Therapeutic Potential of Crocin and Nobiletin in a Mouse Model of Dry Eye Disease: Modulation of the Inflammatory Response and Protection of the Ocular Surface.

Abstract

Background: Dry eye disease (DED) is a multifactorial condition characterized by ocular surface inflammation, tear film instability, and corneal epithelial damage. Current treatments often provide temporary relief without addressing the underlying inflammatory mechanisms.

Objectives: This study examined the therapeutic potential of crocin and nobiletin, two naturally derived compounds with well-known antioxidant and anti-inflammatory properties, in a mouse model of DED induced by lacrimal gland excision (LGE).

Methods: Thirty female Balb/c mice were divided into five groups (n = 6 each): Control (sham surgery), untreated DED, nobiletin-treated DED (32.75 µM), crocin-treated DED (34 µM), and 1% betamethasone-treated DED. Treatments were administered three times daily for 28 days. Ocular tissues were evaluated using Hematoxylin and Eosin (H&E) staining and fluorescein staining. Conjunctival inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), were measured by enzyme-linked immunosorbent assay (ELISA).

Results: Histological analysis showed that the crocin and nobiletin treatment groups exhibited reduced epithelial disruption, keratinization, and inflammatory cell infiltration compared to the untreated DED group. The ELISA assay revealed that both compounds efficiently inhibited the production of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β, which are key mediators of DED pathogenesis. Fluorescein staining further confirmed the protective impact of crocin and nobiletin on corneal epithelial integrity. Moreover, the anti-inflammatory and epithelial-preserving effects of these compounds were comparable to those of the corticosteroid betamethasone.

Conclusions: Overall, these findings suggest that crocin and nobiletin have therapeutic potential for DED management by modulating inflammatory responses and enhancing ocular surface healing. These naturally derived compounds offer promising avenues for the development of safer and more effective treatments for this challenging condition. However, further investigations, including clinical trials, are essential to elucidate the underlying mechanisms of action and optimize therapeutic approaches.