PARALLEL ANTIOXIDANT AND ANTIEXCITOTOXIC THERAPY IMPROVES OUTCOME AFTER INCOMPLETE GLOBAL CEREBRAL-ISCHEMIA IN DOGS

Background and Purpose We have previously shown that incomplete global cerebral ischemia complicated by dense acidosis produces a profound s econdary deterioration of energy metabolism and cerebral blood flow. A ntioxidant treatment only partially averts this deterioration, suggest ing that parallel or sequential mechanisms are involved in cerebral is chemic injury. We tested the hypothesis that a novel competitive N-met hyl-D-aspartate (NMDA) receptor antagonist GPI 3000 (GPI) ameliorates metabolic injury and that the effectiveness of the iron-chelator and a ntioxidant deferoxamine (DFO) is augmented by combined therapy with GP I after incomplete global cerebral ischemia. Methods Anesthetized dogs were treated with 30 minutes of global incomplete cerebral ischemia. Preischemic plasma glucose was raised to approximately 500 mg/dL to ex aggerate lactic acidosis. Brain ATP, phosphocreatine, and pH(i) were m easured by P-31 MR spectroscopy for 180 minutes of reperfusion. Neurop hysiological outcomes were assessed by evoked potential monitoring. Fi ve groups were treated with either saline; 75 mg/kg DFO preischemia pl us 75 mg/kg at reperfusion onset, followed by 27.5 mg/kg per hour for the remainder of reperfusion (DFO group); 25 mg/kg GPI pretreatment, f ollowed by 5 mg/kg per hour (GPI-pre group); 25 mg/kg GPI at reperfusi on, followed by 5 mg/kg per hour (GPI-post group); or DFO and GPI-pre at the same doses (Combined group). Results Ischemic cerebral blood fl ow (microspheres: 5 to 8 mL/min per 100 g) was similar among the group s. End-ischemic pH(i) was also similar: 5.9 in saline, 6.1 in DFO, 6.2 in GPI-pre, 6.2 in Combined, and 6.1 in GPI-post groups. Progressive hypoperfusion was observed in all groups except Combined during reperf usion. Metabolic recovery was improved relative to saline in all drug- treated groups. Phosphocreatine recovery was improved in Combined comp ared with DFO and GPI-pre groups. Somatosensory evoked potential recov ery was not observed in the saline group and incomplete in all treatme nt groups. At 60 and 90 minutes of reperfusion, DFO, GPI-pre, and Comb ined groups demonstrated improved recovery relative to the saline grou p. Conclusions Pretreatment and posttreatment with GPI ameliorated pos tischemic metabolic failure, suggesting that NMDA-mediated mechanisms are more important in global cerebral ischemia complicated by dense ac idosis than early studies indicated. Combined treatment with GPI and D FO improved cerebral blood Bow during reperfusion and one indicator of energy recovery. These data support the hypothesis that parallel ther apy aimed at antioxidant and antiexcitotoxic mechanisms of ischemic br ain injury augment recovery compared with the individual agents.