Glutamate in the Pathogenesis of Gliomas

Abstract

Recent studies have shown that glutamate may serve important roles in the pathobiology of primary brain tumors. Glutamate is produced and secreted from gliomas via specific glutamate transporters as a byproduct of glutathione synthesis. Glutamate also plays a major role in the phenotype of malignant gliomas by several mechanisms. The consequential interaction of glutamate with peritumoral neuronal glutamate receptors leads to the development of seizures and excitotoxicity. The latter is thought to promote the expansion gliomas in the vacated surrounding tissue. Glutaminergic receptors such as α-Amino-3-hydroxy-5-methyl-4-isoaxazolepropionic acid (AMPA) which lack the GluR2 subunit can activate the AKT and MAPK pathway, to promote the invasion of glioma cells into normal brain tissue. Stimulation of glutaminergic receptors also leads to the activation of focal adhesion kinase, which regulates the proliferation and motility of malignant glioma cells. Given the extensive involvement of glutamate in development of gliomas, it is likely that pharmacological therapies targeting glutaminergic receptors and glutamate transport may be useful to inhibit glutamate-mediated glioma growth.