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  • Title: Co-culture of neurones with glutathione deficient astrocytes leads to increased neuronal susceptibility to nitric oxide and increased glutamate-cysteine ligase activity.
    Author: Gegg ME, Clark JB, Heales SJ.
    Journal: Brain Res; 2005 Mar 02; 1036(1-2):1-6. PubMed ID: 15725395.
    Abstract:
    The antioxidant glutathione (GSH) plays an important role in protecting the mitochondrial electron transport chain (ETC) from damage by oxidative stress in astrocytes and neurones. Neurones co-cultured with astrocytes have greater GSH levels, compared to neurones cultured alone, leading to the hypothesis that astrocytes play a key role in brain GSH metabolism by supplying essential GSH precursors to neurones. A previous study has postulated that damage to the ETC following exposure to reactive nitrogen species (RNS) is less in co-cultured neurones, compared to neurones cultured alone, because of the greater GSH levels in the former cells. To investigate this further, primary culture rat neurones were co-cultured with either rat astrocytes activated with IFN-gamma and LPS to produce NO, or NO-generating astrocytes that had been depleted of intracellular GSH by 87% following incubation with the GSH synthesis inhibitor L-buthionine-S,R-sulfoximine (L-BSO). Neurones incubated with NO-generating astrocytes depleted of GSH were unable to elevate GSH levels, unlike neurones co-cultured with NO-generating astrocytes. Complexes II + III and IV of the neuronal ETC were significantly inhibited following exposure to NO-generating astrocytes depleted of GSH. No ETC damage was observed in neurones co-cultured with NO-generating astrocytes. Although neurones co-cultured with GSH depleted astrocytes did not increase cellular GSH levels, the activity of glutamate cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis, was increased by 218%, compared to neurones cultured with control astrocytes. This suggests that neuronal GCL activity could be modulated when GSH metabolism is inhibited in neighboring astrocytes.
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