TY - JOUR
T1 - Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation
AU - Im, Joo Young
AU - Kim, Doyeun
AU - Paik, Sang Gi
AU - Han, Pyung Lim
N1 - Funding Information:
This research was supported by a grant (M103KV010014 06K2201 01410) from Brain Research Center, The 21st Century Frontier Research Program of the Ministry of Science and Technology, Republic of Korea.
PY - 2006/9/15
Y1 - 2006/9/15
N2 - Cyclooxygenase-2 (COX-2) expression is induced in the neurons of the pathologic brain and elevated COX-2 expressions can lead to neuronal death. Here, we report that COX-2 induction in cortical neurons induced by LPS pretreatment for more than 12 h increased the neurotoxic effects of low doses of Fe2+ by more than 2.5-fold. Moreover, the neurotoxicity induced by 30 μM Fe2+ in LPS-pretreated cells exceeded that induced by 100 μM Fe2+ in LPS-untreated cells. LPS pretreatment also similarly aggravated the neurotoxic effects of low doses of H2O2, Zn2+, and sodium nitroprusside. This LPS-induced Fe2+-toxicity enhancement was blocked by trolox, vitamin C, the SOD mimetic MnTBAP, and by the COX-2-specific inhibitor NS398, but not by inhibitors of xanthine oxidase, NADPH oxidase, NOS, and monoamine oxidase. Cortical neurons with enhanced COX-2 expression showed superoxide generation, GSH depletion, and lipid peroxidation in response to low doses of Fe2+, and all of these changes were repressed by MnTBAP or NS398. Consistent with this pharmacological data, cortical neurons prepared from COX-2 knockout mice showed marked reductions in LPS-induced Fe2+-toxicity enhancement and superoxide generation. These results suggest that COX-2 functions as a cellular factor which induces superoxide-mediated cell death in primary cortical neurons.
AB - Cyclooxygenase-2 (COX-2) expression is induced in the neurons of the pathologic brain and elevated COX-2 expressions can lead to neuronal death. Here, we report that COX-2 induction in cortical neurons induced by LPS pretreatment for more than 12 h increased the neurotoxic effects of low doses of Fe2+ by more than 2.5-fold. Moreover, the neurotoxicity induced by 30 μM Fe2+ in LPS-pretreated cells exceeded that induced by 100 μM Fe2+ in LPS-untreated cells. LPS pretreatment also similarly aggravated the neurotoxic effects of low doses of H2O2, Zn2+, and sodium nitroprusside. This LPS-induced Fe2+-toxicity enhancement was blocked by trolox, vitamin C, the SOD mimetic MnTBAP, and by the COX-2-specific inhibitor NS398, but not by inhibitors of xanthine oxidase, NADPH oxidase, NOS, and monoamine oxidase. Cortical neurons with enhanced COX-2 expression showed superoxide generation, GSH depletion, and lipid peroxidation in response to low doses of Fe2+, and all of these changes were repressed by MnTBAP or NS398. Consistent with this pharmacological data, cortical neurons prepared from COX-2 knockout mice showed marked reductions in LPS-induced Fe2+-toxicity enhancement and superoxide generation. These results suggest that COX-2 functions as a cellular factor which induces superoxide-mediated cell death in primary cortical neurons.
KW - COX-2
KW - MnTBAP
KW - Neuronal death
KW - NS398
KW - SOD
KW - Superoxide
UR - http://www.scopus.com/inward/record.url?scp=33747348720&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2006.06.001
DO - 10.1016/j.freeradbiomed.2006.06.001
M3 - Article
C2 - 16934679
AN - SCOPUS:33747348720
VL - 41
SP - 960
EP - 972
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 6
ER -