Neuroprotective effects of paeoniflorin, but not the isomer albiflorin, are associated with the suppression of intracellular calcium and calcium/calmodulin protein kinase II in PC12 cells

The root of Paeonia lactiflora Pall (family Ranunculaceae) or peony root, a herbal medicine, possesses therapeutic potential for neurodegenerative diseases. The isomers paeoniflorin (PF) and albiflorin (AF) are major constituents contained in peony root. Our previous study has shown notable neuroprotective effects of PF. In the present study, we further compared the effects of AF and PF against glutamate (Glu)-induced cell damage and the underlying mechanisms in differentiated PC12 cells. Both AF and PF significantly ameliorated Glu-induced reduction of cell viability, nuclear and mitochondrial apoptotic alteration, Reactive Oxygen Species accumulation, and B-cell lymphoma 2 (Bcl-2)/Bax ratio. The two isomers also enhanced phosphorylation of Akt and its downstream element glycogen synthase kinase-3β, and this effect was abrogated by the Akt Inhibitor LY294002. PF, but not AF, however, suppressed intracellular Ca(2+) overload and the expression of calcium/Calmodulin protein kinase II (CaMKII). The improvement of cell damage by the CaMKII inhibitor KN93 further confirms the role of CaMKII in PF-mediated neuroprotection. These results suggest that both AF and PF possess robust effects in protecting neuronal cells against Glu toxicity. PF further displayed remarkable effects in preventing intracellular Ca(2+) overload and suppressing overexpression of CaMKII. Differential mechanisms may be involved in neuroprotective action of the two isomers.