Characterization Of Neuroprotection From Excitotoxicity By Moderate And Profound Hypothermia In Cultured Cortical Neurons Unmasks A Temperature- Insensitive Component Of Glutamate Neurotoxicity
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 (30Â°C) and profound hypothermia (12Â°to 20Â°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 (12Â°to 37Â°C). Cooling neurons to 30Â°C and 20Â°C was neuroprotective, but cooling to 12Â°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 (20Â°and 30Â°C) persisted after rewarming to 37Â°C, but rewarming from 12Â°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.
Journal of Cerebral Blood Flow and Metabolism
Digital Object Identifier (DOI)
Tymianski, Michael; Sattler, Rita; Zabramski, Joseph M.; and Spetzler, Robert F., "Characterization Of Neuroprotection From Excitotoxicity By Moderate And Profound Hypothermia In Cultured Cortical Neurons Unmasks A Temperature- Insensitive Component Of Glutamate Neurotoxicity" (1998). Translational Neuroscience. 367.