p-Terphenyl curtisians protect cultured neuronal cells against glutamate neurotoxicity via iron chelation.
The hyperactivity of ionotropic glutamate receptors has been implicated in the development of the neuronal cell death seen in many neurodegenerative processes including ischemic stroke, traumatic brain injury, and epilepsy. Thus neuronal protection against glutamate-induced neurotoxicity is considered as an appropriate therapeutic strategy for preventing and treating neurodegenerative diseases. Whilst searching for blockers of glutamate-induced toxicity in mouse cortical cells, we isolated p-terphenyl curtisians A - D from the mushroom Paxillus curtisii. Curtisians protected cortical neurons from glutamate-induced toxicity in a dose-dependent manner. Among the glutamate receptor subtypes, curtisians were found to block NMDA receptor-mediated but not AMPA/kainate-mediated cell death. In addition, we found that curtisians exhibited potent antioxidative activity against iron-mediated oxidative damage which was generated by H2O2 neurotoxocity and lipid peroxidation, but no activity was detected in the superoxide, DPPH and ABTS radical scavenging systems, and in protection of N18-RE-105 cells subjected to glutamate-induced glutathione depletion. This effect was likely due to the iron chelating properties of curtisians. The iron chelation ability of curtisians was then further investigated on DNA single strand breakage (SSB) induced by the addition of iron and H2O2, and curtisians prevented DNA SSB like the iron chelator desferrioxamine. These results suggest that the neuroprotective action of curtisians is dependent on their ability to chelate iron as well as to block the NMDA receptor, and that in this context curtisians may be useful as neuroprotective agents against neurological disorders which result in neuronal cell death.
Lee
In-Kyoung
IK
Laboratory of Antioxidant, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon, Korea.
Yun
Bong-Sik
BS
Kim
Jong-Pyung
JP
Kim
Won-Gon
WG
Ryoo
In-Ja
IJ
Oh
Seikwan
S
Kim
Young-Ho
YH
Yoo
Ick-Dong
ID
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001487:Basidiomycota; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid; D020128:Inhibitory Concentration 50; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008517:Phytotherapy
D000975:Antioxidants; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D010648:Phenylacetates; D018698:Glutamic Acid