Oxidative stress, mitochodrial permeability transition and activation of caspases in calium ionophore A23187-induced death of cultured striatal neurons

Laboratory for Experimental Brain Researc, Lund University, Lund, Skåne, Sweden
Brain Research (Impact Factor: 2.84). 03/2000; 857(1-2):20-9. DOI: 10.1016/S0006-8993(99)02320-3
Source: PubMed


Disruption of intracellular calcium homeostasis is thought to play a role in neurodegenerative disorders such as Huntington's disease (HD). To study different aspects of putative pathogenic mechanisms in HD, we aimed to establish an in vitro model of calcium-induced toxicity in striatal neurons. The calcium ionophore A23187 induced a concentration- and time-dependent cell death in cultures of embryonic striatal neurons, causing both apoptosis and necrosis. Cell death was significantly reduced by the cell-permeant antioxidant manganese(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP). Cyclosporin A and its analogue N-MeVal-4-cyclosporin also reduced the incidence of cell death, suggesting the participation of mitochondrial permeability transition in this process. Furthermore, addition of either of two types of caspase inhibitors, Ac-YVAD-CHO (acetyl-Tyr-Val-Ala-Asp-aldehyde) and Ac-DEVD-CHO (acetyl-Asp-Glu-Val-Asp-aldehyde), to the striatal cells blocked A23187-induced striatal cell death in a concentration-dependent manner. These results suggest that oxidative stress, opening of the mitochondrial permeability transition pore and activation of caspases are important steps in A23187-induced cell death.

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Available from: Tadeusz Wieloch
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    • "Opening of the permeabilization transition pore complex is thought to mediate release of cytochrome c from the mitochondria (Ansari et al., 2006). Mitochondrial permeability transitionresults indisruption of the outer membrane, release of cytochrome c, apoptosis inducing factor (AIF) and the activation of caspases (Alksne et al., 2000; Petersen et al., 2000; Gravance et al., 2001; Cordero et al., 2009). Our study showed that the incubation with plasmid pFLAG-hLY caused release of cytochrome c via the mitochondrial signaling pathway (Fig. 2). "
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    • "Exposure to high levels of calcium or oxidative stress results in the mPTP opening of the inner mitochondrial membrane, causing disruption of m , and swelling of mitochondria [40] [47] [58]. In vitro CsA attenuates apoptosis induced by the mitochondrial complex 1 inhibitor rotenone [68], and also the calcium ionophore A23187 [58]. CsA also prevents m loss resulting from exposure to NMDA in cortical neurons [52]. "
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    • "eviously reported results ( Bockaert et al . 1986 ; Luk et al . 2003 ) . The results are also in agreement with previous reports suggesting that GABAergic medium spiny neurons and their precursors make up the majority of cells in these early cultures , with a minority of interneurons and glia ( Ivkovic et al . 1997 ; Ventimiglia and Lindsay 1998 ; Petersen et al . 2000 ; Luk et al . 2003 ) . Finally , the results are consistent with evidence that forebrain gliogenesis occurs in the late prenatal and early postnatal periods ( Schultze et al . 1974 ; Bayer and Altman 1991 ) . Neuroblasts in proliferating 1 DIV cultures expressed mGluR5 receptors consistent with in vivo data in embryonic telencephalon ge"
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