The application of hydroxytyrosol in ophthalmic drugs

Hydroxytyrosol (HT), a highly active polyphenol in olive leaf extract, owes its potent antioxidant, anti-inflammatory, and cytoprotective properties to its unique 3,4-dihydroxyphenethyl alcohol structure. In ophthalmic pharmacology, HT demonstrates significant therapeutic potential in dry eye disease (DED) and retinal oxidative damage-related disorders by targeting ocular surface oxidative stress injury and tear secretion regulatory pathways. Its mechanism of action and application value are analyzed in depth as follows:

I. Targeted Inhibition Mechanism of Ocular Surface Oxidative Stress

Root Blocking of Tear Oxidative Damage

In DED patients, reactive oxygen species (ROS, such as superoxide anions and hydroxyl radicals) in tears are 2-3 times higher than in healthy individuals. HT's catechol structure directly scavenges ROS with an oxygen radical absorption capacity (ORAC value) of 3000 μmol/g—over 10 times that of vitamin C. In vitro experiments show 10 μM HT reduces H₂O₂-induced lipid peroxidation products (MDA) in tears by 65% and inhibits Fenton reactions by chelating transitional metal ions (Fe²⁺, Cu²⁺), blocking ROS generation at its source.

Enhanced Antioxidant Defense in Ocular Surface Epithelial Cells

HT upregulates antioxidant enzymes (superoxide dismutase SOD, glutathione peroxidase GPx) in ocular surface epithelial cells by activating the Nrf2/ARE signaling pathway. Experiments show HT treatment increases Nrf2 nuclear translocation in corneal epithelial cells by 2.3-fold and GPx activity by 40%, enhancing cell resistance to UVB- or hyperosmotic stress-induced oxidative damage (cell viability increases by 35% vs. control). Additionally, HT's lipophilic side chain embeds into the cell membrane phospholipid bilayer, protecting membrane proteins from oxidative modification and maintaining tight junction integrity (transepithelial electrical resistance increases by 25%).

II. Multi-Pathway Regulation of DED Pathogenesis

Repair and Activation of Lacrimal Gland Secretion Function

Lacrimal gland cells in DED often undergo apoptosis due to chronic inflammation or oxidative stress. HT reduces lacrimal acinar cell apoptosis (apoptosis rate decreases by 60%) by inhibiting caspase-3 activity, involving PI3K/Akt pathway activation: HT phosphorylates Akt (Ser473) to suppress pro-apoptotic protein Bad and upregulates anti-apoptotic protein Bcl-2. In a rat DED model, topical 0.1% HT eye drops restore tear secretion to 85% of normal levels, significantly outperforming artificial tears (50% recovery).

Cascade Inhibition of Ocular Surface Inflammatory Networks

HT reduces pro-inflammatory factor (TNF-α, IL-1β) secretion in ocular surface epithelial cells by inhibiting nuclear factor κB (NF-κB) activation. In vitro, HT treatment decreases LPS-induced IL-6 secretion by 70% and promotes macrophage polarization to the anti-inflammatory M2 phenotype (CD206 expression increases 3-fold). In DED models, HT alleviates tear film mucin degradation by downregulating matrix metalloproteinase MMP-9 activity (55% reduction), restoring tear film stability (tear break-up time [BUT] extends from 5 to 12 seconds).

III. Special Value in Corneal and Retinal Protection

Accelerated Corneal Epithelial Repair

HT promotes corneal epithelial cell proliferation and migration via the ERK1/2-MAPK pathway. Scratch assays show 10 μM HT increases cell migration speed by 1.8-fold vs. control and enhances cell-basement membrane adhesion by upregulating integrin α5β1 expression. In an alkali burn model, HT eye drops shorten corneal epithelial defect healing time from 7 to 4 days and reduce neovascularization (vessel area decreases by 40%), attributed to inhibiting VEGF overexpression (mRNA levels decrease by 60%).

Potential Application in Retinal Neuroprotection

In age-related macular degeneration (AMD) models, HT reduces complement factor C3 deposition (50% reduction) by inhibiting oxidative stress injury in retinal pigment epithelial cells (RPE). Its antioxidant properties also protect photoreceptor cells from blue light-induced apoptosis (cell viability increases by 45%), involving inhibition of JNK pathway activation and maintenance of mitochondrial membrane potential. While current research is primarily in vitro, its blood-retina barrier permeability (retinal drug concentration reaches 15% of plasma after intravenous injection in rats) offers new possibilities for retinal disease therapy.

IV. Optimized Design of Ophthalmic Drug Delivery Systems

Development of Mucoadhesive Eye Drops

HT is compounded with chitosan (CS) to form pH-sensitive eye drops: CS's amino groups form hydrogen bonds with sialic acid residues in the ocular surface mucus layer, prolonging ocular residence time (half-life extends from 5 to 45 minutes). CS's positive charge promotes HT penetration through corneal epithelial tight junctions (permeability coefficient increases 2-fold). Rabbit eye experiments show 0.1% HT/CS eye drops achieve 3.2-fold higher intraocular bioavailability than pure HT solution, with no obvious irritation (rabbit eye irritation score: 0).

Synergy Strategies for Nano-Drug Delivery Systems

PLGA-PEG nanoparticles (150nm) encapsulated with HT are surface-modified with hyaluronic acid (HA) to target ocular surface CD44 receptors. This system enables sustained HT release for 72 hours (cumulative release rate: 80%), and HA's moisturizing property reduces tear 冲刷损耗 (flushing loss). In DED models, nanoparticle eye drops maintain corneal stromal HT concentration >1μM for 6 hours, significantly inhibiting ocular surface inflammatory cell infiltration (CD45⁺ cells decrease by 70%)—superior to traditional eye drops (maintenance time <2 hours).

Clinical Translation: Advantages and Challenges

As a natural polyphenol, HT exhibits low cytotoxicity (corneal epithelial cell IC₅₀ >100μM) and excellent biocompatibility, with its multi-target mechanism ideally suited for comprehensive DED treatment. Current challenges include: limited water solubility (0.3mg/mL at 25℃) restricting eye drop concentration, and potential impacts on ocular surface microbiota with long-term use. These delivery efficiency issues can be gradually addressed through nanocrystal preparation (solubility increased to 5mg/mL) or synergistic formulation with artificial tear matrices. With deeper insights into ocular surface oxidative stress pathogenesis, HT is poised to become the first novel molecule for DED therapy integrating antioxidant, anti-inflammatory, and tear secretion regulatory functions.