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

Abstract

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 signi®cant 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.

A New Transgenic Mouse Model for Studying the Neurotoxicity of Spermine Oxidase Dosage in the Response to Excitotoxic Injury

“…This explanation is in line with the treatment of organotypic hippocampal slice cultures with N,N 1 -bis(2,3-butadienyl)-1,4-butanediamine (MDL72,527), a SMO inhibitor, that resulted in a considerable neuronal protection against KA-induced toxicity and significantly prevented neuronal death in ischemia and mechanical injury models [54]. In the work of Liu et al [54] has been reported that while the pre-treatment with a combination of MDL72,527 and cyclosporin A (a blocker of the formation of the mitochondrial permeability transition pore) provided additive neuronal protection, on the contrary a combination of MDL72,527 and EUK-134 (a specific scavenger of hydrogen peroxide [55], [56]) did not produce an additive neuronal protective effect on KA neuronal toxicity. These observations strongly suggest that SMO overexpression is only partially affecting the increase of apoptosis after KA treatment, while is the major source of H 2 O 2 production which increases vulnerability to a KA-induced neuronal death.…”

Neuroprotective Effect of Melatonin against Kainic Acid-Induced Oxidative Injury in Hippocampal Slice Culture of Rats

“…The generation of the endogenous ROS by antimycin A increases up-regulation of 5-LO activity three-fold [29]. Apoptotic neuronal death with KA injury induces rapid induction of bax, collapse of mitochondrial membrane potential, release of cytochrome c from mitochondria, and activation of caspase-3, suggesting that multiple apoptotic pathways are activated in response to KA [30]. Caspase-3 participates in various apoptosis pathways including KA-induced injury.…”

Role of oxidative stress in epileptic seizures

“…However, these agents blocked KA-induced neuronal death, lipid peroxidation, nitrite formation, and nucleic acid oxidation in vivo (Rong et al, 1999; Liang et al, 2000) and in vitro (Liu et al, 2001). Rong et al (1999) suggested that EUK-134-mediated inhibition of AP-1 and NF-κB DNA-binding activity, oxidative stress-sensitive transcription factors, is important in protection of KA-induced neurotoxicity.…”