Abstract
Purpose :
Retina and surrounding tissues are vulnerable to oxidative damage due to a unique combination of direct light exposure, their high rate of oxidative metabolism, and the high content of the fatty acid DHA. Deuteration at the bis allylic positions dramatically increases the resilience of DHA in vitro and in vivo. We studied the increase and washout kinetics of orally consumed D-DHA in mice over several months to understand how it is incorporated and removed from target tissues.
Methods :
At 12 weeks of age, mice were placed on a diet with 0.5% D-DHA for 78 days, then switched to an identical diet with normal H-DHA. Animals were sacrificed periodically, and tissues were collected. Lipids were extracted, converted to fatty acid methyl esters, and analyzed by high-resolution gas chromatography chemical ionization mass spectrometry to quantify the relative proportions of D-DHA and H-DHA, expressed at D-DHA as a % of total DHA in the relevant pool, the key figure of merit for drug efficacy. Doubling time and half-lives were calculated by least-squares fitting to single exponential models.
Results :
D-DHA rose more rapidly in RPE-choroid/Sclera than in the neural retina or optic nerve. By day 78 D-DHA was over 90% in all tissues. RPE-choroid/Sclera and retina had more similar washout curves. Doubling times and half-lives were 20-22 days for both retina and optic nerve. Doubling time for RPE-choroid/Sclera and liver were similar at about 9 days, while half-lives were 18 and 14 days, respectively, for these two tissues.
Conclusions :
The therapeutic threshold for D-DHA efficacy is considered to be about 20%. Retina reached that level by 8 days of feeding. The vascularized RPE-choroid doubling time was at about 40% D-DHA by 8 days similar to the liver. We conclude that D-DHA rapidly crosses the blood-retina-barrier and enters visually active tissues just as its natural DHA parent and may offer protection against oxidative lipid peroxidation.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.