Abstract
ABSTRACTGranulocyte colony-stimulating factor (G-CSF) was reported to have a neuroprotective effect in a rat model of anterior ischemic optic neuropathy (rAION model). However, the therapeutic window and anti-inflammatory effects of G-CSF in a rAION model have yet to be elucidated. Thus, this study aimed to determine the therapeutic window of G-CSF and investigate the mechanisms of G-CSF via regulation of optic nerve (ON) inflammation in a rAION model. Rats were treated with G-CSF on day 0, 1, 2 or 7 post-rAION induction for 5 consecutive days, and a control group were treated with phosphate-buffered saline (PBS). Visual function was assessed by flash visual evoked potentials at 4 weeks post-rAION induction. The survival rate and apoptosis of retinal ganglion cells were determined by FluoroGold labeling and TUNEL assay, respectively. ON inflammation was evaluated by staining of ED1 and Iba1, and ON vascular permeability was determined by Evans Blue extravasation. The type of macrophage polarization was evaluated using quantitative real-time PCR (qRT-PCR). The protein levels of TNF-α and IL-1β were analyzed by western blotting. A therapeutic window during which G-CSF could rescue visual function and retinal ganglion cell survival was demonstrated at day 0 and day 1 post-infarct. Macrophage infiltration was reduced by 3.1- and 1.6-fold by G-CSF treatment starting on day 0 and 1 post-rAION induction, respectively, compared with the PBS-treated group (P<0.05). This was compatible with 3.3- and 1.7-fold reductions in ON vascular permeability after G-CSF treatment compared with PBS treatment (P<0.05). Microglial activation was increased by 3.8- and 3.2-fold in the early (beginning treatment at day 0 or 1) G-CSF-treated group compared with the PBS-treated group (P<0.05). Immediate (within 30 mins of infarct) treatment with G-CSF also induced M2 microglia/macrophage activation. The cytokine levels were lower in the group that received immediate G-CSF treatment compared to those in the later G-CSF treatment group (P<0.05). Early treatment with G-CSF stabilized the blood–ON barrier to reduce macrophage infiltration and induced M2 microglia/macrophage polarization to decrease the expressions of pro-inflammatory cytokines in this rAION model.
Highlights
Non-arteritic anterior ischemic optic neuropathy (NAION) is characterized clinically by acute, painless visual loss with optic disc swelling (Hayreh, 2009)
We previously demonstrated that Granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect in a rat model of anterior ischemic optic neuropathy via the dual actions of anti-apoptosis of retinal ganglion cell (RGC) and anti-inflammation on the optic nerve (ON) (Chang et al, 2014)
Early G-CSF treatments post-infarction was beneficial in preserving visual function The latency of the P1 wave was consistently 34.9±3.6 ms among the groups in the flash visual evoked potential (FVEP) tests
Summary
Non-arteritic anterior ischemic optic neuropathy (NAION) is characterized clinically by acute, painless visual loss with optic disc swelling (Hayreh, 2009). NAION is thought to result from an ischemic insult to the optic nerve (ON) followed by an inflammatory reaction and edema (Salgado et al, 2011; Zhang et al, 2009). In a rat model of anterior ischemic optic neuropathy (rAION), breakdown of the blood–ON barrier was found to occur within hours post-induction of infarct (Bernstein and Miller, 2015), followed by the early recruitment of extrinsic macrophages and activation of resident microglia at the core of the ischemic ON (Slater et al, 2008; Bernstein et al, 2011; Chang et al, 2014; Huang et al, 2015). By selective manipulation of inflammatory responses, it might be possible to develop new treatment approaches for NAION
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