February 2008
Saadia Rashid, MD; Yiping Jin, MD, PhD; Tatiana Ecoiffier, MSc; Stefano Barabino, MD, PhD; Debra A. Schaumberg, ScD, MPH; M. Reza Dana, MD, MSc, MPH
 

Abstract

Objective: To study the efficacy of topical application of alpha-linolenic acid (ALA) and linoleic acid (LA) for dry eye treatment.

Methods: Formulations containing ALA, LA, combined ALA and LA, or vehicle alone, were applied to dry eyes induced in mice. Corneal fluorescein staining and the number and maturation of corneal CD11b+ cells were determined by a masked observer in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva.

Results: Dry eye induction significantly increased corneal fluorescein staining; CD11b+ cell number and major histocompatibility complex Class II expression; corneal IL-1α and tumor necrosis factor α (TNF-α) expression; and conjunctival IL-1α, TNF-α, interferon γ, IL-2, IL-6, and IL-10 expression.

Treatment with ALA significantly decreased corneal fluorescein staining compared with both vehicle and untreated controls. Additionally, ALA treatment was associated with a significant decrease in CD11b+ cell number, expression of corneal IL-1α and TNF-α, and conjunctival TNF-α.

Conclusions: Topical ALA treatment led to a significant decrease in dry eye signs and inflammatory changes at both cellular and molecular levels.

Clinical Relevance: Topical application of ALA omega-3 fatty acid may be a novel therapy to treat the clinical signs and inflammatory changes accompanying dry eye syndrome.

Dry eye syndrome (DES) is a highly prevalent health problem that affects more than 10 million people, primarily women, in the United States alone.1,2 It is a frequent cause of office visits due to ocular discomfort and commonly leads to problems with sustained visual activities such as reading and driving.3 Inflammation has been recognized as an important component of DES.4 The recently introduced topical cyclosporin A (Restasis; Allergen, Irvine, California) has been shown to decrease ocular surface inflammation, stimulate tear production, and improve signs and symptoms of dry eye,5 further signifying the role of inflammation and anti-inflammatory agents for dry eye treatment.

Naturally occurring essential polyunsaturated fatty acids (PUFA) of omega-3 (n-3) and omega-6 (n-6) series are promising natural anti-inflammatory agents shown to have beneficial effects in many inflammatory conditions such as rheumatoid arthritis and ulcerative colitis.6

The n-3 FAs include alpha-linolenic acid (18:3n-3; ALA) and its elongation and desaturation products, stearidonic acid (18:4n-3), eicosapentaenoic acid (20:5n-3; EPA), and docosahexaenoic acid (22:5n-3; DHA). The n-6 FAs include linoleic acid (18:2n-6; LA) and its products, gammalinolenic acid (18:3n-6; GLA), dihomogammalinoleic acid (20:3n-6; DGLA), and arachidonic acid (20:4n-6; AA). Both ALA and LA are called “essential” FAs because they cannot be synthesized by mammals and must be supplied in diet.

Recent studies have shown beneficial effects of dietary supplementation of FAs in DES.7-9 In a cross-sectional study of 32 470 women, women with a higher n-3 FA intake (more than 5-6 tuna servings per week as opposed to less than 1) were found to have 68% lower prevalence of DES.9

In 2 randomized clinical trials, oral supplementation with LA and GLA ameliorated the signs and symptoms of dry eye.7,8 It is postulated that when the n-6 to n-3 ratio is approximately 4:1 or lower, the conversion of DGLA to AA undergoes competitive inhibition with enhanced metabolism of DGLA to prostaglandin E1 (PGE1) series,10 an eicosanoid with anti-inflammatory properties.

In aggregate, these data indicate that n-3 and n-6 FAs may play a role in the pathogenesis and treatment of DES. However, several important issues remain unresolved, in particular whether FAs can be provided topically, thereby bypassing excess caloric intake and gastrointestinal adverse effects associated with their oral supplementation. The purpose of this study was to evaluate the efficacy of topical n-3 and n-6 FAs using the controlled environmental chamber murine model of dry eye.