Abstracts

Rationale: Hypothermia is neuroprotective when induced following cardiac arrest, stroke, and traumatic brain injury. The physiological effects of hypothermia are multifaceted and therefore a better knowledge of its therapeutic targets will be central to developing innovative combination therapies to augment the protective benefits of hypothermia. Development of a calcium plateau following status epilepticus has been implicated in expression of acquired epilepsy and cognitive deficits. This study was therefore initiated to evaluate the effect of hypothermia on calcium plateau. The contribution of various modes of calcium entry into a neuron following hypothermia was also evaluated. Methods: Status epilepticus was induced into hippocampal neuronal cultures by exposing them to a solution containing no added MgCl2. Fluorescent calcium indicator Fura-2AM was used to compare calcium ratio under normothermic (37oC) and hypothermic (31oC) conditions. We also utilized pharmacological agents to stimulate major routes of calcium entry in hippocampal neurons. Results: The results of this study indicate that hypothermia blocks the development of calcium plateau following status epilepticus. Hypothermia preferentially reduces calcium entry through N-methyl-D-aspartate receptors and ryanodine receptors. Hypothermia, on the other hand, did not have a significant effect on calcium entry through the voltage-dependent calcium channels or the inositol tri-phosphate receptors. Conclusions: Altered neuronal calcium dynamics have been implicated following stroke, status epilepticus and traumatic brain injury. The ability of hypothermia to block the calcium plateau which is shown to be mediated by both N-methyl-D-aspartate receptors and ryanodine receptors-mediated calcium systems makes it an attractive pharmacological target for alleviating calcium elevations that are present following many neurological injuries.