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P. F. Kador, J. Randazzo, H. Jin, K. Blessing; In vivo Evaluation of Orally Active Multifunctional Antioxidants. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3256.
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Oxidative stress contributes to the development of cataracts and macular degeneration. Evidence also indicates that redox active metals contribute to the generation of reactive oxygen species (ROS). We have previously reported that in vitro our multifunctional antioxidants (M-As) selectively bind Cu > Fe > Zn with no binding of Ca or Mg observed. Moreover, in SRA-1 lens cells our M-As reduced ROS-induced cell death through both Fe chelation and free radical scavenging (FRS) activity. Here, we report that our M-As also delay in vivo lens changes induced by diabetes and ionizing radiation.
A series of novel compounds possessing both chelating and FRS groups or structurally similar compounds possessing either the chelating or FRS groups were orally administered at a 0.05% concentration in rat chow to young (100 g) Sprague Dawley rats. After 6 days drug levels were determined in the lens and posterior segment of each eye. Subsequently, the M-As were administered in rat chow at concentration of 0.025% to young, streptozotocin diabetic rats and their rate of cataract formation were compared to a similar group of untreated diabetic rats and diabetic rats treated with diet containing 0.0125% of the aldose reductase inhibitor (ARI) AL1576. These M-As were also administered at 0.05% in chow to pigmented Long Evans rats receiving 15 Gy of whole head Gamma radiation (Cobalt-60 Source). Their ability to reduce the effects of radiation were compared to rats receiving only radiation (untreated rats) and similar rats administered pantethine (1g/kg i.p.) just prior to radiation.
Six-day oral feeding of diet containing 0.05% compounds resulted in the accumulation of 1-1.7 µg of compound /mg protein in the posterior segment and 100-225 ng/mg protein in the lens. Administration of these M-As to diabetic rats did not result in reduction of lens sorbitol levels; however, cataract formation was significantly delayed. In the diabetic rats, 45 day oral administration resulted in 2-fold higher M-A levels in the lens and retina. No lens changes or sorbitol accumulation were observed in ARI-treated rats. M-As also demonstrated protection against ionizing radiation. While currently only at two-months post-irradiation, FRS protection of the salivary glands has been observed in feeding studies of rats treated with M-As but not with pantethine.
These novel M-As accumulate in the lens and retina of rats and ameliorate the effects of ROS and ionizing radiation.
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