Artikel
Continuous administration of the glutamate receptor antagonist memantine fails to supress orthotopic glioma growth
Kontinuierliche Gabe des Glutamatrezeptor-Antagonisten Memantine unterdrückt nicht das orthotope Gliomwachstum
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Autoren
Veröffentlicht: | 23. April 2004 |
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Gliederung
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Objective
Glutamate excitoxicity is involved in numerous CNS disorders. In addition, it has been suggested that glutamate is involved in the pathogenesis of malignant glioma and that inhibition of glutamate-mediated signalling may suppress tumor growth. The aim of the present study was to assess the effects of a continuous administration of the glutamate receptor antagonist memantine on orthotopic glioma growth.
Methods
500000 C6 rat glioma cells were implantated stereotactically (depth of 6mm, right striatum) into 16 male Wistar rats (200-250g). Before implantation, glutamate release/uptake of our C6 cell line was analyzed in vitro using a photometric, enzyme-kinetic analyzer. Following tumor implantation, rats were randomly assigned to two groups and received subcutaneous osmotic mini pumps loaded with memantine (n=8) or saline (n=8). Memantine loading dose was calculated to achieve continuous therapeutic levels over 14 days. Memantine plasma levels were controlled on days 2 and 14. After 14 days the rats were sacrified and their brains processed for histological analysis. Brain specimens were embedded in paraffin, serially sectioned (5mm), and tumor volume was determined using an image analysis system.
Results
Our C6 cells were characterized by a balanced glutamate release/uptake. Determination of memantine levels demonstrated that continuous administration of the drug had resulted in plasma levels well within the therapeutic range (day2, 144±12ng/ml; day14, 148±41ng/ml). Nevertheless, memantine failed to significantly supress tumor growth. Control tumors ranged between 4.6mm3 and 17.3mm3 (mean±SD:9.4±5.5mm3) and memantine treated tumors ranged between 3.5mm3 and 14.4mm3 (mean±SD:8.0±3.9mm3).
Conclusions
The glutamate receptor antagonist memantine is ineffective in suppressing orthotopic glioma growth, even if the compound is administered continuously at therapeutic levels that have been shown to be effective in preventing neuronal damage in other CNS disorders.