Mouse spinal cord compression injury is ameliorated by intrathecal cationic manganese(III) porphyrin catalytic antioxidant therapy

Abstract

This study evaluated the effects of the cationic manganese(III) tetrakis( N,N′-diethylimidazolium-2-yl)porphyrin catalytic antioxidant Mn IIITDE-2-ImP 5+ (AEOL 10150) on outcome from spinal cord compression (SCC) in the mouse. C57BL/6J mice were subjected to 60 min thoracic SCC after discontinuation of halothane anesthesia. In Experiment 1, mice were given intravenous Mn IIITDE-2-ImP 5+ (0.5 mg/kg bolus followed by 1 mg kg −1 h −1 for 24 h), methylprednisolone (30 mg/kg bolus followed by 5.4 mg kg −1 h −1 for 24 h), or vehicle ( n = 25 per group). In Experiment 2, mice were given intrathecal Mn IIITDE-2-ImP 5+ (2.5 or 5.0 μg/kg) or vehicle ( n = 18 per group). In both experiments, treatment began 5 min post-SCC onset. Rotarod performance was measured on post-SCC days 3, 7, 14, and 21. On post-SCC day 21, the spinal cord was histologically examined and a total damage score was calculated. Neither intravenous Mn IIITDE-2-ImP 5+ nor methylprednisolone altered rotarod performance (accelerated rate P = 0.11, fixed rate P = 0.11) or mean ± S.D. total damage score (Mn IIITDE-2-ImP 5+ = 21 ± 9, methylprednisolone = 24 ± 8, vehicle = 22 ± 10; P = 0.47; shams = 0). Intrathecal Mn IIITDE-2-ImP 5+ (both 2.5 and 5.0 μg) given at SCC-onset improved rotarod performance ( P = 0.05) and total damage score (2.5 μg = 19 ± 10, P = 0.04; 5.0 μg =19 ± 8, P = 0.03) versus vehicle (26 ± 10). These studies demonstrate sustained benefit from manganese(III) porphyrin catalytic antioxidant therapy after SCC. However, efficacy was dependent upon route of administration suggesting that bioavailability is critical in defining efficacy.