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Tetramethylpyrazine inhibits activities of glioma cells and glutamate neuro-excitotoxicity: Potential therapeutic application for treatment of gliomas

Department of Anatomy (Y.-S.F.), Department of Pharmacology (H.C.); Institute of Anatomy and Cell Biology (Y.-Y.L., S.-C.C., S.-Y.H.), and Institute of Traditional Medicine (T.-H.T.), School of Medicine, National Yang-Ming University, Taipei, Taiwan; Faculty of Life Sciences, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan (L.-S.K.); Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (Y.-S.F., T.-H.T.); Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan (F.-C.C.); Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan (Y.-H.S.); School of Medicine, Taipei Medical University, Taipei, Taiwan (Y.-H.S.); Neural Regeneration Laboratory and Center for Neural Regeneration, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan (H.C.); Department of Automation Engineering, Nan Kai Institute of Technology, Nantou, Taiwan (Y.-Y.F.); and Department of Physiology, National Defense University, Taipei, Taiwan (J.-Y.W.)

Address correspondence to Yu-Show Fu, Department of Anatomy, School of Medicine, National Yang-Ming University, 155 Sec. 2, Li-Nung Street, Taipei, Taiwan, 112 (ysfu{at}ym.edu.tw).

We tested the herbal extract 2,3,5,6-tetramethylpyrazine (TMP) for possible therapeutic efficacy against a glioma cell line and against gliomas transplanted into rat brains. In the cultured glioma cells, 50 µM TMP significantly inhibited glutamate-induced increase in intracellular calcium. Significant cell damage (30%) and proliferation suppression (10%), however, occurred only at higher concentrations (200-400 µM). Gliomaneuronal co-culturing resulted in significant neuronal damage and higher proliferation of the glioma cells (140%) compared with single cultures. Low concentrations of TMP (200 µM) attenuated the neuronal damage, suppressed glioma migration, and decreased glioma proliferation in the neuronal-glioma co-culture. Gliomas transplanted into the frontal cortical area exhibited high proliferation, with untreated rats dying 10-23 days later. TMP treatment inhibited tumor growth and significantly extended survival time. The results indicate that TMP can suppress glioma activity, including growth, and protect neurons against glioma-induced excitotoxicity, suggesting that TMP may have therapeutic potential in the treatment of malignant gliomas.

Key Words: calcium • excitotoxicity • glioblastoma multiforme • tetramethylpyrazine