Carnosine protects against Aβ42-induced neurotoxicity in differentiated rat PC12 cells

(1) The present study was designed to investigate whether histamine is involved in the protective effect of carnosine on A beta 42-induced impairment in differentiated PC12 cells. (2) PC12 cells were exposed to A beta 42 (5 mu M) for 24 h after carnosine (5 mM) applied for 18 h. Histamine receptor antagonists (diphenhydramine, zolantidine, thioperamide, clobenpropit) or histidine decarboxylase inhibitor (alpha-fluoromethylhistidine) were added 15 min before carnosine. Cell viability, glutamate release or cell surface expression of NMDA receptor was examined. (3) A beta 42 caused a concentration-dependent reduction of viability in PC12 cells and pretreatment with carnosine ameliorated this impairment. This amelioration was reversed by the H-3 receptor antagonists thioperamide and clobenpropit, but not by either the H-1 receptor antagonist diphenhydramine or the H-2 receptor antagonist zolantidine. Further, alpha-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, also had no effect. In the presence of A beta 42, 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 A beta 42-induced neurotoxicity is independent of the carnosine-histidine-histamine pathway, but may act through regulation of glutamate release and NMDA receptor trafficking.