Abstract
Neuroinflammation has been well recognized as a key pathological event in acute glaucoma. The medical therapy of acute glaucoma mainly focuses on lowering intraocular pressure (IOP), while there are still scarce anti-inflammatory agents in the clinical treatment of acute glaucoma. Here we reported that β,3α,5α-trihydroxy-androst-6-one (sterone), a novel synthetic polyhydric steroid, blocked neuroinflammation mediated by microglia/macrophages and alleviated the loss of retinal ganglion cells (RGCs) caused by acute intraocular hypertension (AIH). The results showed that sterone significantly inhibited the morphological changes, the up-regulation of inflammatory biomarker ionized calcium-binding adapter molecule 1 (Iba-1), and the mRNA increase of proinflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) in BV2 microglia and RAW264.7 macrophages. Moreover, immunofluorescence and western blotting analysis revealed that sterone markedly abrogated the nuclear translocation and phosphorylation of nuclear factor-κB (NF-κB) p65 subunit. Furthermore, sterone significantly suppressed the inflammatory microglial activation and RGCs’ reduction caused by retinal ischemia/reperfusion (I/R) injury in a rat AIH model. These results suggest sterone may be a potential candidate in the treatment of acute glaucoma caused by microglial activation-mediated neuroinflammatory injury.
Highlights
Acute glaucoma is a leading cause of blindness characterized by progressive loss of retinal ganglion cells (RGCs) and axons in the optic nerves, which is mainly caused by rapid increase of intraocular pressure (IOP), i.e., acute intraocular hypertension (AIH)
Since a trend has been set in the development of neuroactive steroids as therapeutic agents for numerous central nervous system (CNS) diseases, ocular neurological diseases including acute glaucoma may benefit from these promising neuroprotectants, especially the structure-modified synthetic steroids
The present study showed that a synthetic compound sterone possessed anti-neuroinflammatory features by targeting the inflammatory activation of microglia/macrophages via inhibiting the nuclear factor-κB (NF-κB) pathway
Summary
Acute glaucoma is a leading cause of blindness characterized by progressive loss of retinal ganglion cells (RGCs) and axons in the optic nerves, which is mainly caused by rapid increase of intraocular pressure (IOP), i.e., acute intraocular hypertension (AIH). Emerging evidence has shown that neuroinflammation is implicated with RGCs death during acute glaucoma [5,6], and a few agents with anti-inflammatory properties exert a considerable suppression effect on disease progression [7,8], implying the critical role of the inhibition of neuroinflammation in acute glaucoma treatment. Microglia/macrophages activation in ocular tissues is considered to be a key event in acute glaucoma, which is typically characterized by the morphological change from ramified to ameboid, increased phagocytosis-related protein, such as ionized calcium-binding adapter molecule 1 (Iba-1), and excess production of pro-inflammatory molecules such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) [9]
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