Role of Glutamate Excitotoxicity in Glioblastoma Growth and Its Implications in Treatment

Abstract

Glioblastoma is a highly malignant and invasive type of primary brain tumor that originates from astrocytes. Glutamate, a neurotransmitter in the brain plays a crucial role in excitotoxic cell death. Excessive glutamate triggers a pathological process known as glutamate excitotoxicity, leading to neuronal damage. This excitotoxicity contributes to neuronal death and tumor necrosis in glioblastoma, resulting in seizures and symptoms such as difficulty in concentrating, low energy, depression, and insomnia. Glioblastoma cells, derived from astrocytes, fail to maintain glutamate-glutamine homeostasis, releasing excess glutamate into the extracellular space. This glutamate activates ionotropic N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on nearby neurons, causing hyperexcitability and triggering apoptosis through caspase activation. Additionally, glioblastoma cells possess calcium-permeable AMPA receptors, which are activated by glutamate in an autocrine manner. This activation increases intracellular calcium levels, triggering various signaling pathways. Alkylating agent temozolomide has been used to counteract glutamate excitotoxicity, but its efficacy in directly combating excitotoxicity is limited due to the development of resistance in glioblastoma cells. There is an unmet need for alternative biochemical agents that can have the greatest impact on reducing glutamate excitotoxicity in glioblastoma. In this review, we discuss the mechanism and various signaling pathways involved in glutamate excitotoxicity in glioblastoma cells. We also examine the roles of various receptor and transporter proteins, in glutamate excitotoxicity and highlight biochemical agents that can mitigate glutamate excitotoxicity in glioblastoma and serve as potential therapeutic agents.

Keywords: GLAST; cystine‐glutamate antiporter; glioblastoma; glutamate; mGlu3R; temozolomide.

Figure 1

Glutamine‐Glutamate cycle between a neuron and a glioblastoma cell, facilitates excessive glutamate accumulation within the extracellular environment. This cycle manipulates neurons by inducing glutamate production by glutaminase, which is then fed to other proximal neurons. GBM cells take up glutamate via GLAST transporter. Inside GBM cells glutamate is converted into glutamine by glutamine synthetase. GBM cells release glutamine into the extracellular space which neurons take up via SNAT1 and SNAT2 and convert back to glutamate. GLAST, glutamate‐aspartate transporter; SNAT1, sodium coupled neutral amino acid transporter 1; SNAT2, sodium coupled neutral amino acid transporter 2; SN1 Receptor, System N glutamine transporter or System N1. Created with BioRender.com

Figure 2

Biochemicals that can diminish the effect of glutamate excitoxicity in glioblastoma microenvironment by either targeting the glutamine‐glutamate cycle or the SXc antiporter. GLAST, glutamate‐aspartate transporter; GLT‐1, glutamate transporter 1; SN1, System N 1; SAT1, System A Transporter 1; AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; NMDAR, N‐methyl‐d‐aspartic acid or N‐methyl‐d‐aspartate receptor; Trojan Horse Carrier, IgG fusion protein that binds to anti‐TNF agents and a blood‐brain barrier receptor, allowing the agent to enter the brain. Created with BioRender.com