Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures

Polyamines are ubiquitous cations that are essential for cell growth, regen eration and differentiation. Increases in polyamine metabolism have been im plicated 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 poly amine interconversion pathway in kainic acid (KA) neurotoxicity using organ otypic 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 protectio n, especially in CA1 region. In addition, this pre-treatment also attenuate d KA-induced increase in levels of lipid peroxidation, cytosolic cytochrome C release and glial cell activation. Furthermore, pre-treatment with a com bination of cyclosporin A (an inhibitor of the mitochondrial permeability t ransition pore) and MDL 72527 resulted in an additive and almost total neur onal protection against KA toxicity, while the combination of MDL 72527 and EUK-134 (a synthetic catalase/superoxide dismutase mimetic) did not provid e additive protection. These data strongly suggest that the polyamine inter conversion pathway partially contributes to KA-induced neurodegeneration vi a the production of reactive oxygen species.