POSTISCHEMIC, SYSTEMIC ADMINISTRATION OF POLYAMINE-MODIFIED SUPEROXIDE-DISMUTASE REDUCES HIPPOCAMPAL CA1 NEURODEGENERATION IN RAT GLOBAL CEREBRAL-ISCHEMIA

Antioxidant enzymes such as superoxide dismutase (SOD) have shown neur oprotective effects in animal models of cerebral ischemia, but only at very high doses. Modifications to increase the plasma half-life or bl ood-brain barrier (BBB) permeability of SOD have resulted in limited n europrotective effects. No one has demonstrated neuroprotection with p ostischemic administration. The specific aim of the present study was to administer systemically a polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, following global ce rebral ischemia in rats and analyze the effects on the selective vulne rability of CAI hippocampal neurons. Following 12 min of four-vessel o cclusion, global cerebral ischemia, male Wistar rats were dosed (i.v.) with either saline, native SOD (5000 U/kg), polyamine-modified SOD (5 000 U/kg), or enzymatically inactive, polyamine-modified SOD (2.1 mg/k g) twice daily for 3 days. Neuroprotective effects on hippocampal CA1 neurons were assessed using standard histological methods. Saline-trea ted animals had very few remaining CA1 neurons (1.44 +/- 0.66 neurons/ reticle; (x) over bar +/-S.E.M.) compared to sham rats (58.57 +/- 0.69 ). Native (10.38 +/- 2.96) or inactive, polyamine-modified SOD (7.32 /- 2.68) did not show significant neuroprotective effects. Polyamine-m odified SOD, however, resulted in the survival of significantly more C A1 neurons (24.61 +/- 5.90; P < 0.01). Postischemic, systemic administ ration of polyamine-modified SOD, having increased BBB permeability an d preserved enzymatic activity, significantly reduced hippocampal CA1 neuron loss following global cerebral ischemia. Similar modification o f other antioxidant enzymes and neurotrophic factors with polyamines m ay provide a useful technique for the systemic delivery of therapeutic proteins across the BBB for the treatment of stroke and other neurode generative disorders.