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.

Agathisflavone, purified from Cenostigma pyramidale (Tul.) has been shown to be neuroprotective in in vitro models of glutamate-induced excitotoxicity and inflammatory damage. However, the potential role of microglial regulation by agathisflavone in these neuroprotective effects is unclear. Here we investigated the effects of agathisflavone in microglia submitted to inflammatory stimulus in view of elucidating mechanisms of neuroprotection. Microglia isolated from cortices of newborn Wistar rats were exposed to Escherichia coli lipopolysaccharide (LPS, 1 µg/mL) and treated or not with agathisflavone (1 µM). Neuronal PC12 cells were exposed to a conditioned medium from microglia (MCM) treated or not with agathisflavone. We observed that LPS induced microglia to assume an activated inflammatory state (increased CD68, more rounded/amoeboid phenotype). However, most microglia exposed to LPS and agathisflavone, presented an anti-inflammatory profile (increased CD206 and branched-phenotype), associated with the reduction in NO, GSH mRNA for NRLP3 inflammasome, IL1-β, IL-6, IL-18, TNF, CCL5, and CCL2. Molecular docking also showed that agathisflavone bound at the NLRP3 NACTH inhibitory domain. Moreover, in PC12 cell cultures exposed to the MCM previously treated with the flavonoid most cells preserved neurites and increased expression of β-tubulin III. Thus, these data reinforce the anti-inflammatory activity and the neuroprotective effect of agathisflavone, effects associated with the control of NLRP3 inflammasome, standing out it as a promising molecule for the treatment or prevention of neurodegenerative diseases.

The imbalance between the overproduction of reactive species and antioxidant mechanisms can result in astrogliosis and oxidative stress associated with neurodegeneration. Based on the described antioxidant activity of naturally occurring flavonoids, this study evaluated the antioxidant mechanisms of the flavonoid naringenin and the senecioic acid ester derivatives in cortical astrocytes. Naringenin and (S)-naringenin were purified from Citrus paradisi, and from them 7,4-O-disenecioic ester naringenin, (S)-7,4-O-disenecioic ester naringenin, and 7-O-senecioic ester naringenin were synthesized and tested for antioxidant activity by the free-radical scavenging reaction with DPPH. The flavonoids’ toxicity and glutathione (GS) depletion were determined in rat astrocyte cultures; the effects on the astrocytes’ reactivity was determined by the expression of the glial fibrillary acidic protein (GFAP) and by measuring nitric oxide (NO) production in astrocytes treated with lipopolysaccharide (LPS, 1 µg/mL/24 h). The compounds (1–10 μM) presented antioxidant effects, and the (S)-7,4′-O-disenecioic ester naringenin was the most effective. The compounds (1–100 μM) were not toxic to the astrocytes, also promoting an antioxidant effect by increasing GSH. Moreover, naringenin, (S)-7,4′-O-disenecioic ester naringenin, and 7-O-senecioc ester naringenin mitigated the astrocyte reactivity induced by LPS, reducing GFAP expression and NO production. These findings indicate that naringenin and senecioic acid ester derivatives present a pharmacological potential as antioxidant and anti-inflammatory compounds for brain diseases via the modulation of astrocyte response.