Progesterone inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity

Jessie I. Luoma, Brooke G. Kelley, Paul G. Mermelstein

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The therapeutic use of progesterone following traumatic brain injury has recently entered phase III clinical trials as a means of neuroprotection. Although it has been hypothesized that progesterone protects against calcium overload following excitotoxic shock, the exact mechanisms underlying the beneficial effects of progesterone have yet to be determined. We found that therapeutic concentrations of progesterone to be neuroprotective against depolarization-induced excitotoxicity in cultured striatal neurons. Through use of calcium imaging, electrophysiology and the measurement of changes in activity-dependent gene expression, progesterone was found to block calcium entry through voltage-gated calcium channels, leading to alterations in the signaling of the activity-dependent transcription factors NFAT and CREB. The effects of progesterone were highly specific to this steroid hormone, although they did not appear to be receptor mediated. In addition, progesterone did not inhibit AMPA or NMDA receptor signaling. This analysis regarding the effect of progesterone on calcium signaling provides both a putative mechanism by which progesterone acts as a neuroprotectant, as well as affords a greater appreciation for its potential far-reaching effects on cellular function.

Original languageEnglish (US)
Pages (from-to)845-855
Number of pages11
JournalSteroids
Volume76
Issue number9
DOIs
StatePublished - Aug 2011

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health [Grant NS41302 ] (PGM); the IRACDA Post-Doctoral Fellowship [Grant GM074628 ] (BGK).

Keywords

  • Brain injury
  • Calcium
  • Excitotoxicity
  • Glutamate
  • Ion channels
  • Neuroprotection

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