Abstract
Purpose: :
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.
Methods: :
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).
Results: :
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.
Conclusions: :
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.
Keywords: ischemia • antioxidants • inflammation