ABSTRACT
Cobalt focus is a seizure focus model in which cerebral neurons exhibit long-lasting severe spike discharges, followed by neuronal death. However, the neuronal death is prevented when peony root extract (PR) is administered prior to cobalt application. We tested the hypothesis that PR modulates the expression of neuroprotective proteins in the cerebrum of mouse cobalt focus by proteomic analysis using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry to screen for differentially expressed proteins. Analyses revealed that transthyretin, a carrier protein for thyroid hormones and retinoids, and the brain form of phosphoglycerate mutase, a glycolytic enzyme, were upregulated in the cobalt-treated mouse cerebrum and further increased by PR administration in association with upregulation of neurogranin/RC3, a target of the transcriptional activation by thyroid hormones and retinoids. These findings suggest that PR-induced protection of mouse cerebral neurons involves neurotrophic events caused by thyroid hormones and/or retinoids and enhanced glycolysis.
Subject(s)
Anticonvulsants/administration & dosage , Cerebrum/drug effects , Paeonia , Phosphoglycerate Mutase/metabolism , Plant Extracts/administration & dosage , Plant Roots , Prealbumin/metabolism , Seizures/prevention & control , Animals , Cerebrum/metabolism , Cobalt/antagonists & inhibitors , Cobalt/toxicity , Disease Models, Animal , Electrophoresis, Gel, Two-Dimensional , Mice , Mice, Inbred C57BL , Neurogranin/analysis , Neurogranin/metabolism , Phosphoglycerate Mutase/analysis , Prealbumin/analysis , Proteomics , Seizures/chemically induced , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Thyroid Hormones/metabolism , Up-RegulationABSTRACT
To elucidate the mechanism of inhibitory action of peony root extract on pentylenetetrazol-induced bursting activity, effects of peony root extract on the iberiotoxin-sensitive large conductance calcium-activated potassium (BKCa) current that plays an essential role in the production of bursting activity were investigated. Peony root extract showed a clear inhibitory effect on the iberiotoxin-sensitive calcium-activated potassium current. Peony root extract also showed clear inhibitory effects on spontaneous bursting activity and BKCa current in the cerebral cortical neurons of the EL mouse, a hereditary epilepsy animal model. These results together with our previous studies, including the protective effect against neuron damage, indicate that peony root extract is a promising herbal drug for inhibition of convulsions.
Subject(s)
Action Potentials/drug effects , Anticonvulsants/pharmacology , Paeonia , Phytotherapy , Plant Extracts/pharmacology , Potassium Channels, Calcium-Activated/drug effects , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/therapeutic use , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Mice , Mice, Inbred Strains , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , Plant Roots , Seizures/drug therapyABSTRACT
We investigated the cytotoxic activity of 2-substituted naphtho[2,3-b]furan-4,9-diones. We have previously synthesized 33 types of 2-substituted and related compounds, and the cytotoxic activity of these compounds was then examined by a KB cell culture assay. 2-(3-Furanoyl)benzoic acids and 1,4-naphthoquinones had no activity. 2-Acetyl-4,9-dimethoxynaphtho[2,3-b]furan 4 showed low activity. However, parent naphtho[2,3-b]furan-4,9-dione 2 and most 2-substituted derivatives exhibited cytotoxic activity. The parent structure was therefore for cytotoxicity. 2-Formylnaphtho[2,3-b]furan-4,9-dione 11 had particularly potent activity (ED50=0.09 microg/ml).
Subject(s)
Naphthoquinones/chemistry , Naphthoquinones/toxicity , Cell Proliferation/drug effects , Humans , KB Cells , Molecular Structure , Structure-Activity RelationshipABSTRACT
The molecular mechanism of the protective effects of peony root extract and its component substances on neuron damage induced by the cobalt focus epilepsy model and the EL mouse was investigated. Long-term administration of peony root extract for 30 days prior to metallic cobalt powder application to the cerebral cortex of mice resulted in increased expression of A20, an inhibitor gene of cell death. In the EL mouse, a hereditary epilepsy animal model with vulnerable neurons, increased expression of A20 was observed even without administration of peony root extract. Long-term administration of peony root extract to the EL mouse resulted in a marked increase of expression of A20. These results suggested that an increase in A20 expression is the main molecular mechanism of protective action of peony root extract on neuron damage.
