Long term therapeutic effects of icariin‐loaded PLGA microspheres in an experimental model of optic nerve ischemia via modulation of CEBP‐β/G‐CSF/noncanonical NF‐κB axis

Abstract

An ischemic insult at optic nerve (ON) is followed by detrimental neuroinflammation that results in progressive and long‐lasting retinal ganglion cell (RGC) death and vision loss. Icariin was reported to be a safe and effective natural anti‐inflammatory drug. Herein, we evaluated the long‐term therapeutic effects of a single intravitreal injection of poly(lactide‐co‐glycolide) PLGA–icariin in a rat model of anterior ischemic optic neuropathy (rAION). Treatment with PLGA microspheres of icariin preserved the visual function and RGC density for 1 month in the rAION model. In addition, ON edema and macrophage infiltration were inhibited by treating PLGA microspheres of icariin. We found that the binding complex of icariin and CCAAT enhancer binding protein beta (CEBP‐β) significantly induced endogenous granulocyte colony‐stimulating factor (G‐CSF) expression to activate noncanonical nuclear factor kappa B (NF‐κB) signaling pathway by promoting an alternative phosphorylation reaction of IKK‐β. Activation of noncanonical NF‐κB signaling pathway promoted the M2 microglia/macrophage polarization and AKT1 activation, which prevented neuroinflammation and RGC apoptosis after ON infarct. This study concluded that protective mechanism of icariin is a CEBP‐β/G‐CSF axis‐induced noncanonical NF‐κB activation, which provides the long‐term neuroprotective effects via anti‐inflammatory and antiapoptotic actions after ON ischemia.

Neuroprotective Mechanism of Icariin on Hypoxic Ischemic Brain Damage in Neonatal Mice

“…Focusing on the IKK/NF- κ B pathway as a way to regulate the neuroinflammatory injury induced by hypoxia-ischemia may be a promising therapeutic strategy to reduce HIBD in neonatal mice [ 88 ]. Studies have shown that ICA can exert a neuroprotective effect on neuroinflammation induced by microglial activation by inhibiting the IKK/NF- κ B pathway [ 89 ]. Narciclasine attenuates the secretion of proinflammatory factors by downregulating the Akt/IKK/NF- κ B signaling pathway and directly inhibits the catalytic activity of IKK- α to offer neuroprotection against lipopolysaccharide-induced neuroinflammation [ 90 ].…”

Role of microglia/macrophage polarisation in intraocular diseases (Review)

“…Another study demonstrated that the binding complex of icariin and CCAAT enhancer-binding protein β significantly induces endogenous G-CSF expression by promoting alternative phosphorylation of IκB kinase-β, inhibitor of NF-κB ( 123 ). The elevated G-CSF expression then triggers noncanonical NF-κB activation, which further activates the PI3K/serine/threonine protein kinase B-a (AKT1) signalling pathway and promotes M2 microglia/macrophage polarisation, thereby preventing neuroinflammation and RGC apoptosis after optic nerve infarction in a rAION.…”