Mechanism of progesterone neuroprotection of rat cerebellar Purkinje cells following oxygen-glucose deprivation

The survival of rat Purkinje cell (PCs) cerebellar cultures was used to test the hypothesis that progesterone is protective against oxygen–glucose deprivation through potentiation of GABAA receptor activity. Electrophysiological recordings confirm that PCs develop robust excitatory and inhibitory sy...

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Bibliographic Details
Published in:The European journal of neuroscience 2006-11, Vol.24 (9), p.2567-2574
Main Authors: Ardeshiri, A., Kelley, M. H., Korner, I. P., Hurn, P. D., Herson, P. S.
Format: Article
Language:English
Subjects:
allopregnanolone
Animals
Apoptosis - physiology
Cell Hypoxia - physiology
Cells, Cultured
Cerebellum - metabolism
Excitatory Postsynaptic Potentials - physiology
excitotoxicity
Female
GABAA receptor
Glucose - deficiency
Hypoxia-Ischemia, Brain - metabolism
Immunohistochemistry
In Situ Nick-End Labeling
ischemia
Male
Oxygen - metabolism
Patch-Clamp Techniques
Progesterone - metabolism
Purkinje Cells - metabolism
Purkinje Cells - pathology
Rats
Rats, Sprague-Dawley
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Summary:The survival of rat Purkinje cell (PCs) cerebellar cultures was used to test the hypothesis that progesterone is protective against oxygen–glucose deprivation through potentiation of GABAA receptor activity. Electrophysiological recordings confirm that PCs develop robust excitatory and inhibitory synapses in culture. Exposure of cultured PCs to increasing concentrations of progesterone during oxygen–glucose deprivation revealed a concentration‐dependent protection by progesterone, with significant protection observed at physiological concentrations, as low as 10 nm. The concurrent application of the GABAA receptor antagonist picrotoxin (100 µm) completely abolished the neuroprotection afforded by progesterone, indicating that progesterone is neuroprotective through activation of GABAA receptors. Progesterone potentiates GABAA receptor activity indirectly through its metabolites, such as allopregnanolone (ALLO). Therefore, ALLO was applied to PC cultures and was observed to produce significant protection at all concentrations tested, from 10 to 1000 nm. Finally, the inhibition of progesterone metabolism with finasteride abolished the protection afforded by progesterone without having any effect on the neuroprotection caused by ALLO. These data indicate that progesterone protects cerebellar PCs at physiological concentrations through a GABA‐active metabolite.
ISSN:0953-816X
1460-9568
DOI:10.1111/j.1460-9568.2006.05142.x