Glial cells play an essential role in the complex function of the nervous
system. In particular, astrocytes provide nutritive support for neuronal cells
and are involved in regulating synaptic transmission. Oligodendrocytes ensheath
axons and support information transfer over long distances. Microglial cells
constitute part of the innate immune system in the brain. Glial cells are
equipped with the glutamate-cystine-exchanger xCT (SLC7A11), the catalytic
subunit of system x, and the excitatory amino acid transporter 1
(EAAT1, GLAST) and EAAT2 (GLT-1). Thereby, glial cells maintain balanced
extracellular glutamate levels that enable synaptic transmission and prevent
excitotoxic states. Expression levels of these transporters, however, are not
fixed. Instead, expression of glial glutamate transporters are highly regulated
in reaction to the external situations. Interestingly, such regulation and
homeostasis is lost in diseases such as glioma, (tumor-associated) epilepsy,
Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis or
multiple sclerosis. Upregulation of system x (xCT or SLC7A11)
increases glutamate export from the cell, while a downregulation of EAATs
decreases intracellular glutamate import. Occurring simultaneously, these
reactions entail excitotoxicity and thus harm neuronal function. The release of
glutamate via the antiporter system x is accompanied by the import of
cystine—an amino acid essential in the antioxidant glutathione. This
homeostasis between excitotoxicity and intracellular antioxidant response is
plastic and off-balance in central nervous system (CNS) diseases. System
x is highly expressed on glioma cells and sensitizes them to
ferroptotic cell death. Hence, system x is a potential target for
chemotherapeutic add-on therapy. Recent research reveals a pivotal role of system
x and EAAT1/2 in tumor-associated and other types of epilepsy.
Numerous studies show that in Alzheimer’s disease, amyotrophic lateral sclerosis
and Parkinson’s disease, these glutamate transporters are dysregulated—and
disease mechanisms could be interposed by targeting system x and
EAAT1/2. Interestingly, in neuroinflammatory diseases such as multiple sclerosis,
there is growing evidence for glutamate transporter involvement. Here, we propose
that the current knowledge strongly suggest a benefit from rebalancing glial
transporters during treatment.