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Abstract

The current study determined the extracellular content of glutamate, 10 additional amino acids, lactate, glucose and some antioxidants in a rodent model of malignant glioma, its peritumoral space and the adjacent cortex. RG2 tumors were induced in the right frontal cortex of Fischer-344 rats (n = 10) by a standardized procedure to obtain a maximum sagittal tumor width of 3-4 mm diameter. After confirmation of tumor growth and localization by contrast enhanced MRI three microdialysis probes were implanted simultaneously in the cortex: at the tumor implantation site (tumor), 2 mm caudally, brain around tumor (BAT) and 4 mm caudally (cortex) to the site of implantation. Dialysate concentrations of glutamate were increased 3.9-fold in tumor and 2-fold in BAT compared with cortex. Glycine was elevated 11.4-fold in tumor and 2.6-fold in BAT. Lactate was increased 1.7-fold in tumor, 1.2-fold in BAT. Levels of glucose, ascorbic acid and uric acid were not significantly different in tumor, BAT and cortex. The increased dialysate levels of glutamate and glycine in the peritumoral space may contribute to impaired neuronal function and epileptiform activity associated with this tumor type in humans.

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

“…The rationale for this came from previous reports indicating that SAS is a potent pharmacological agent inhibiting the glutamate antiporter xCT [12], [21]. Numerous studies demonstrated that glioma cells secrete high levels of the neurotransmitter glutamate, resulting in neuronal cell death [4], [22], [23], [24] and brain edema [4] via excitatory activation of neuronal glutamate receptors. Glutamate receptor antagonists block neuronal degeneration in the tumor vicinity and lessen glioma growth in vivo , suggesting that neurodegeneration is a prerequisite for rapid glioma progression [25].…”

Neuronal activity in the glioma microenvironment

“…Both glial progenitor cells and glioma cells express glutamate receptors (Gallo et al, 1994; Ishiuchi et al, 2002; Labrakakis et al, 1998), and furthermore, non-synaptic secretion of glutamate by glioblastoma cells has been directly observed in vitro (Ye and Sontheimer, 1999) and supported by in vivo studies describing increased extracellular glutamate levels in brain tissue proximal to glioblastomas (Behrens et al, 2000). Glutamate has been found to promote glioblastoma cell survival, growth and migration via calcium influx-mediated activation of PI3K-Akt signaling through AMPA receptors (Ishiuchi et al, 2002; Ishiuchi et al, 2007; Takano et al, 2001).…”

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

“…Significant increases were also demonstrated in the peritumoral space surrounding experimental brain tumors in rats [6] and in malignant gliomas and oligodendrogliomas in human patients [7, 8]. Glu release occurs via system X(c), a Glu-cystine exchanger that releases Glu in exchange for cystine [9], which is used for the synthesis of the cellular antioxidant glutathione.…”