Involvement of Multitargets in Paeoniflorin-Induced Preconditioning

Dong-Mei Chen; Liang Xiao; Xin Cai; Rong Zeng; Xing-Zu Zhu

doi:10.1124/jpet.106.104380

Abstract

Paeoniflorin (PF) is the principal component of Paeoniae radix prescribed in traditional Chinese medicine. The delayed neuroprotection induced by PF preconditioning and its underlying mechanisms were investigated in rat middle cerebral artery occlusion (MCAO) and reperfusion model. At a dosage of 20 or 40 mg/kg, PF preconditioning 48 h before MCAO followed by 24-h reperfusion significantly reduced the mortality and infarct volume and reversed the neurological deficits caused by ischemia. Likewise, the ameliorative effects on mortality, infarct size, and neurological impairment induced by MCAO emerged as well when PF was administered 24 h, 48 h, or 5 days before MCAO at the dose of 20 mg/kg. Furthermore, comparative proteomics analysis was adopted to identify the differentially expressed proteins induced by PF preconditioning itself. The relative levels of 42 proteins were altered after PF preconditioning, among which 20 were elevated and 22 reduced. In summary, A₁ receptor-regulator of G protein signaling-K_ATP signaling, arachidonic acid cascade, nitric oxide system, markers of neuronal damage, mitochondrial damage-related molecules, and the mitogen-activated protein kinase and nuclear factor-κB pathway are associated with the mechanisms of PF preconditioning.

Footnotes

This work was supported by the Ministry of Science and Technology of China (Grant 2004CB720305) and by the Shanghai Metropolitan Fund for Research and Development (Grant 04DZ14005). The authors have declared that they have no conflicting financial interests.
D.-M.C. and L.X. contributed equally to this work.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.106.104380.
ABBREVIATIONS: MCA, middle cerebral artery; PF, paeoniflorn; IPC, ischemic preconditioning; PPC, pharmacological preconditioning; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; TTC, 2,3,7-triphenyltetrazolium chloride; COX, cyclooxygenase; 5-LOX, 5-lipoxygenase; NF, nuclear factor; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; iNOS, inducible nitric-oxide synthase; TH, tyrosine hydroxylase; BDNF, brain-derived neurotrophic factor; HSP70, heat shock protein 70; RGS, regulator of G protein signaling; MCAO, middle cerebral artery occlusion; PCR, polymerase chain reaction; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; 2D, two-dimensional; MALDI, matrix-assisted laser desorption ionization; TOF, time-of-flight; MS, mass spectrometry; LC-ESI-MS/MS, liquid chromatography electrospray ionization tandem mass spectrometry; SNAP25, synaptosomal-associated protein of 25 kDa; PPIase, peptidyl-prolyl cis/trans isomerase; I/R, ischemia and reperfusion injury; 2-DE, two-dimensional electrophoresis.
- Received March 10, 2006.
- Accepted July 12, 2006.