Polyhydroxylated C(60), fullerenols, as glutamate receptor antagonists and neuroprotective agents.
Derivatives of C(60) have been shown to be effective free radical scavengers. Hence, many of the biological functions of fullerene are believed to be due to their antioxidant properties. Here we present evidence to show that fullerenols, that are caged fullerene oxides, exert their neuroprotective functions by blocking glutamate receptors and lowering the intracellular calcium, [Ca(2+)](i). In neuronal cultures, fullerenols reduce glutamate-induced neurotoxicity by about 80% at 50microM. No significant effect was observed on H(2)O(2)/Fe(2+)-induced neurotoxicity under the same conditions. Fullerenols were found to inhibit glutamate receptor binding in a dose-dependent manner inhibiting 50% of glutamate binding at 50 microM. Furthermore, AMPA receptors were found to be more sensitive to fullerenols than NMDA and KA receptors. On the other hand, GABA(A) receptors and taurine receptors were not significantly affected by fullerenols at the same concentrations used, suggesting that fullerenols inhibit primarily the glutamate receptors. In addition, fullerenols were also found to lower glutamate (Glu) receptor-induced elevation of [Ca(2+)](i), suggesting that the underlying mechanism of neuronal protective function of fullerenols is likely due to its ability to block the glutamate receptors and to reduce the level of [Ca(2+)](i).
Jin
H
H
Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, USA.
Chen
W Q
WQ
Tang
X W
XW
Chiang
L Y
LY
Yang
C Y
CY
Schloss
J V
JV
Wu
J Y
JY
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002244:Carbon / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005290:Ferric Compounds / Q000494:pharmacology; D005333:Fetus; D016166:Free Radical Scavengers / Q000494:pharmacology*; D037741:Fullerenes; D018698:Glutamic Acid / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism
D002712:Chlorides; D018691:Excitatory Amino Acid Antagonists; D005290:Ferric Compounds; D016166:Free Radical Scavengers; D037741:Fullerenes; D018696:Neuroprotective Agents; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; C030803:taurine receptor; C108127:fullerenol; D018698:Glutamic Acid; D002244:Carbon; D006861:Hydrogen Peroxide; D002118:Calcium; C024555:ferric chloride