Samenvatting
Malfunctioning of system xc-, responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress as well as excitotoxicity, important phenomenons in the pathogenesis of Parkinson's disease and epilepsy.
We used mice lacking xCT (xCT-/- mice), the specific subunit of system xc-, to study in vivo the effect of system xc- deficiency on striatal and hippocampal glutathione content and extracellular glutamate concentrations. Next, we investigated the sensitivity of xCT-/- mice for a Parkinson's disease inducing toxin (6-hydroxydopamine, 6-OHDA) as well as for chemoconvulsants evoking limbic seizures.
Although cystine, imported via system xc-, is intracellularly reduced to cysteine, the rate-limiting substrate in glutathione synthesis, deletion of xCT did not affect striatal or hippocampal glutathione levels. Accordingly, no signs of increased oxidative stress were seen in xCT-/- mice. However, extracellular hippocampal and striatal glutamate levels were decreased with >60% in xCT-/- mice compared to controls. In addition, intrahippocampal perfusion with system xc- inhibitors lowered extracellular glutamate whereas the system xc- activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system xc- may be an interesting target for pathologies associated with excessive extracellular glutamate release. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of N-acetylcysteine. Moreover, in sharp contrast to the expectations, xCT-/- mice were less susceptible to 6-OHDA-induced neurodegeneration in substantia nigra pars compacta compared to wildtype littermates.
The current data sustain that system xc- is an important source of hippocampal and striatal extracellular glutamate and an innovative target for the future development of antiepileptic and/or neuroprotective drugs.
We used mice lacking xCT (xCT-/- mice), the specific subunit of system xc-, to study in vivo the effect of system xc- deficiency on striatal and hippocampal glutathione content and extracellular glutamate concentrations. Next, we investigated the sensitivity of xCT-/- mice for a Parkinson's disease inducing toxin (6-hydroxydopamine, 6-OHDA) as well as for chemoconvulsants evoking limbic seizures.
Although cystine, imported via system xc-, is intracellularly reduced to cysteine, the rate-limiting substrate in glutathione synthesis, deletion of xCT did not affect striatal or hippocampal glutathione levels. Accordingly, no signs of increased oxidative stress were seen in xCT-/- mice. However, extracellular hippocampal and striatal glutamate levels were decreased with >60% in xCT-/- mice compared to controls. In addition, intrahippocampal perfusion with system xc- inhibitors lowered extracellular glutamate whereas the system xc- activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system xc- may be an interesting target for pathologies associated with excessive extracellular glutamate release. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of N-acetylcysteine. Moreover, in sharp contrast to the expectations, xCT-/- mice were less susceptible to 6-OHDA-induced neurodegeneration in substantia nigra pars compacta compared to wildtype littermates.
The current data sustain that system xc- is an important source of hippocampal and striatal extracellular glutamate and an innovative target for the future development of antiepileptic and/or neuroprotective drugs.