Astrocyte mediated protection of fetal cerebral cortical neurons from rotenone and paraquat

Primary cultures of fetal rat cortical neurons and astrocytes were used to test the hypothesis that astrocyte-mediated control of neuronal glutathione (GSH) is a potent factor in neuroprotection against rotenone and paraquat. In neurons, rotenone (0.025–1 μM) for 4 and 24 h decreased viability as did paraquat (2–100 μM). Rotenone (30 nM) decreased neuronal viability and GSH by 24% and 30%, while ROS were increased by 56%. Paraquat (30 μM) decreased neuronal viability and GSH by 36% and 70%, while ROS were increased by 23%. When neurons were co-cultured with astrocytes, their GSH increased 1.5 fold and 5 fold at 12 and 24 h. Co-culturing with astrocytes blocked neuronal death and damage by rotenone and paraquat. Astrocyte-mediated neuroprotection was dependent on the activity of components of the γ-glutamyl cycle. These studies illustrate the importance of astrocyte-mediated glutathione homeostasis for protection of neurons from rotenone and paraquat and the role of the γ-glutamyl cycle in this neuroprotection.

► The developing brain can be damaged by rotenone (R) and paraquat (P). ► Fetal neurons are more sensitive to rotenone and paraquat than astrocytes. ► Mature astrocytes can augment neuron GSH homeostasis via the γ-glutamyl cycle. ► Co-culturing fetal neurons with astrocytes protects from R and P-related damage and death. ► This protection is provided by the γ-glutamyl cycle.