Hydrogen peroxide increases gap junctional communication and induces astrocyte toxicity: regulation by brain macrophages.
Cultured astrocytes are highly coupled by gap junction channels mainly constituted by connexin 43. We have previously shown that gap junctional communication (GJC) represents a functional property of astrocytes that is a target for their interaction with other brain cell types, including neurons and brain macrophages. In pathological situations, neurons as well as brain macrophages produce superoxide ions leading to the formation of hydrogen peroxide (H2O2) that can be cytotoxic. We report here that 10-min exposure to 100 microM H2O2 increases GJC in astrocytes. Moreover, 30-min exposure to 100 microM H2O2 induces, 24 h later, an astrocyte cell death by both apoptosis and necrosis. This H2O2-induced astrocyte cell death is not affected when gap junctions are inhibited by several uncoupling agents, including 18alpha-glycyrrhetinic acid, halothane, heptanol, and endothelin-1, indicating that the proportion of cell death is not related to the level of GJC. The effect of H2O2 on gap junction channels does not result from the production of free radicals but is rather linked to modification of the redox equilibrium in astrocytes. Indeed, an oxidative agent reproduces the H2O2-evoked response while reducing agents prevent the effect of H2O2. Finally, when astrocytes are cocultured with brain macrophages, the effects of H2O2 on both GJC and toxicity are not observed, revealing a new protective role of brain macrophages during oxidative stress.
Rouach
Nathalie
N
INSERM U114, Collège de France, Paris, France.
Calvo
Charles-Felix
CF
Duquennoy
Helene
H
Glowinski
Jacques
J
Giaume
Christian
C
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats
D006861:Hydrogen Peroxide