Protein Disulfide Levels and Lens Elasticity Modulation: Applications for Presbyopia

Abstract

PurposeThe purpose of the experiments described here was to determine the effects of lipoic acid (LA)-dependent disulfide reduction on mouse lens elasticity, to synthesize the choline ester of LA (LACE), and to characterize the effects of topical ocular doses of LACE on mouse lens elasticity.MethodsEight-month-old mouse lenses (C57BL/6J) were incubated for 12 hours in medium supplemented with selected levels (0–500 μM) of LA. Lens elasticity was measured using the coverslip method. After the elasticity measurements, P-SH and PSSP levels were determined in homogenates by differential alkylation before and after alkylation. Choline ester of LA was synthesized and characterized by mass spectrometry and HPLC. Eight-month-old C57BL/6J mice were treated with 2.5 μL of a formulation of 5% LACE three times per day at 8-hour intervals in the right eye (OD) for 5 weeks. After the final treatment, lenses were removed and placed in a cuvette containing buffer. Elasticity was determined with a computer-controlled instrument that provided Z-stage upward movements in 1-μm increments with concomitant force measurements with a Harvard Apparatus F10 isometric force transducer. The elasticity of lenses from 8-week-old C57BL/6J mice was determined for comparison.ResultsLipoic acid treatment led to a concentration-dependent decrease in lens protein disulfides concurrent with an increase in lens elasticity. The structure and purity of newly synthesized LACE was confirmed. Aqueous humor concentrations of LA were higher in eyes of mice following topical ocular treatment with LACE than in mice following topical ocular treatment with LA. The lenses of the treated eyes of the old mice were more elastic than the lenses of untreated eyes (i.e., the relative force required for similar Z displacements was higher in the lenses of untreated eyes). In most instances, the lenses of the treated eyes were even more elastic than the lenses of the 8-week-old mice.ConclusionsAs the elasticity of the human lens decreases with age, humans lose the ability to accommodate. The results, briefly described in this abstract, suggest a topical ocular treatment to increase lens elasticity through reduction of disulfides to restore accommodative amplitude.

Presbyopia: Effectiveness of correction strategies

“…However, the studies are generally poorly conduced with no measurement of the range of clear focus (defocus curve) or objective accommodation measurement (Table 5). Potential new approaches include lipoic acid treatment EV06 which in mice leads to a concentrationdependent decrease in lens protein disulfides concurrent with an increase in lens elasticity (Garner and Garner, 2016). EV06 (Novartis) is a prodrug comprised of lipoic acid choline ester 1.5%.EV06 aims to restore and maintain accommodative amplitude (lens softening) by reducing crystalline protein disulfide bonding between crystalline proteins within lens fibre cells, which causes the crystalline lens to become stiff, inducing presbyopia (Babizhaev et al, 1990).…”

Factors Influencing Pseudo-Accommodation—The Difference between Subjectively Reported Range of Clear Focus and Objectively Measured Accommodation Range

“…The study showed that the maximum accommodation level was maintained in most participants beyond their point of blur and pupil size did not significantly alter. Hence studies measuring the maximum accommodation possible with new devices or techniques such as ‘accommodating’ IOLs or pharmaceutical agents [65] need only assess best corrected distance refraction and that at a close near distance in order to determine the maximum amount of physiologically driven accommodation possible. The DoF will aid the range of clear focus with such devices; hence, given a DoF on average of 1.0 D (subjectively tolerated defocus beyond objective accommodation) and considering that around eighty percent of the residual accommodation can be effectively used, even in sustained reading tasks [45] to read at 40 cm would require only 2.1 D of objective accommodation to be restored.…”

γ-Crystallin redox–detox in the lens

“…The article also provides new impetus to explore oxidation chemistry-based solutions to the global challenge of treating cataracts, particularly in parts of the world where advanced surgery and laser treatments are unavailable, but also where limited medical resources could be deployed more efficiently in favor of pharmacological solutions. Indeed, recent reports have shown the efficacy of redox-active lipoic acid to prevent presbyopia (10) and an antioxidant mixture to ameliorate cataractogenesis in animal models (11), providing new opportunities to augment the redox balance in the eye lens.…”