Anti-inflammatory action of fluvoxamine in an endotoxin-induced uveitis rat model: Histopathological evidence

• Introduction
• Methods
• Results
• Discussion

Abstract

Purpose: To investigate the potential protective effects of fluvoxamine (FVX), a selective serotonin reuptake inhibitor with known anti-inflammatory properties, on corneal, limbal, and retinal tissues in a rat model of endotoxin-induced uveitis (EIU), clinical and histopathologic evaluations were performed.

Methods: Twenty-eight female Wistar Albino rats were divided into four groups: controls, EIU, EIU + FVX, and FVX (n = 7 per group). EIU was induced by a single intraperitoneal injection of lipopolysaccharide (LPS). FVX or normal saline (NS) was administered 30 min before LPS or NS injection. Clinical ocular inflammation was assessed using slit-lamp biomicroscopy 6 h postinjection. Following euthanasia, enucleated eyes were processed for histopathologic analysis of corneal, limbal, and retinal tissues.

Results: Total corneal and epithelial thickness were measured, while limbal and retinal lesions were semiquantitatively graded. The EIU group exhibited significantly increased clinical ocular inflammation scores compared to the control, EIU + FVX, and FVX groups (p < 0.0001 for all). At the microscopical analysis, the EIU group showed significant corneal epithelial thickening, cellular changes, edema, hemorrhage, and increased total corneal thickness compared to the control group (p < 0.001). In addition, histopathologic analysis revealed retinal hyperemia and edema in the EIU group but not in the EIU + FVX, FVX, or control groups. Histopathologic scores confirmed significant retinal changes in the EIU group compared to the others (p < 0.001).

Conclusions: FVX significantly reduced clinical signs of ocular inflammation and mitigated histopathologic damage in the cornea, limbus, and retina.

Uveitis is an inflammatory condition of the uveal tract that can result in significant visual impairment and is frequently associated with systemic autoimmune or infectious diseases [1]. Epidemiologic studies indicate a substantial disease burden, with reported incidence rates ranging from 17 to 52 per 100,000 individuals and prevalence rates varying from 38 to 714 per 100,000, particularly among young adults [2]. Clinically, uveitis presents with blurred vision, ocular pain, photophobia, and floaters. If left untreated, it may lead to sight-threatening complications such as uveitic glaucoma, cystoid macular edema, retinal neovascularization, and retinal ischemia [1,3].

The eye possesses unique immune-regulatory mechanisms, including the blood-retinal barrier, absence of lymphatic drainage, and anterior chamber–associated immune deviation (ACAID), which collectively help maintain ocular immune privilege [4]. Disruption of these mechanisms can lead to uncontrolled inflammation, although the precise pathophysiology of uveitis remains incompletely understood [4]. Animal models, particularly the endotoxin-induced uveitis (EIU) model, have been instrumental in elucidating disease mechanisms and evaluating potential therapeutic interventions. Intraperitoneal administration of lipopolysaccharide (LPS) triggers an acute inflammatory response characterized by the release of proinflammatory cytokines and chemokines, replicating key features of human uveitis [5]. The EIU model effectively mirrors immune pathways observed in human anterior uveitis and provides a reproducible platform for preclinical drug screening [6,7].

Current management of uveitis primarily relies on corticosteroids during acute phases and immunomodulatory agents for chronic control and relapse prevention [1]. However, long-term corticosteroid use is associated with significant ocular and systemic side effects, including cataract formation, glaucoma, and increased susceptibility to infections. Although immunosuppressants reduce relapse rates, they may also compromise systemic immunity [6,8]. These limitations underscore the need for novel therapeutic agents with favorable safety profiles and alternative mechanisms of action [9].

Fluvoxamine (FVX), a selective serotonin reuptake inhibitor (SSRI), is commonly used in the treatment of depression and anxiety disorders. Beyond its neurologic effects, emerging evidence suggests that FVX possesses anti-inflammatory and immunomodulatory properties [10]. Experimental studies have demonstrated its potential to attenuate neuroinflammation in conditions such as traumatic brain injury and multiple sclerosis [11,12]. Proposed mechanisms include suppression of proinflammatory cytokine production, inhibition of inflammatory gene expression, and modulation of microglial/macrophage activity [12]. Additionally, FVX has been shown to interact with glucocorticoid receptors, further supporting its potential role in inflammatory regulation. Despite these promising effects, the therapeutic potential of FVX in uveitis remains unexplored.

Given its anti-inflammatory profile, this study aimed to investigate the protective effects of FVX on corneal, limbal, and retinal tissues in a rat model of EIU using clinical and histopathologic assessments.

