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Journal of Neuroscience, Vol 16, 65-70, Copyright © 1996 by Society for Neuroscience
11 beta-Hydroxysteroid dehydrogenase in cultured hippocampal cells reactivates inert 11-dehydrocorticosterone, potentiating neurotoxicity
V Rajan, CR Edwards and JR Seckl
Edinburgh University, Department of Medicine, Western General Hospital, United Kingdom.
11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the conversion
of the glucocorticoid corticosterone (cortisol in humans) to inert
11-dehydrocorticosterone (cortisone). 11 beta-HSD activity is present in
the hippocampus, where it is induced by glucocorticoids and stress in vivo,
prompting suggestions that the enzyme may attenuate the deleterious effects
of chronic glucocorticoid excess on neuronal function and survival. Two
isoforms exist: 11 beta-HSD1, a bidirectional NADPH-dependent enzyme, and
11 beta-HSD2, an NAD(+)- dependent exclusive 11 beta-dehydrogenase
(corticosterone-inactivating enzyme). In this study, 11 beta-HSD1 activity
and mRNA synthesis were demonstrated in primary fetal hippocampal cell
cultures. Unexpectedly, the reaction direction in intact hippocampal cells
was 11 beta- reduction (reactivation of inert 11-dehydrocorticosterone),
although homogenization revealed that the enzyme was capable of 11 beta-
dehydrogenation when removed from its normal cellular context.
Dexamethasone (10(-7) M) increased 11 beta-HSD activity in homogenates of
hippocampal cultures (102% increase). In intact hippocampal cells,
dexamethasone induced 11 beta reductase, not dehydrogenase. To determine
the functional relevance of hippocampal 11 beta-reductase, glucocorticoid
potentiation of kainic acid neurotoxicity was examined. Pretreatment of
hippocampal cells with corticosterone reduced survival on kainate exposure.
Hippocampal cell 11 beta-HSD activity was potently inhibited by
carbenoxolone. Carbenoxolone had no effect on cell survival after kainate
alone and did not alter the effect of corticosterone.
11-Dehydrocorticosterone also potentiated kainate neurotoxicity; this
effect was lost, however, if 11 beta-HSD was inhibited with carbenoxolone.
Thus, hippocampal 11 beta-HSD seems to be a functional 11 beta-reductase in
intact cells. Measures to attenuate hippocampal 11 beta-reductase may
reduce neuronal vulnerability to glucocorticoid toxicity.
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