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Minzhong Yu, Kai Kang, Matthew Tarchick, Xiaoshan Yu; Carnosic acid slows photoreceptor degeneration in Pde6rd10 mice by regulating multiple pathways related to oxidative stress and endoplasmic reticulum stress. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):813.
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© ARVO (1962-2015); The Authors (2016-present)
Recent evidence suggests that oxidative stress (OS) is the main factor underlying photoreceptor degeneration in animal models of retinitis pigmentosa (RP). Carnosic acid (CA) is an effective polyphenolic antioxidant, with the ability to prevent lipid peroxidation and biological membrane disruption by scavenging oxygen hydroxyl radicals and lipid peroxyl radicals. Our aim was to evaluate the efficacy of CA in ameliorating retinal degeneration in the Pde6rd10 mouse and to determine the underlying mechanism.
CA (15 mg/kg) or vehicle (canola oil) was administered by intraperitoneal injection to Pde6rd10 mice on a daily basis from postnatal day (P) 6 to P20. At P21, animals were examined by electroretinography (ERG), TUNEL staining, and immunohistochemical techniques.
In comparison to vehicle-treated animals, mice treated with CA had larger amplitude ERGs under both dark- and light-adapted conditions (all p < 0.01), fewer TUNEL-positive cells in the outer nuclear layer (ONL; p < 0.01) and a thicker ONL (p < 0.01). None of these measures, however, matched those of wild-type mice. Immunohistochemical staining showed that retinas of mice treated with CA had higher levels of activity in the Nrf2-ARE pathway, increased Nrf2 accumulation in cell nuclei, decreased the expression of phosphor-p38 and phosphor-p65, attenuated the markers of endoplasmic reticulum stress, and decreased expression of ER chaperones including phosphor-PERK and ATF6 (all p <0.01).
CA treatment reduces OS and ER stress in the ONL by down-regulating Nrf2-ARE, the unfolded protein response pathway, MAPK, and NF-κB pathways, resulting in greater survival of Pde6rd10 photoreceptors. CA is a potentially effective antioxidant for slowing the photoreceptor degeneration associated with RP.
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