Postischemic, systemic administration of polyamine-modified superoxide dismutase reduces hippocampal CA1 neurodegeneration in rat global cerebral ischemia

Thomas M. Wengenack, Geoffry L. Curran, Joseph F. Poduslo

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Antioxidant enzymes such as superoxide dismutase (SOD) have shown neuroprotective effects in animal models of cerebral ischemia, but only at very high doses. Modifications to increase the plasma half-life or blood-brain barrier (BBB) permeability of SOD have resulted in limited neuroprotective effects. No one has demonstrated neuroprotection with postischemic 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 cerebral ischemia in rats and analyze the effects on the selective vulnerability of CA1 hippocampal neurons. Following 12 min of four-vessel occlusion, global cerebral ischemia, male Wistar rats were dosed (i.v.) with either saline, native SOD (5000 U/kg), polyamine-modified SOD (5000 U/kg), or enzymatically inactive, polyamine-modified SOD (2.1 mg/kg) twice daily for 3 days. Neuroprotective effects on hippocampal CA1 neurons were assessed using standard histological methods. Saline-treated animals had very few remaining CA1 neurons (1.44 ± 0.60 neurons/reticle; x̄ ± 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-modified SOD, however, resulted in the survival of significantly more CA1 neurons (24.61 ± 5.90; P < 0.01). Postischemic, systemic administration of polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, significantly reduced hippocampal CA1 neuron loss following global cerebral ischemia. Similar modification of other antioxidant enzymes and neurotrophic factors with polyamines may provide a useful technique for the systemic delivery of therapeutic proteins across the BBB for the treatment of stroke and other neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)46-54
Number of pages9
JournalBrain Research
Volume754
Issue number1-2
DOIs
StatePublished - Apr 18 1997

Keywords

  • blood-brain barrier
  • cerebral ischemia
  • free radical
  • hippocampus
  • polyamine
  • rat
  • superoxide dismutase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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