title: 17beta-estradiol protects cortical neurons against oxidative stress-induced cell death through reduction in the activity of mitogen-activated protein kinase and in the accumulation of intracellular calcium.
abstract: Although many studies have suggested that estrogen acts as a neuroprotective agent in oxidative stress, the underlying mechanism has not been fully elucidated. In the present study, we examined the effect of 17beta-estradiol (17beta-E2) on H(2)O(2)-induced death signaling in cultured cortical neurons. Exposure of the cortical neurons to H(2)O(2) triggered a series of events, including overactivation of p44/42 MAPK and intracellular Ca(2+) accumulation via voltage-gated Ca(2+) channels and ionotropic glutamate receptors, resulting in apoptotic-like cell death. The MAPK pathway might work as death signaling in our system, because the MAPK pathway inhibitor, U0126, blocked H(2)O(2)-induced MAPK activation, Ca(2+) overload, and cell death. Interestingly, a similar inhibitory effect on H(2)O(2)-triggered MAPK activation, Ca(2+) accumulation, and cell death was observed in cultures incubated with 17beta-E2 for 24 h before exposure to H(2)O(2), suggesting that the protective effect of 17beta-E2 is induced via attenuating overactivation of the MAPK pathway. Furthermore, we found that ionotropic glutamate receptor subunits, including NR2A and GluR2/3, but not NR2B and GluR1, were down-regulated in the 17beta-E2-treated cultures. The down-regulation of these glutamate receptor subunits was also observed after chronic treatment with U0126. Therefore, it is possible that 17beta-E2 down-regulates the expression of the ionotropic glutamate receptors by reducing activity of the MAPK pathway, which might be important for the protective effect of 17beta-E2 against oxidative stress-induced toxicity.
authors.affiliation: Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Numakawa
authors.forename: Tomoya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yokomaku
authors.forename: Takahisa
authors.initials: T
authors.lastname: Taguchi
authors.forename: Etsuo
authors.initials: E
authors.lastname: Niki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Numakawa
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011960:Receptors, Estrogen / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism
chemical_list: D002070:Butadienes; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009570:Nitriles; D016877:Oxidants; D011960:Receptors, Estrogen; D017470:Receptors, Glutamate; C113580:U 0126; D004958:Estradiol; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium