Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures.
Polyamines are ubiquitous cations that are essential for cell growth, regeneration and differentiation. Increases in polyamine metabolism have been implicated in several neuropathological conditions, including excitotoxicity. However, the precise role of polyamines in neuronal degeneration is still unclear. To investigate mechanisms by which polyamines could contribute to excitotoxic neuronal death, the present study examined the role of the polyamine interconversion pathway in kainic acid (KA) neurotoxicity using organotypic hippocampal slice cultures. Treatment of cultures with N1,N(2)-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527), an irreversible inhibitor of polyamine oxidase, resulted in a partial but significant neuronal protection, especially in CA1 region. In addition, this pre-treatment also attenuated KA-induced increase in levels of lipid peroxidation, cytosolic cytochrome C release and glial cell activation. Furthermore, pre-treatment with a combination of cyclosporin A (an inhibitor of the mitochondrial permeability transition pore) and MDL 72527 resulted in an additive and almost total neuronal protection against KA toxicity, while the combination of MDL 72527 and EUK-134 (a synthetic catalase/superoxide dismutase mimetic) did not provide additive protection. These data strongly suggest that the polyamine interconversion pathway partially contributes to KA-induced neurodegeneration via the production of reactive oxygen species.
Liu
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Neuroscience Program, School of Medicine, University of Southern California, Los Angeles, California 90089-2520, USA.
Liu
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Schreiber
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SS
Baudry
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D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D009942:Organometallic Compounds / Q000494:pharmacology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D011700:Putrescine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology; D000097667:Polyamine Oxidase
D015317:Biogenic Polyamines; D016572:Cyclosporine; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D007608:Kainic Acid; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011700:Putrescine; D017382:Reactive Oxygen Species; D012459:Salicylates; D000097667:Polyamine Oxidase; C433928:EUK-134; C044445:MDL 72527