Combined Application of Glutamate Transporter Inhibitors and Hypothermia Discriminates Principal Constituent Processes Involved in Glutamate Homo- and Heteroexchange in Brain Nerve Terminals.

Deep and profound hypothermia is successfully practiced in the prevention of ischemic stroke consequences and aortic arch cardiac surgery accompanied by reduction of cerebral circulation. Hypothermia is a current neuroprotection standard in hypoxic/ischemic encephalopathy. Drug-hypothermia administration is proposed as a new approach in pharmacotherapy for neonatal seizures. Also, hypothermia is useful as neuroprotective approach in long-term interplanetary space missions. We recently revealed gradual dynamics of hypothermia-induced decrease in transporter-mediated release and uptake of L-[C]glutamate in presynaptic rat brain nerve terminals (synaptosomes), thereby confirming potent unspecific neuroprotective effect of hypothermia. Glutamate homo- and heteroexchange are significant mechanisms involved in the maintenance of the extracellular glutamate level in nerve terminals. We have analyzed whether glutamate homo- and heteroexchange in nerve terminals is temperature sensitive. In this study we showed that synaptosomal glutamate-induced L-[C]glutamate release (homoexchange) and D-aspartate- and DL-threo-β-hydroxyaspartate-induced L-[C]glutamate release (heteroexchange) gradually decreased from deep (27°C) to profound (17°C) hypothermia with dynamics similar to that of glutamate transporter reversal. Interestingly, ambient L-[C]glutamate concentration in the nerve terminal preparations remained unaltered during hypothermia administration. Therefore, we demonstrated that glutamate homo- and heteroexchange decreased from deep to profound hypothermia thereby preventing further elevation of extracellular glutamate. Hypothermia uncovered the principal processes contributing to glutamate homo- and heteroexchange in nerve terminals and the maintenance of definite ambient glutamate concentration. Additionally, we showed that glutamate transporter reversal can be nonpathological and occurs under physiological conditions at least as a part of homo- and heteroexchange mechanisms.