(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.
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Airaksinen MS, Paetau A, Paljarvi L, Reinikainen K, Riekkinen P, Suomalainen R, Panula P (1991) Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains. Neuroscience 44(2):465–481
Bonfanti L, Peretto P, De Marchis S, Fasolo A (1999) Carnosine related dipeptides in the mammalian brain. Prog Neurobiol 59(4):333–353
Carmosino M, Procino G, Nicchia GP, Mannucci R, Verbavatz JM, Gobin R, Svelto M, Valenti G (2001) Histamine treatment induces rearrangements of orthogonal arrays of particles (OAPs) in human AQP4-expressing gastric cells. J Cell Biol 154(6):1235–1243
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):1390–1400
Doble A (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 81(3):163–221
Donzanti BA, Yamamoto BK (1988) An improved and rapid HPLC-EC method for the isocratic separation of amino acid neurotransmitters from brain tissue and microdialysis perfusates. Life Sci 43(11):913–922
Flancbaum L, Fitzpatrick JC, Brotman DN, Marcoux AM, Kasziba E, Fisher H (1990) The presence and significance of carnosine in histamine-containing tissues of several mammalian species. Agents Actions 31(3–4):190–196
Fonteh AN, Harrington RJ, Tsai A, Liao P, Harrington MG (2007) Free amino acid and dipeptide changes in the body fluids from Alzheimer’s disease subjects. Amino Acids 32(2):213–224
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):146–149
Haas H, Panula P (2003) The role of histamine and the tuberomammillary nucleus in the nervous system. Nat Rev Neurosci 4(2):121–130
Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M (1998) Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1(5):355–358
Hipkiss AR (1998) Carnosine, a protective, anti-ageing peptide? Int J Biochem Cell Biol 30(8):863–868
Hobart LJ, Seibel I, Yeargans GS, Seidler NW (2004) Anti-crosslinking properties of carnosine: significance of histidine. Life Sci 75(11):1379–1389
Jin CL, Yang LX, Wu XH, Li Q, Ding MP, Fan YY, Zhang WP, Luo JH, Chen Z (2005) Effects of carnosine on amygdaloid-kindled seizures in Sprague-Dawley rats. Neuroscience 135(3):939–947
Kasziba E, Flancbaum L, Fitzpatrick JC, Schneiderman J, Fisher H (1988) Simultaneous determination of histidine-containing dipeptides, histamine, methylhistamine and histidine by high-performance liquid chromatography. J Chromatogr 432:315–320
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):191–199
Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, Salter MW (2003) Glycine binding primes NMDA receptor internalization. Nature 422(6929):302–307
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):572–586
Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T, Kalimo H, Relja M (1998) Neuronal histamine deficit in Alzheimer’s disease. Neuroscience 82(4):993–997
Passani MB, Bacciottini L, Mannaioni PF, Blandina P (2000) Central histaminergic system and cognition. Neurosci Biobehav Rev 24(1):107–113
Prestona JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN (1998) Toxic effects of beta-amyloid(25–35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Neurosci Lett 242(2):105–108
Schwartz JC, Arrang JM, Garabarg M, Pollard H, Ruat M (1991) Histaminergic transmission in the mammalian brain. Physiol Rev 71(1):1–51
Sharpan IuV (1984) Influence of carnosine on the immunosuppressive effect of histamine. Biull Eksp Biol Med 98(11):603–604
Shen Y, Hu WW, Fan YY, Dai HB, Fu QL, Wei EQ, Luo JH, Chen Z (2007) Carnosine protects against NMDA-induced neurotoxicity in differentiated rat PC12 cells through carnosine-histidine-histamine pathway and H(1)/H(3) receptors. Biochem Pharmacol 73(5):709–717
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8(8):1051–1058
Tanzi PE, Bertram L (2005) Twenty years of the Alzheimer’s review disease amyloid hypothesis: a genetic perspective. Cell 120(4):545–555
Trombley PQ, Horning MS, Blakemore LJ (1998) Carnosine modulates zinc and copper effects on amino acid receptors and synaptic transmission. Neuroreport 9(15):3503–3507
Trombley PQ, Horning MS, Blakemore LJ (2000) Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry (Mosc) 65(7):807–816
Walton HS, Dodd PR (2006) Glutamate–glutamine cycling in Alzheimer’s disease. Neurochem Int 50:1052–1066
Wu X, Ding M, Zhu-Ge Z, Zhu Y, Jin C, Chen Z (2006) Carnosine, a precursor of histidine, ameliorates pentylenetetrazole-induced kindled seizures in rat. Neurosci Lett 400(1–2):146–149
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.
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Fu, Q., Dai, H., Hu, W. et al. Carnosine Protects Against Aβ42-induced Neurotoxicity in Differentiated Rat PC12 Cells. Cell Mol Neurobiol 28, 307–316 (2008). https://doi.org/10.1007/s10571-007-9235-0
- Alzheimer’s disease
- NMDA receptor