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Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity

S Z Lei1, D Zhang, A E Abele

  • 1Department of Neurology, Children's Hospital, Boston, MA.

Brain Research
|December 11, 1992
PubMed

Insights

Excessive calcium influx from NMDA receptor activation triggers intracellular calcium release, causing neurotoxicity. Dantrolene blocks this release, protecting neurons and reducing NMDA receptor-mediated damage.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Pharmacology

Background:

  • NMDA receptor activation increases intracellular calcium (Ca2+), potentially leading to neurotoxicity.
  • The source of this elevated Ca2+ (influx vs. intracellular stores) in response to NMDA is not fully understood.

Purpose of the Study:

  • To investigate whether NMDA-induced Ca2+ responses involve mobilization of intracellular Ca2+ stores.
  • To determine if blocking intracellular Ca2+ release protects neurons from NMDA receptor-mediated neurotoxicity.

Main Methods:

  • Utilized ionomycin and EGTA to deplete intracellular Ca2+ stores.
  • Administered dantrolene to block Ca2+ release from intracellular stores.
  • Measured Ca2+ responses to NMDA in cultured rat cortical and retinal ganglion cells.

Main Results:

  • Depleting intracellular Ca2+ stores reduced NMDA-evoked Ca2+ responses by approximately 50%.
  • Dantrolene significantly inhibited NMDA-evoked Ca2+ responses, indicating a major contribution from intracellular Ca2+ release.
  • Dantrolene demonstrated neuroprotective effects against NMDA receptor-induced toxicity.

Conclusions:

  • A significant portion of the NMDA receptor-mediated Ca2+ response originates from intracellular Ca2+ stores, triggered by initial Ca2+ influx.
  • Intracellular Ca2+ release is a critical step in NMDA receptor-induced neurotoxicity.
  • Targeting intracellular Ca2+ release pathways, such as with dantrolene, offers a potential therapeutic strategy for neuroprotection.

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