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Anne Kasus-Jacobi, Huaiwen Wang, Feng Li, Kevin Wu, Mark Babizhayev, H. Anne Pereira; The Multi-functional and Neuroprotective Peptide Derivative Carcinine Has Strong Potential for Therapeutic Applications In Retinopathies. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5390.
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Carcinine (β-alanyl histamine) combines antioxidant, peroxidase-like, and 4-hydroxynonenal-scavenging activities and is a potent neuroprotector in mouse retina subjected to light-induced oxidative damage. Our hypothesis is that it could be beneficial for therapeutic applications in progressive retinopathies involving oxidative damage.
Carcinine was administered topically through eyedrops to Balb/C mice and pharmacokinetic and pharmacodynamic studies were performed. Carcinine was quantified in dissected retinas by mass spectrometry. Mice were exposed to damaging bright light (3,000 lux, 4h) and carcinine-mediated protection of retinal structure was evaluated by optical coherence tomography and quantitative histology. The mechanism of protection was investigated by immunoblot quantification of 4-hydroxynonenal-modified protein, photoreceptor retinol dehydrogenase 12 (RDH12), and hexokinase 1 (HK1).
Following topical administration, carcinine reaches the retina in a dose- and time-dependant manner. Retinal levels of carcinine reach a plateau starting at 0.2 M carcinine in eyedrops, suggesting a saturable transport mechanism. This concentration is sufficient to maintain a normal retinal architecture and prevent rod photoreceptor cells from apoptosis when carcinine is administered both during and after exposure to bright light, but not if administered only during exposure. Carcinine significantly decreased the amount of retinal 4-hydroxynonenal-modified protein. It maintained high level of retinal RDH12, a detoxification enzyme that is otherwise rapidly degraded following light-induced oxidative modification. Finally, carcinine decreased the level of a putative retinal splicing variant of HK1.
Oxidative damage is an established aggravating factor in progressive retinopathies such as age-related macular dystrophy, diabetic retinopathy and retinitis pigmentosa. Thus, carcinine is a good candidate for therapeutic applications in these retinopathies. This small molecule could be administered non-invasively through eyedrops every day to protect photoreceptor cells and delay vision loss associated with these retinopathies.
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