Paeoniflorin, a natural neuroprotective agent, modulates multiple anti-apoptotic and pro-apoptotic pathways in differentiated PC12 cells

Cell Mol Neurobiol. 2013 May;33(4):521-9. doi: 10.1007/s10571-013-9914-y. Epub 2013 Feb 24.


Numerous studies have shown robust neuroprotective effects of paeoniflorin (PF), a natural compound derived from the herbal medicine Paeony radix. In the present study, we determined associations of PF neuroprotection with its modulation of various apoptotic and anti-apoptotic pathways. PF (50-400 μM) pretreatment significantly improved viability of differentiated PC12 cells exposed to methyl-4-phenylpyridine ion (MPP(+)), a neurotoxin, and inhibited over-release of lactate dehydrogenase, a biomarker of neuronal cell death. PF also ameliorated MPP(+)-induced nuclear and mitochondrial apoptotic alteration and intracellular calcium overload. PF treatment reversed MPP(+) suppression of activity of B cell lymphoma-extra large, which is a mitochondrial membrane molecule that protects cells from DNA damage-induced apoptosis, and strikingly inhibited the enhanced level of cleaved poly(ADP-ribose)polymerase, which is involved in the process of apoptosis. PF alone and coadministration with MPP(+) enhanced phospho activation of extracellular signal-regulated kinases, Akt, and its downstream element glycogen synthase kinase-3, but the effects were completely abolished in the presence of their blockers PD98059 and LY294002. The presence of the blockers also diminished the potency of PF in improving viability of MPP(+)-exposed cells. These results indicate that neuroprotective effects of PF are related to its modulation of multiple anti-apoptotic and pro-apoptotic pathways, including blockade of intracellular calcium overload, prevention of mitochondrial membrane integrity, inhibition of pro-apoptotic molecules, and up-regulation of anti-apoptotic proteins associated with cell survival and proliferation. The study provides evidence supporting PF as a potential therapeutic agent used for the treatment of neurodegenerative diseases and neural injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Apoptosis / drug effects*
  • Benzoates / pharmacology*
  • Bridged-Ring Compounds / pharmacology*
  • Calcium / metabolism
  • Cell Differentiation / drug effects*
  • Cell Survival / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glucosides / pharmacology*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Monoterpenes
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • bcl-X Protein / metabolism


  • Benzoates
  • Bridged-Ring Compounds
  • Glucosides
  • Monoterpenes
  • Neuroprotective Agents
  • bcl-X Protein
  • peoniflorin
  • Poly(ADP-ribose) Polymerases
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3
  • 1-Methyl-4-phenylpyridinium
  • Calcium