1. ¹Department of Neurology, University of California, San Francisco, California, USA
2. ²Department of Anesthesiology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
3. ³Department of Pain Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
4. ⁴Departments of Anesthesiology, Sanggye Paik Hospital, Inje University, School of Medicine, Seoul, Korea
5. ⁵Department of Physiology, College of Medicine, Hallym University, Chun Cheon, Korea

Correspondence: Dr SW Suh, Department of Neurology (127), 4150 Clement Street, UCSF, VAMC, San Francisco, CA 94121, USA. E-mail: sang.suh@ucsf.edu

⁶These authors equally contributed to this work.

Received 14 May 2009; Revised 26 August 2009; Accepted 30 September 2009; Published online 28 October 2009.

Abstract

Hypothermia reduces neuronal damage after cerebral ischemia and traumatic brain injury, while hyperthermia exacerbates damage from these insults. Previously we have shown that temperature-dependent modulation of excitotoxic neuronal death is mediated in part by temperature-dependent changes in the synaptic release/translocation of Zn²⁺. In this study, we hypothesize that brain temperature also affects hypoglycemia-induced neuronal death by modulation of vesicular Zn²⁺ release from presynaptic terminals. To test our hypothesis, we used a rat model of insulin-induced hypoglycemia. Here we found that hypoglycemia-induced neuronal injury was significantly affected by brain temperature, that is, hypothermia inhibited while hyperthermia aggravated neuronal death. To investigate the mechanism of temperature-dependent neuronal death after hypoglycemia, we measured zinc release/translocation, reactive oxygen species (ROS) production, and microglia activation. Here we found that hypoglycemia-induced Zn²⁺ release/translocation, ROS production, and microglia activation were inhibited by hypothermia but aggravated by hyperthermia. Even when the insult was accompanied by hyperthermic conditions, zinc chelation inhibited ROS production and microglia activation. Zinc chelation during hyperthermia reduced neuronal death, superoxide production, and microglia activation, which was comparable to the protective effects of hypothermia. We conclude that neuronal death after hypoglycemia is temperature-dependent and is mediated by increased Zn²⁺ release, superoxide production, and microglia activation.