fu Q, Dai H, Shen Y (2007) Reversing effect of histamine on neurotoxicity induced by β-amyloid1–42. J Zhejiang Univ Med Sci 36(2):146–149Google Scholar
- McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, DeLucia M, Lin, WL, Dolios, G, Wang, R, Eckman, CB, Dickson, DW, Eckman, CB, Dickson, DW (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47(2):191–199PubMedCrossRefGoogle Scholar
- Pannaccione A, Secondo A, Scorziello A, Cali G, Taglialatela M, Annunziato L (2005) Nuclear factor-kappaB activation by reactive oxygen species mediates voltage-gated K+ current enhancement by neurotoxic beta-amyloid peptides in nerve growth factor-differentiated PC-12 cells and hippocampal neurones. J Neurochem 94(3):572–586PubMedCrossRefGoogle Scholar
- Trombley PQ, Horning MS, Blakemore LJ (2000) Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry (Mosc) 65(7):807–816Google Scholar
- Walton HS, Dodd PR (2006) Glutamate–glutamine cycling in Alzheimer’s disease. Neurochem Int 50:1052–1066Google Scholar