Characterization of neuroprotection from excitotoxicity by moderate and profound hypothermia in cultured cortical neurons unmasks a temperature- insensitive component of glutamate neurotoxicity

Michael Tymianski, Rita Sattler, Joseph M. Zabramski, Robert F. Spetzler

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Although profound hypothermia has been used for decades to protect the human brain from hypoxic or ischemic insults, little is known about the underlying mechanism. We therefore report the first characterization of the effects of moderate (30°C) and profound hypothermia (12°to 20°C) on excitotoxicity in cultured cortical neurons exposed to excitatory amino acids (EAA; glutamate, N-methyl-D-aspartate [NMDA], AMPA, or kainate) at different temperatures (12°to 37°C). Cooling neurons to 30°C and 20°C was neuroprotective, but cooling to 12°C was toxic. The extent of protection depended on the temperature, the EAA receptor agonist employed, and the duration of the EAA challenge. Neurons challenged briefly (5 minutes) with all EAA were protected, as were neurons challenged for 60 minutes with NMDA, AMPA, or kainate. The protective effects of hypothermia (20°and 30°C) persisted after rewarming to 37°C, but rewarming from 12°C was deleterious. Surprisingly, however, prolonged (60 minutes) exposures to glutamate unmasked a temperature-insensitive component of glutamate neurotoxicity that was not seen with the other, synthetic EAA; this component was still mediated via NMDA receptors, not by ionotropic or metabotropic non-NMDA receptors. The temperature-insensitivity of glutamate toxicity was not explained by effects of hypothermia on EAA-evoked [Ca2+](i) increases measured using high- and low-affinity Ca2+ indicators, nor by effects on mitochondrial production of reactive oxygen species. This first characterization of excitotoxicity at profoundly hypothermic temperatures reveals a previously unnoticed feature of glutamate neurotoxicity unseen with the other EAA, and also suggests that hypothermia protects the brain at the level of neurons by blocking, rather than slowing, excitotoxicity.

Original languageEnglish (US)
Pages (from-to)848-867
Number of pages20
JournalJournal of Cerebral Blood Flow and Metabolism
Volume18
Issue number8
DOIs
StatePublished - Aug 1998
Externally publishedYes

Keywords

  • Calcium
  • Calcium imaging
  • Dihydrorhodamine
  • Excitotoxicity
  • Free radicals
  • Glutamate
  • Glutamate receptors
  • Hypothermia
  • Temperature

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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