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Glutamate release promotes growth of malignant gliomas


Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative diseases. Although recent data show that cultured glioma cells secrete glutamate, the growth potential of brain tumors has not yet been linked to an excitotoxic mechanism. Using bioluminescence detection of glutamate release from freshly prepared brain slices, we show that implanted glioma cells continue to secrete glutamate. Moreover, gliomas with high glutamate release have a distinct growth advantage in host brain that is not present in vitro. Treatment with the NMDA receptor antagonists MK801 or memantine slowed the growth of glutamate-secreting tumors in situ, suggesting that activation of NMDA receptors facilitates tumor expansion. These findings support a new approach for therapy of brain tumors, based upon antagonizing glutamate secretion or its target receptors.

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We thank S. Goldman for critical review of this manuscript. This study was supported by NIH/NINDS grants NS30007 and NS38073 (to M.N.).

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Correspondence to Maiken Nedergaard.

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Figure 1: Glutamate-secreting glioma cells kill cocultured neurons.
Figure 2: Expression and properties of glutamate transporter in C6 subclones.
Figure 3: Rapid growth of glutamate-secreting gliomas.
Figure 4: MK801 reduces expansion of glutamate-secreting gliomas.
Figure 5: Neuronal death and inflammatory response surrounding glutamate-secreting tumors.
Figure 6: Memantine reduces the expansion of glutamate-secreting gliomas.