Levetiracetam-mediated improvement of decreased NMDA-induced glutamate release from nerve terminals during hypothermia.

A combination of a beneficial neuroprotectant, hypothermia, with targeted medication is a perspective therapeutic approach. Here, we analyzed both non-specific (deep and profound hypothermia, 27 °C and 17 °C, respectively) and targeted (anticonvulsant drug levetiracetam) modulation of l-[14C]glutamate release induced by activation of presynaptic NMDA, AMPA, and kainate receptors in rat brain nerve terminals (synaptosomes). Gradual dynamics of hypothermia-mediated decrease in synaptosomal l-[14C]glutamate release evoked by the receptor agonists NMDA-, AMPA-, and kainate (250 μM) has been demonstrated that can be of value for the justification of optimal temperature regimes in therapeutic hypothermia. 250 μM NMDA-induced l-[14C]glutamate release from nerve terminals was higher in the presence of levetiracetam (100 μM) as compared to that without the drug. Despite levetiracetam effects decreased in hypothermia, combined application of hypothermia and levetiracetam resulted in higher NMDA-induced l-[14C]glutamate release from nerve terminals as compared to that without the drug. These effects were not revealed for synaptosomal AMPA- and kainate-induced l-[14C]glutamate release in the presence of levetiracetam at the similar concentration. Therefore, levetiracetam administration significantly mitigated a hypothermia-induced decrease in NMDA receptor response at the presynaptic level and can be used for the targeted neurocorrection to reduce side effects of hypothermia in cardiac surgery. However, levetiracetam-mediated improvement of NMDA receptor response is not applicable in stroke, brain trauma and neonatal asphyxia therapies, where the main neuroprotective action of hypothermia is associated with prevention of damaging consequence of pre-existing acute glutamate exitotoxicity.