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Jing Zhuang, Keming Yu, Pei Chen, Xiaoxiao Cai, Ying Yang, Nandan Wu, Lijun Xu; Tetramethylpyrazine (TMP), a Unique Small Molecule Modulator of Chemokine receptor, CXCR4.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2465.
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© ARVO (1962-2015); The Authors (2016-present)
TMP has been used in many clinical treatments with mild side effects, including glaucoma, diseases of the central nervous system, and tumor in China. However, TMP’s precise molecular mechanism remains unclear. In this study, we aimed to elucidate whether the mechanism of TMP-medicated is involved in the chemokine receptor, CXCR4, which plays a fundamental role in many pathological processes.
To investigate the mechanism of TMP’s inhibition of neovascularization, we established murine models: alkali burn-induced corneal neovascularization (NV). Moreover, the whole-blood viscosity and platelet aggregation rate of the SD rats treated with TMP or vehicle (normal saline). Furthermore, the neuroprotective effects of TMP were tested with the primary neurocytes. The rise of Ca2+ and glutamate levels induced by H2O2 was measured by LSCM and ELISA kit respectively. Glioma-neuronal co-culturing system was used to investigate the TMP bioactivity in inhibition of glioma and neural protection. And the expression of CXCR4 was analyzed by real-time RT-PCR and western blot assay.
Compared to controls, TMP significantly suppresses corneal neovascularization in rat model of corneal alkali burn injury. CXCR4 expression in rat cornea is significantly increased with alkali burn, and is dramatically down-regulated with TMP treatment. Moreover, TMP significantly down-regulates the expression of CXCR4 of platelets, lymphocytes and blood red cells. Whole-blood viscosity and platelet aggregation in rats are significantly decreased by TMP treatment. Furthermore, compared to controls, TMP can significantly promote neurons survival by inhibiting H2O2-induced rise of [Ca(2+)]i and glutamate releasing in neurocytes. Using glioma-neuronal co-culturing system, we further confirm TMP bioactivity in inhibition of glioma cells and neural protection. More importantly, the expression of CXCR4 is significantly decreased in neurocytes as well as in glioma cells with TMP treatment, cultured alone or co-cultured. These findings above are confirmed by siRNA interference and CXCR4 antagonist, AMD3100.
Our findings suggest that the CXCR4/SDF-pathway may be a mechanism, which we believe to be novel, underlying TMP-mediated inhibition of neovascularization and tumor, and neural protection. This study will further extend the application of TMP treatment in clinical therapy.
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