Pharmaceutics · 8 authors, 2 centres
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Topical fluoxetine treatment preserved retinal ganglion cell function and reduced neuroinflammation in a mouse model of retinal ischemia/reperfusion injury. Fluoxetine significantly attenuated the upregulation of glial markers (Iba-1, S100β) and pro-inflammatory cytokines (TNF-α, IL-1β) while improving pattern electroretinogram amplitudes. These findings suggest fluoxetine may be a promising neuroprotective agent for glaucoma and other retinal ischemic conditions.
**Background:** Glaucoma is a progressive optic neuropathy characterized by retinal ganglion cell (RGC) death and irreversible vision loss, often associated with elevated intraocular pressure (IOP). Despite IOP-lowering treatments, many patients continue to experience RGC loss, highlighting the need for neuroprotective strategies. Selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, have demonstrated neuroprotective, anti-inflammatory, and antioxidant properties in various neurodegenerative models, including brain ischemia. This study aimed to evaluate the neuroprotective effect of topical fluoxetine in a mouse model of retinal ischemia/reperfusion (I/R) injury, which mimics the ischemic component of glaucoma.
**Methods:** Male C57BL6/J mice were divided into three groups (n=6 each): control (CTRL), ischemia/reperfusion (I/R), and I/R treated with fluoxetine (I/R+FLX). Retinal I/R was induced by elevating IOP to 90 mmHg for 60 minutes via anterior chamber cannulation. Fluoxetine (1% solution, 10 µL) was applied topically 60 minutes before ischemia and again at 1 and 2 hours after reperfusion. Retinal function was assessed 72 hours post-injury using pattern electroretinogram (PERG), measuring P1-N2 amplitude and P1 latency. Retinal mRNA expression of glial markers (Iba-1, S100β) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) was quantified by droplet digital PCR (ddPCR), normalized to HPRT. Statistical analysis used one-way ANOVA with Tukey's post hoc test; p ≤ 0.05 was considered significant.
**Key Results:** PERG amplitude was reduced by more than 50% in the I/R group compared to controls, indicating significant RGC dysfunction. Fluoxetine treatment significantly attenuated this reduction (p < 0.05 I/R+FLX vs. I/R). PERG latency was significantly prolonged in I/R mice compared to controls (p < 0.05), and fluoxetine significantly reduced latency (p < 0.01 I/R+FLX vs. I/R). ddPCR analysis showed that I/R injury significantly upregulated mRNA expression of glial markers S100β (p < 0.01) and Iba-1 (p < 0.001) compared to controls. Fluoxetine significantly counteracted these increases (S100β: p < 0.01; Iba-1: p < 0.05). Pro-inflammatory cytokines TNF-α (p < 0.001), IL-1β (p < 0.05), and IL-6 (p < 0.05) were significantly elevated in I/R retinas. Fluoxetine significantly reduced TNF-α (p < 0.0001) and IL-1β (p < 0.05) expression, but did not significantly affect IL-6 levels.
**Clinical Implications:** This study provides preclinical evidence that topical fluoxetine protects RGC function and attenuates neuroinflammation in a retinal I/R model. The preservation of PERG amplitude and reduction in glial activation and pro-inflammatory cytokines suggest fluoxetine may act through anti-inflammatory and neuroprotective mechanisms independent of IOP reduction. Given the unmet need for neuroprotective therapies in glaucoma, these findings support further investigation of fluoxetine as a potential adjunctive treatment. However, the study is limited by its short duration (72 hours), use of a single dose, and lack of assessment of long-term RGC survival or visual function. Future studies should explore dose-response relationships, chronic treatment effects, and translation to human clinical trials.