Clinical-molecular correlation of glutamatergic signalling in multiple sclerosis

Abstract

Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Here, we have examined if glutamate homeostasis is altered in peripheral blood from MS patients. We initially observed that plasma glutamate levels are elevated in MS patients. In addition, we have studied the presence of a polymorphism sited in the promoter of the glutamate transporter EAAT2 whose mutant genotype results in lower transporter expression. We found that the polymorphism is associated with higher glutamate plasma levels during the course of a relapse. Alteration of glutamate levels in MS is probably related to monocyte immune reaction because LPS-activated monocytes, but not PHA-activated lymphocytes, release glutamate through the cystine/glutamate antiporter system xc-. In addition, the expression of the catalytic L chain of cystine/glutamate antiporter xCT is highly increased in EAE, in MS samples as well as in LPS-activated monocytes. Immunohistochemistry analysis showed that xCT is highly upregulated in inflamed meningeal membranes and in inflammatory foci in EAE animals. Moreover, glutamate transporter EAAT1 expression is also slightly increased in the three aforementioned paradigms, probably as a compensatory mechanism to the elevated glutamate levels in MS. Together, these results suggest that disturbances in glutamatergic signalling could contribute to MS pathophysiology and point to xCT as a therapeutic target of the disease.