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, epilepsy and many other neurological disorders. We observed increased expression levels of xCT, the specific subunit of system xc-, in brain samples of rodent models for several neurological disorders. Therefore, we used mice lacking xCT (xCT-/- mice) 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 Parkinson's disease inducing toxins as well as for chemoconvulsants evoking limbic seizures. Although cystine, imported via system xc-, is intracellularly reduced to cysteine, the rate-limiting building block 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 rat hippocampus, suggesting that system xc- might 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, 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 that might become activated in pathological conditions and as such cause accumulation of extracellular glutamate. Inhibition of system xc- might thus represent an innovative strategy for the future development of drugs for the treatment of neurological disorders that are characterized by dysregulated glutamatergic neurotransmission.
|Tijdschrift||Journal of Neurochemistry|
|Nummer van het tijdschrift||s1|
|Status||Published - 2013|
|Evenement||The 24th Biennial Meeting of the International Society for Neurochemistry and the American Society for Neurochemistry - Cancun, Mexico|
Duur: 20 apr 2013 → 24 apr 2013