Disrupted glutamate homeostasis as a target for glioma therapy

Pharmacol Rep. 2024 Dec;76(6):1305-1317. doi: 10.1007/s43440-024-00644-y. Epub 2024 Sep 11.

Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Gliomas, malignant brain tumors with a dismal prognosis, alter glutamate homeostasis in the brain, which is advantageous for their growth, survival, and invasion. Alterations in glutamate homeostasis result from its excessive production and release to the extracellular space. High glutamate concentration in the tumor microenvironment destroys healthy tissue surrounding the tumor, thus providing space for glioma cells to expand. Moreover, it confers neuron hyperexcitability, leading to epilepsy, a common symptom in glioma patients. This mini-review briefly describes the biochemistry of glutamate production and transport in gliomas as well as the activation of glutamate receptors. It also summarizes the current pre-clinical and clinical studies identifying pharmacotherapeutics targeting glutamate transporters and receptors emerging as potential therapeutic strategies for glioma.

Keywords: Glioblastoma; Glutamate; Glutamate receptors; Glutamate transport; Neurotoxicity.

Publication types

  • Review

MeSH terms

  • Amino Acid Transport System X-AG / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Glioma* / drug therapy
  • Glioma* / metabolism
  • Glioma* / pathology
  • Glutamic Acid* / metabolism
  • Homeostasis*
  • Humans
  • Receptors, Glutamate / metabolism
  • Tumor Microenvironment / drug effects

Substances

  • Glutamic Acid
  • Receptors, Glutamate
  • Amino Acid Transport System X-AG
  • Antineoplastic Agents