Uveitis, a sight-threatening inflammatory condition of the uveal tract, presents significant challenges in both understanding its complex pathogenesis and developing effective treatments [3]. Animal models, particularly the EIU model, have been instrumental in elucidating disease mechanisms and evaluating potential therapeutic agents [16]. Our study used this well-established model, where a single intraperitoneal injection of LPS triggers acute ocular inflammation characterized by leukocyte adhesion to iris microvasculature within 2 h [17] and increased protein leakage into the anterior chamber [18,19], effectively mirroring key aspects of human anterior uveitis [20].

While corticosteroids remain the mainstay of uveitis treatment, their chronic use is associated with significant ocular and systemic side effects, including cataract formation, glaucoma, diabetes, and hypertension [9]. These limitations underscore the urgent need for alternative anti-inflammatory therapies with improved safety profiles.

FVX, primarily known as an SSRI, has recently emerged as a promising anti-inflammatory candidate. The mechanism underlying FVX’s immunomodulatory effects appears multifaceted. Human peripheral blood mononuclear cells express serotonin and norepinephrine transporters [19,21], and antidepressants may directly influence these cells [22,23]. Furthermore, serotonin and noradrenaline released from lymphocytes and monocytes can exert immunomodulatory effects through receptors present on immune cells [24]. FVX has been shown to reduce proinflammatory cytokine-induced PGE2 and nitric oxide production [25], both of which are elevated in ocular inflammation [26]. Additionally, FVX demonstrates glucocorticoid receptor activity [27] and suppresses expression of key inflammatory genes, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), in various experimental models [23,28].

To our knowledge, this study is the first to demonstrate the protective effects of FVX against EIU through comprehensive clinical and histopathologic evaluation. Our findings align with previous research showing FVX’s anti-inflammatory properties in diverse contexts. In traumatic brain injury models, FVX inhibited peripheral immune cell infiltration and promoted the polarization of microglia/macrophages toward an anti-inflammatory phenotype [29]. Similarly, in multiple sclerosis models, FVX alleviated inflammation and demyelination [30]. These consistent findings across different disease models strengthen the evidence for FVX’s broad anti-inflammatory properties.

Our results demonstrate that FVX pretreatment significantly attenuated clinical signs of ocular inflammation and mitigated histopathologic damage in corneal, limbal, and retinal tissues. Specifically, FVX reduced LPS-induced corneal thickening, epithelial changes, limbal hyperemia, edema, inflammatory cell infiltration, and retinal abnormalities. The therapeutic effects of FVX were evident in both anterior and posterior segment tissues, suggesting a comprehensive protective action against EIU.

Histopathologic examination revealed important morphologic alterations in retinal tissues across experimental groups. The EIU group exhibited significant thickening of the inner plexiform layer in addition to hyperemia and edema. While FVX treatment substantially attenuated these pathologic changes, mild thickening persisted in some EIU + FVX specimens, suggesting either a dose–response relationship or potential need for optimized treatment protocols. Furthermore, careful analysis revealed subtle architectural irregularities in both inner and outer nuclear layers in some FVX group samples, although these changes did not reach statistical significance in our semiquantitative assessment. These observations highlight the importance of further investigating both the therapeutic potential and possible ocular effects of FVX using more sensitive analytical methods.

Despite these promising findings, our study has several limitations that should be addressed in future research. First, we evaluated FVX effects at only a single time point (6 h postinjection). Examination at multiple time points would provide a more comprehensive understanding of the temporal dynamics of FVX’s therapeutic effects. Second, the therapeutic potential of FVX administered after the induction of uveitis (rather than as a pretreatment) remains unknown and represents a crucial area for future investigation. Third, comparative studies evaluating the efficacy of FVX against conventional therapies such as corticosteroid or nonsteroidal anti-inflammatory eye drops would be highly valuable in defining its potential clinical role. Fourth, while no significant toxicity was observed with FVX treatment alone based on our histopathologic scoring, a more meticulous analysis for subtler signs of toxicity (e.g., using electron microscopy or specific apoptotic markers) should be considered in future work to comprehensively establish the safety profile of FVX in ocular tissues. Finally, as our findings are limited to the EIU rat model, further clinical investigations are necessary to determine the potential applicability of FVX in human patients with uveitis.

In conclusion, our study provides compelling evidence that FVX exerts significant protective effects against EIU in rats, reducing both clinical signs of inflammation and histopathologic damage across multiple ocular tissues. These findings support the potential therapeutic value of FVX in uveitis management and warrant further investigation into its mechanisms of action and clinical applications.