Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat

D. L. McCullers, P. G. Sullivan, S. W. Scheff, J. P. Herman

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

The present study addresses mineralocorticoid receptor and glucocorticoid receptor effects on hippocampal neuron viability after experimental traumatic brain injury. Rats were pretreated for 48 h with vehicle, the mineralocorticoid receptor antagonist spironolactone, or the glucocorticoid receptor antagonist mifepristone (RU486) and subsequently subjected to sham operation or unilateral controlled cortical impact injury. To determine the effects of receptor antagonist pretreatments on cell survival, neurons in regions CA1, CA3, and dentate gyrus of the hippocampal formation were counted 24 h post-injury using the optical fractionator method. Injury decreased the number of viable neurons in CA1 and CA3 of vehicle-pretreated animals. Notably, this cell loss was prevented in CA1 by RU486 pretreatment. Neuronal loss was also observed in dentate gyrus. The effects of receptor blockade and injury on the expression of viability-related genes were also assessed by comparing relative bcl-2, bax, and p53 messenger RNA levels using in situ hybridization analysis. Spironolactone and RU486 decreased basal bcl-2 messenger RNA levels in CA1 and dentate gyrus but did not affect basal bax or p53 levels. Injury decreased bcl-2 messenger RNA levels in dentate gyrus but did not affect bax or p53 levels in vehicle-pretreated animals. These data demonstrate that RU486 pretreatment prevents the loss of CA1 pyramidal neurons 24 h after traumatic brain injury. RU486 modulation of bcl-2, bax, or p53 messenger RNA expression does not predict neuronal viability at this time point, suggesting that RU486-mediated preservation of CA1 neurons does not involve transcriptional regulation of these cell death-related genes.

Original languageEnglish
Pages (from-to)219-230
Number of pages12
JournalNeuroscience
Volume109
Issue number2
DOIs
StatePublished - Jan 28 2002

Bibliographical note

Funding Information:
This work was supported by AG12962 (J.P.H.), AG10836 (J.P.H.), AG00242 (D.L.M.), NS39828 (S.W.S.), and KSCHIRT (S.W.S.). The authors would like to thank Mark Dolgas and Katie Kraft for expert technical assistance.

Keywords

  • Cortical impact
  • Glucocorticoid receptor
  • Mineralocorticoid receptor
  • Spironolactone
  • bax
  • bcl-2

ASJC Scopus subject areas

  • General Neuroscience

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