Preconditioning with estradiol abolishes its neuroprotection in cerebellar neurons.
Certain steroids are neuroprotective because they are modulators of neuronal activity or ROS scavengers. We examined neuroprotection following glutamate-induced excitotoxicity in cerebellar granule neuron cultures. 17beta-Estradiol, 17alpha-estradiol (nonestrogenic), or vitamins C+E were equally neuroprotective when coadministered with glutamate, consistent with protection by ROS scavenging. Progesterone protected mainly by an action on GABA-A receptors. Since exogenous antioxidants may influence the level of glutathione, the main endogenous antioxidant in neurons, we investigated if a preconditioning period with the neuroprotectors changed their efficacy as protectors. The neuroprotection by 17beta-estradiol and 17alpha-estradiol, but not progesterone or vitamins C+E, was almost abolished following a preconditioning period of 24h. This reduction was accompanied by an inhibition of the gamma-glutamylcysteine synthetase promoter, and a reduced level of glutathione when preconditioning was combined with the subsequent glutamate exposure. Thus, vitamins C+E and progesterone were more effective long-term neuroprotectors, since preconditioning did not reduce glutathione.
Fallgren
Asa B
AB
Department of Pharmaceutical Biosciences, University of Oslo, P.O. Box 1068 Blindern, N-0316 Oslo, Norway.
Mathisen
Gro H
GH
Maehlen
Jan
J
Blomhoff
Rune
R
Paulsen
Ragnhild E
RE
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats
D004958:Estradiol; D005721:Glutamate-Cysteine Ligase