Phytoestrogen Agathisflavone Ameliorates Neuroinflammation-Induced by LPS and IL-1β and Protects Neurons in Cocultures of Glia/Neurons

Abstract

Inflammation and oxidative stress are common aspects of most neurodegenerative diseases in the central nervous system. In this context, microglia and astrocytes are central to mediating the balance between neuroprotective and neurodestructive mechanisms. Flavonoids have potent anti-inflammatory and antioxidant properties. Here, we have examined the anti-inflammatory and neuroprotective potential of the flavonoid agathisflavone (FAB), which is derived from the Brazilian plant Poincianella pyramidalis, in in vitro models of neuroinflammation. Cocultures of neurons/glial cells were exposed to lipopolysaccharide (LPS, 1 µg/mL) or interleukin (IL)-1β (10 ng/mL) for 24 h and treated with FAB (0.1 and 1 µM, 24 h). FAB displayed a significant neuroprotective effect, as measured by nitric oxide (NO) production, Fluoro-Jade B (FJ-B) staining, and immunocytochemistry (ICC) for the neuronal marker β-tubulin and the cell death marker caspase-3, preserving neuronal soma and increasing neurite outgrowth. FAB significantly decreased the LPS-induced microglial proliferation, identified by ICC for Iba-1/bromodeoxyuridine (BrdU) and CD68 (microglia M1 profile marker). In contrast, FAB had no apparent effect on astrocytes, as determined by ICC for glial fibrillary acidic protein (GFAP). Furthermore, FAB protected against the cytodestructive and proinflammatory effects of IL-1β, a key cytokine that is released by activated microglia and astrocytes, and ICC showed that combined treatment of FAB with α and β estrogen receptor antagonists did not affect NF-κB expression. In addition, qPCR analysis demonstrated that FAB decreased the expression of proinflammatory molecules TNF-α, IL-1β, and connexins CCL5 and CCL2, as well as increased the expression of the regulatory molecule IL-10. Together, these findings indicate that FAB has a significant neuroprotective and anti-inflammatory effect in vitro, which may be considered as an adjuvant for the treatment of neurodegenerative diseases.

Lipopolysaccharide From E. coli Increases Glutamate-Induced Disturbances of Calcium Homeostasis, the Functional State of Mitochondria, and the Death of Cultured Cortical Neurons

“…This leads to the cytodestructive and pro-inflammatory effects of IL-1β, a key cytokine secreted by LPS-activated microglia and astrocytes. Together, these processes in vivo contribute to the development of neurodegenerative diseases ( O’Brien and Austin, 2019 ; de Almeida et al, 2020 ). LPS are ligands for Toll-like receptors (TLRs) of the fourth type (TLR4) on the surface of antigen-presenting cells related to innate immune cells ( Bsibsi et al, 2002 ; Uematsu and Akira, 2006 ; Mook-Kanamori et al, 2011 ).…”

The flavonoid agathisflavone modulates the microglial neuroinflammatory response and enhances remyelination

“…Agathisflavone is a flavonoid derived from the Brazilian plant Poincianella pyramidalis (Tul. ), which we have previously shown to have neuroprotective and neuromodulatory effects in vitro [ 12 , 13 ]. Previously, we postulated that agathisflavone may act via estrogen receptors (ER) and retinoic acid receptors (RAR) [ 14 ], which are pharmacological targets for the treatment of demyelinating conditions [ 15 , 16 ].…”

Exploitation of In Vivo-Emulated In Vitro System in Advanced Food Science

“…By exposing the neuron-glial coculture system to LPS or interleukin (IL)-1β, the neuroinflammation status could be successfully built. Detecting inflammatory cytokines expressions helped confirm the neuroprotective effects of agathisflavone . Besides, Zhu et al cocultured BV-2 microglial with human neuroblastoma SH-SY5Y to build inflammation-mediated neuronal oxidative injury.…”