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Neuroprotective effect of mifepristone involves neuron depolarization
Author(s) -
Ghoumari A.M.,
Piochon C.,
Tomkiewicz C.,
Eychenne B.,
Levenes C.,
Dusart I.,
Schumacher M.,
Baulieu E. E.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5832com
Subject(s) - depolarization , neuroprotection , neuroscience , purkinje cell , excitatory postsynaptic potential , cerebellum , glutamatergic , biology , excitotoxicity , neuron , programmed cell death , chemistry , apoptosis , endocrinology , glutamate receptor , receptor , inhibitory postsynaptic potential , biochemistry
In several regions of the developing nervous system, neurons undergo programmed cell death. In the rat cerebellum, Purkinje cell apoptosis is exacerbated when cerebellar slices are cultured during the first postnatal week. To understand the mechanism of this developmental apoptosis, we took advantage of its inhibition by the steroid analog mifepristone. This effect did not involve the classical steroid nuclear receptors. Microarray analysis revealed that mifepristone down‐regulated mRNA levels of the Na + /K + ‐ATPase α3 subunit more than three times. Consistent with the down‐regulation of the Na + /K + ‐ATPase, mifepristone caused Purkinje cell membrane depolarization. Depolarizing agents like ouabain (1 µM), tetraeth‐ylammonium (2 mM), and veratridine (2 µM) protected Purkinje cells from apoptosis. These results suggest a role of excitatory inputs in Purkinje cell survival during early postnatal development. Indeed, coculturing cerebellar slices with glutamatergic inferior olivary neuron preparations allowed rescue of Purkinje cells. These findings reveal a new neuroprotective mechanism of mifepristone and support a pivotal role for excitatory inputs in the survival of Purkinje neurons. Mifepristone may be a useful lead compound in the development of novel therapeutic approaches for maintaining the resting potential of neurons at values favorable for their survival under neuropathological conditions.—Ghoumari, A. M., Piochon, C., Tomkiewicz, C., Eychenne, B., Levenes, C., Dusart, I., Schumacher, M., Baulieu, E. E. Neuroprotective effect of mifepristone involves neuron depolarization. FASEB J. 20, 1377–1386 (2006)