Abstract
Retinal ischemia is a common cause of many retinal diseases, leading to irreversible vision impairment and blindness. Excessive neuroinflammation, including microglial activation and T-cell responses, has been identified as a critical factor associated with neurodegeneration in retinal ischemia. Baicalein is a natural flavonoid reported to have broad anti-inflammatory and neuroprotective bioactivities. Herein, the effects of baicalein on microglia activation in vitro and in vivo were investigated. We found that baicalein exhibited robust anti-inflammatory effect on cultured human and mouse microglia, as demonstrated by decreased induction of pro-inflammatory cytokines and the phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear factor kappa B (NFκB). Proteomic analysis further unraveled baicalein’s effect on modulating IL-17 signaling pathways and its upstream regulator IL-1β. Intravitreal administration of baicalein in the mouse model of retinal ischemia/reperfusion (I/R) injury attenuated microglial activation and retinal T-cell infiltration, particularly the T helper 17 cells. Additionally, baicalein was shown to exert neuroprotective effects by significantly reducing the retinal ganglion cell (RGC) loss after I/R injury, leading to an improved retinal function and spatial vision. These results suggest that baicalein, a natural flavonoid, acts as a negative regulator of activated microglia and immune responses both in vitro and in vivo, effectively alleviating neurodegeneration in retinal I/R injury. This finding indicates that baicalein could be a potential therapeutic agent against currently incurable degenerative retinal diseases.
Highlights
Ischemia is a pathological condition caused by restricted blood supply to tissues, leading to neuronal death and functional loss in the central nervous system (CNS) [1, 2]
The present study demonstrated that baicalein exhibits robust anti-inflammatory effects in both human and mouse microglial cells, which were likely achieved by attenuating the phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear factor-kB (NFkB)
Administration of baicalein in vivo to I/R injured mice resulted in the alleviation of retinal neuroinflammation, as characterized by the suppression of microglial activation, downregulation of interleukin 1 beta (IL-1b), subsequent inhibition of Th17 cell infiltration, and activation of Th17 and Th1 cells in lymph node (LN)
Summary
Ischemia is a pathological condition caused by restricted blood supply to tissues, leading to neuronal death and functional loss in the central nervous system (CNS) [1, 2]. Recent studies demonstrate that acute ischemia induces a prolonged phase of neurodegeneration, presenting a potential therapeutic window for rescuing resulting vision loss [5]. Microglia are the primary resident immune cells and key players of innate immunity in the CNS, providing immune surveillance and neuronal support [6]. They rapidly react to stress by becoming activated [7] and displaying characteristic morphological changes. This is often accompanied by the proliferation, migration, and upregulation of pro-inflammatory cytokines that recruit peripheral immune cells to the CNS [8, 9]. Accumulating evidence from acute retinal ischemia/reperfusion (I/R) studies demonstrated that chronic microglial activation and neuroinflammation play a key role in driving neurodegeneration [5, 11, 12]. Suppression of prolonged microglial activation or driving inflammatory microglia back to their homeostasis may present a critical strategy for neuroprotective therapies
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