Brazilian Green Propolis Suppresses the Hypoxia-Induced Neuroinflammatory Responses by Inhibiting NF-κB Activation in Microglia

Abstract

Hypoxia has been recently proposed as a neuroinflammatogen, which drives microglia to produce proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative, and anti-inflammatory effects, propolis may have protective effects against the hypoxia-induced neuroinflammatory responses. In this study, propolis (50 μg/mL) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, by MG6 microglia following hypoxic exposure (1% O2, 24 h). Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) from mitochondria and the activation of nuclear factor-κB (NF-κB) in microglia. Moreover, systemic treatment with propolis (8.33 mg/kg, 2 times/day, i.p.) for 7 days significantly suppressed the microglial expression of IL-1β, TNF-α, IL-6, and 8-oxo-deoxyguanosine, a biomarker for oxidative damaged DNA, in the somatosensory cortex of mice subjected to hypoxia exposure (10% O2, 4 h). These observations indicate that propolis suppresses the hypoxia-induced neuroinflammatory responses through inhibition of the NF-κB activation in microglia. Furthermore, increased generation of ROS from the mitochondria is responsible for the NF-κB activation. Therefore, propolis may be beneficial in preventing hypoxia-induced neuroinflammation.

Preventing and Reversing “Microglia-Aging” by Nature Materials for Slow Brain-Aging

“…These observations suggest that microglia in the aged brain are primed and over-reacted to systemic challenges [29][30][31][32][33]. More recently, the mean level of IL-1β secreted by primary cultured microglia prepared from the aged brains is significantly higher than that from the young brains [12,29,34]. These observations further support our proposed concept of "microglia-aging" [2,35] (Figure 1).…”

“…We have previous found that excessive production of ROS due to the increased oxidative mtDNA damages in microglia is responsible for exaggerated neuroinflammatory responses in the aged animals after treatment with LPS, because the increased intracellular ROS level activates NF-κB signaling pathway which regulates the expression of several proinflammatory mediators [2]. Hypoxia can drive microglia to generate ROS [3][4][5][6], and we have recently found that hypoxia activates NF-κB signaling pathway to induce exaggerated inflammatory responses by microglia [12] (Figure 1). The brain is highly vulnerable to hypoxic stress due to its high oxygen requirement and therefore, low oxygen availability at high altitudes results in cognitive impairments [47].…”

“…The chronic hypoxia contributes to the onset and progression of AD [12,58,59], because hypoxia activates microglia to produce pro-inflammatory mediators, including IL-1β TNF-α and IL-6 [7-9,12]. Microglia-mediated neuroinflammatory responses are closely associated with AD pathogenesis [13], because pro-inflammatory responses mediated by microglia promote neuronal cell damage and excessive Aβ deposition [13,60].…”

“…We have provided evidence that the excessive reactive oxygen species (ROS) and pro-inflammatory mediators produced by microglia cause neuroinflammation during aging [2]. On the other hand, hypoxia can drive microglia to generate ROS [3][4][5][6][7], resulting in NF-κB-dependent excessive production of pro-inflammatory mediators, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) [8][9][10][11][12]. Furthermore, microglia-mediated neuroinflammation is closely associated with AD pathogenesis [13], because overproduction of pro-inflammatory mediators by microglia triggers neuroinflammatory responses to promote neuronal damages and deposition of amyloid-β (Aβ) [14,15].…”

“…On the other hand, antiinflammatory agents improve cognitive functions in AD [16,17]. Recently, we have found that propolis, a resinous substance produced by honeybees as a defense against intruders, inhibits the hypoxia-induced production of pro-inflammatory mediators by microglia through inhibiting the generation of mitochondria-derived ROS and the subsequent activation of NF-κB signaling pathway [12]. Furthermore, propolis improves the cognitive functions of the people living at the high altitude [18].…”