| Research Abstract |
Recently, we reported the application of an oxygen-independent real-time technique for monitoring glutamate levels in the extracellular space during in vivo ischemia and hypoxia, using a dialysis electrode. This dialysis electrode technique allows detailed analysis of the in vivo dynamics of not only severe acute ischemia produced by transecting the bilateral carotid arteries, but also those of an ischemia-reperfusion model. In particular, during the ischemia-reperfusion period, the mechanisms of glutamate release are assumed to involve three sequential processes : 1) neurotransmitter, i.e.glutamate, release from synaptic vesicles (1st phase of [Glu]_e), 2) reversed uptake of glutamate from the metabolic pool in neuronal cells (2nd phase of release), and 3) re-uptake into the intracellular space by normalization of the glutamate uptake carrier system during the postischemic period (re-uptake phase of [Glu]_e).
We found that the in vivo dynamics of biphasic [Glu]_e output from the intrac
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ellular space, as well as reduced reuptake of [Glu]_e into the intracellular space following 10 minutes of ischemia in terms of the three above-mentioned [Glu]_e compartments, and that an ischemic injury mechanism which is sensitive to temperature may not actually increase the extracellular glutamate concentration ([Glu]_e) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the reversed uptake of glutamate. We speculated that enhancing Glu re-uptake, pharmacologically or hypothermically, may shorten exposure to high [Glu]_e in the postischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells.
Preloading with a novel glutamate transporter inhibitor (tPDC) decreased both the 1st and 2nd phases of [Glu]e evation. Furthermore, rats treated with nicergoline (32 mg /kg, i.p.), an ergot alkaloid derivative, showed minimal mhibition of the [Glu]_e elevation which characteristically occurs during the 10-min intraischemic period, while Glu re-uptake was dramatically improved in the postischemic period, when severe transient global ischemia was caused by mild hyperthennia. Moreover, the nicergoline (32 mg /kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies aimed at inhibition or prevention of the reversed uptake of glutamate release during ischemia, i.e. activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia. Less
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