Investigation of Mechanisms of SSRI Antidepressants and GABAAR Modulators Inhibit High-Grade Glioma Invasion

Glioma is one of the most common primary brain tumors in humans. Treatment options include surgical removal, radiation therapy and chemotherapy. Glioma cells have the ability to invade surrounding brain tissue. This invasion ability limits successful surgical resection and increases recurrence levels. Therefore, recent strategies in the treatment of gliomas have focused on inhibiting the invasion of malignant cells. In the past, it was thought that glioma invasion and migration was mainly due to changes in the intercellular cytoskeleton organization and the extracellular matrix degradation. Recent studies have shown that the hydrodynamic cellular volume changes are keys in understanding the glioma invasion process. First, the leading edge of the glioma invading cell shrinks in order to cross the small spatial barrier interval. Then, the leading edge recovers its volume and drags the lagging edge of the cell over the interval. The hydrodynamic cellular volume change facilitates the invasion process of the glioma cell. The hydrodynamic cell volume change is controlled by the intracellular ion concentration which is regulated by ion channels. By interrupting the regulation of intracellular ion concentrations (especially that of the calcium and chloride ions) it is possible to interfere with the cell volume change and therefore diminish the glioma invasion ability. Our preliminary data shows that the AMPA receptor and GABA receptor are overexpressed in glioma cells. Activation of these ion channels results in the irreversible shrinking of the glioma cells and the invasion ability of the glioma cells is then diminished. Our past study showed that fluoxetine (Prozac®), an antidepressant, could activate the AMPAR, induce calcium ion influx and imbalance the intracellular ion concentration (NSC 102-2314-B-038 -042). In this study, we attempted to explore the therapeutic effects of fluoxetine in inhibiting glioma invasion. In addition, the GABA receptor modulators (including benzodiazepine and phenobarbital) could activate the chloride efflux in glioma cells and this might have the potential to block invasion by glioma cells. The aims of the three-year project are: Aims-1st year: (1) Screen for potential neuropsychological medications using the National Health Insurance Research Database and computer-aided screening platform. (2) Clarify the correlation between the ion channel expression level and the invasion ability of glioma. Aims-2nd year: (1) Research the safe dosage (2) in vitro study to understand the role of ion channels in glioma invasion. (3) Validation of the neuropsychological medications in inhibiting glioma invasion. Aim-3rd year: (1) In vivo pharmacokinetic test. (2) In vivo studies to conform the therapeutic potential.