Effects of Eye Drops Containing Hyaluronic Acid-Nimesulide Conjugates in a Benzalkonium Chloride-Induced Experimental Dry Eye Rabbit Model

Abstract

Dry eye syndrome (DES) is a common ocular disease worldwide. Currently, anti-inflammatory agents and immunosuppressive drugs, such as cyclosporine A, have been widely used to treat this chronic condition. However, the multifactorial etiology of DES, poor tolerance, low bioavailability, and prolonged treatment to response time have limited their usage. In this study, nimesulide, a cyclooxygenase (COX)-2 selective inhibitor, was conjugated with hyaluronic acid (HA), and the HA-nimesulide conjugates were expected to increase the solubility and biocompatibility for alleviating the DES in the benzalkonium chloride (BAC)-induced goblet cell-loss dry eye model. The therapeutic efficacy of HA-nimesulide was assessed using fluorescein staining, goblet cell density by conjunctival impression cytology, and histology and immunohistochemistry of corneal tissues. Compared to commercial artificial tears and Restasis®, the HA-nimesulide conjugates could promote goblet cell recovery and enhance the regeneration of the corneal epithelium. Importantly, immunofluorescent staining studies demonstrated that the HA-nimesulide conjugates could decrease the number of infiltrating CD11b-positive cells after two weeks of topical application. In the anti-inflammatory test, the HA-nimesulide conjugates could inhibit the production of pro-inflammatory cytokines and prostaglandin E2 (PGE2) in the lipopolysaccharide (LPS)-stimulated Raw 264.7 cell model. In conclusion, we demonstrated that HA-nimesulide conjugates had anti-inflammatory activity, and promoted goblet cell recovery and corneal epithelium regeneration when used as topical eye drops; accordingly, the HA-nimesulide conjugates could potentially be effective for the treatment of DES.

Prostaglandin E2 may clinically alleviate dry eye disease by inducing Th17 cell differentiation

“…An analysis of DE based on inflammatory response is therefore of great significance. Several topical ophthalmic NSAIDs, such as diclofenac ophthalmic, flurbiprofen ophthalmic and ketorolac ophthalmic solutions, are commonly used in cataract surgery, refractive surgery and seasonal allergic conjunctivitis (Chen & Tseng, 2021). Yang and Lee (2021) performed a meta-analysis that indicated that hyaluronic acid eye drops might be superior to non-hyaluronic acid eye drops containing normal saline and ATs.…”

Antifungal Combination Eye Drops for Fungal Keratitis Treatment

“…The addition of high molecular weight HA (>1000 KDa) [ 70 ] to eye drops can promote faster corneal wound healing. This is due to the binding of the HA to the CD44 protein (CD44 receptor is expressed when there is damage in the corneal epithelium), which enhances the migration and regeneration of epithelial cells [ 71 ]. Furthermore, the expression of inflammatory cytokines (e.g., IL-1beta and MMP-9) is decreased following the HA administration, suppressing inflammatory responses [ 72 , 73 ].…”

Hyaluronic Acid: Its Versatile Use in Ocular Drug Delivery with a Specific Focus on Hyaluronic Acid-Based Polyelectrolyte Complexes

“…Chen et al [ 120 ] demonstrated the enhanced bioavailability and aqueous solubility of nimesulide, a non-steroidal anti-inflammatory drug, via conjugation to HMWHA (360 kDa) and LMWHA (36 kDa). Exhibiting equivalent tear osmolarity to that of normal human tears (296.7 ± 0.5 mOsm/L–LMWHA, 303.3 ± 4.2 mOsm/L–HMWHA), the nimesulide–HA conjugates significantly decreased interleukin 6 expression post-lipopolysaccharide-stimulated inflammation.…”