Abstract
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.
Key words
Paxillus curtisii
- Paxillaceae - mushroom - curtisians - glutamate neurotoxicity - iron chelator
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Ick Dong Yoo,PhD
Laboratory of Antioxidants
Korea Research Institute of Bioscience and Biotechnology
P. O. Box 115
Yusong
Daejon 305-600
Korea
Email: idyoo@kribb.re.kr
Fax: +82-42-860-4595