Tetramethylpyrazine (TMP) protects cerebral neurocytes and inhibits glioma by down regulating chemokine receptor CXCR4 expression

Abstract

The survival in patients with malignant gliomas still remains limited and novel treatment strategies are urgently needed. Tetramethylpyrazine (TMP) extracted from the Chinese herb Chuanxiong, has been suggested to have a therapeutic potential towards glioma primarily through its neural protection activity. However, the exact mechanisms correlating TMP’s antitumor function and neural protection have not been yet elucidated. Thus, this study aimed to investigate TMP’s molecular target in tumor inhibition and neural protection. The primary cultured cerebral neurocytes were treated with 100μM TMP for 14days in vitro. We found TMP can effectively promote neurons survival, compared to controls. TMP effectively inhibits H2O2-induced rise of [Ca2+]i and glutamate releasing in cerebral neurocytes, compared to controls. In addition, we verify previous results that TMP significantly decreases the migration and proliferation of C6 glioma cells. Using glioma–neuronal co-culturing system, we further confirm TMP bioactivity in inhibition of glioma cells and protection of cerebral neurocytes. More importantly, our study demonstrates that the expression of chemokine receptor, CXCR4, which plays a key role in tumor development and various neurodegenerative diseases, is significantly decreased in both cerebral neurocytes and C6 glioma cells with TMP treatment, cultured alone or co-cultured. Compared with CXCR4 antagonist, AMD3100, TMP is more effective on glioma inhibition and neural protection. Glutamate concentration in medium of co-culturing system was lower after treatment with 100μM TMP. Therefore, our findings suggest that TMP-mediated suppression of C6 gliomas and neural protection involves inhibition of CXCR4 expression. Thus, this study provides new insights into TMP’s therapeutic potential in the treatment of malignant gliomas.