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Daniel M. Rosenbaum, Brian Saunders, Frank C. Barone, Jie Li, Jin Zhou, Samah G. Abdel Baki, Pearl S. Rosenbaum, Peter J. Bergold; Minocycline Synergizes With N-acetylcysteine To Improve Rat Retinal Function Following Ischemia. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2653.
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Many individual drugs have failed clinical trials suggesting a role for drug combinations in CNS injury. Synergistic drug combinations provide an improved intervention strategy (e.g., regarding potency and safety). Recently we showed that Minocycline (MINO; anti-inflammatory antibiotic) synergizes with N-acetylcysteine (NAC; anti-oxidant amino acid) to improve cognition in rat traumatic brain injury (PLoS One. 5(8):e12490, 2010). Here we evaluate these drugs alone or together, compared to control saline (SAL) to determine if synergistic protection of the ischemic retina can be demonstrated.
Retinal ischemia was produced in male Sprague Dawley rats. High intraocular pressure (120 mmHg) induced right eye retinal ischemia for 45 minutes. Electroretinograms (ERG) α- and β-waves were measured in each eye before ischemia and 7 days later. SAL (Vehicle; N=9), MINO (50 mg/kg; N=7), NAC (150 mg/kg; N=7) or MINO+NAC (same doses; N=12) was administered intraperitonially as 4 ml/kg one hour after ischemia. Retinal function was measured as percent normal eye ERG baseline wave response (i.e., calculated as post-wave ratio; post-ischemia eye/post-normal eye, to pre-wave ratio; pre-ischemia eye/pre-normal eye).
Following retinal ischemia, the ERG α-wave did not differ but ERG β-wave was decreased similarly in the SAL (17.4+4.5 %), MINO (28.8+8.1 %) and NAC (25.9+8.9 %) groups. In contrast, the MINO+NAC group increased ERG β-wave retinal function (53.2+24.9 %; only this group differed significantly from all other groups; p< 0.01). Thus, a clear synergistic protective effect was demonstrated for the MINO+NAC combination.
These data demonstrate that post-ischemic administration of MINO+NAC act synergistically to protect the retina from functional injury. Since these drugs are already FDA-approved for uses other than brain injury, they provide a potential opportunity for combined intervention for CNS injury in the future.
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