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The flavonoid apigenin, extracted from the Brazilian plant Croton betulaster Müll. has demonstrated the ability to inhibit proliferation, induce differentiation, and modify the inflammatory profile of glioma cells. The aim of the present study was to evaluate the effect of apigenin on chemotaxis and regulation of inflammatory cytokines of microglia cells and these impacts on glioma cell growth. In cultures of isolated rat microglia, it was observed that apigenin induced changes in Iba1‐positive cells to an ameboid phenotype, associated to an increase in the expression of the activated M1 profile marker OX‐42 and iNOS and a reduction in the expression of the M2 profile marker CD206. Besides, apigenin modulated the tumor necrosis factor and IL‐10 release by microglia. Treatment of C6 glioma cells with conditioned medium of microglia treated with apigenin‐induced reduction of tumor migration and viability, associated with significant reduction in IL‐6 levels. On the other hand, treatment of C6 cells with apigenin‐induced microglia chemotaxis to glioma in vitro. Moreover, apigenin treatment of microglia/C6 co‐cultures induced preferentially reduction in the viability of C6 cells and increased microglia‐activated phenotype, associated with a change in the balance of TNF/IL‐10 levels. Together, these results demonstrated that the flavonoid apigenin restores the immune profile of microglia against glioma cells.

Glioblastomas (GBMs) are tumors that have a high ability to migrate, invade and proliferate in the healthy tissue, what greatly impairs their treatment. These characteristics are associated with the complex microenvironment, formed by the perivascular niche, which is also composed of several stromal cells including astrocytes, microglia, fibroblasts, pericytes and endothelial cells, supporting tumor progression. Further microglia and macrophages associated with GBMs infiltrate the tumor. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by GBM cells and exploited in the process. In this review we discuss the context of the GBM microenvironment together with the actions of flavonoids, which have attracted scientific attention due to their pharmacological properties as possible anti-tumor agents. Flavonoids act on a variety of signaling pathways, counteracting the invasion process. Luteolin and rutin inhibit NFκB activation, reducing IL-6 production. Fisetin promotes tumor apoptosis, while inhibiting ADAM expression, reducing invasion. Naringenin reduces tumor invasion by down-regulating metalloproteinases expression. Apigenin and rutin induce apoptosis in C6 cells increasing TNFα, while decreasing IL-10 production, denoting a shift from the immunosuppressive Th2 to the Th1 profile. Overall, flavonoids should be further exploited for glioma therapy.

Thus, this study suggests that the seed extracts from A. Cearensis exhibit neuroprotective potential against oxidative stress and excitotoxicity induced by glutamate and can be considered a potential therapeutic agent in the treatment of neurodegenerative diseases.