norbixin and Disease-Models--Animal

The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9'-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally-injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin-trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9'-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial.

Topics: Alcohol Oxidoreductases; Animals; ATP-Binding Cassette Transporters; Bixaceae; Carotenoids; Cells, Cultured; Disease Models, Animal; In Vitro Techniques; Intravitreal Injections; Macular Degeneration; Mice; Mice, Knockout; Photoreceptor Cells, Vertebrate; Plant Extracts; Rats; Retinal Pigment Epithelium; Retinoids; Swine

Modifying potential of annatto extract (norbixin) on liver carcinogenesis was investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given annatto extract at dietary levels of 0, 0.03, 0.1 and 0.3%, or phenobarbital sodium at 0.05% as a positive control for 6 weeks. All animals were subjected to partial hepatectomy at week 3, and were killed at week 8. There were no deaths related to annatto extract ingestion, and the treatment had no effects on body weights, or food and water consumption. Statistically significant increases of absolute and relative liver weights were apparent in the 0.1 and 0.3% groups. However, annatto extract did not significantly increase the quantitative values for glutathione S-transferase placental form positive liver cell foci observed after DEN initiation, in clear contrast to the positive control case. The results thus demonstrate that annatto extract at a dietary level of 0.3% (200 mg/kg/day) lacks modifying potential for liver carcinogenesis in our medium-term bioassay system.

Topics: Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Carotenoids; Disease Models, Animal; Food Coloring Agents; Liver; Liver Neoplasms; Male; Organ Size; Phenobarbital; Rats; Rats, Inbred F344