TY - JOUR
T1 - Characterization of neuroprotection from excitotoxicity by moderate and profound hypothermia in cultured cortical neurons unmasks a temperature- insensitive component of glutamate neurotoxicity
AU - Tymianski, Michael
AU - Sattler, Rita
AU - Zabramski, Joseph M.
AU - Spetzler, Robert F.
PY - 1998/8
Y1 - 1998/8
N2 - 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.
AB - 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.
KW - Calcium
KW - Calcium imaging
KW - Dihydrorhodamine
KW - Excitotoxicity
KW - Free radicals
KW - Glutamate
KW - Glutamate receptors
KW - Hypothermia
KW - Temperature
UR - http://www.scopus.com/inward/record.url?scp=0031852221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031852221&partnerID=8YFLogxK
U2 - 10.1097/00004647-199808000-00005
DO - 10.1097/00004647-199808000-00005
M3 - Article
C2 - 9701346
AN - SCOPUS:0031852221
SN - 0271-678X
VL - 18
SP - 848
EP - 867
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 8
ER -