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Astrocytic Gap Junctional Communication Decreases Neuronal Vulnerability to Oxidative Stress‐Induced Disruption of Ca 2+ Homeostasis and Cell Death
Author(s) -
Blanc Emmanuelle M.,
BruceKeller Annadora J.,
Mattson Mark P.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70030958.x
Subject(s) - astrocyte , biology , oxidative stress , microbiology and biotechnology , neuron , programmed cell death , glutamate receptor , gap junction , intracellular , chemistry , biochemistry , endocrinology , neuroscience , apoptosis , receptor , central nervous system
We investigated the effect of uncoupling astrocytic gap junctions on neuronal vulnerability to oxidative injury in embryonic rat hippocampal cell cultures. Mixed cultures (neurons growing on an astrocyte monolayer) treated with 18‐α‐glycyrrhetinic acid (GA), an uncoupler of gap junctions, showed markedly enhanced generation of intracellular peroxides (2,7‐dichlorofluorescein fluorescence), impairment of mitochondrial function [(dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide reduction], and cell death (lactate dehydrogenase release) following exposure to oxidative insults (FeSO 4 and 4‐hydroxynonenal). GA alone had little or no effect on basal levels of peroxides, mitochondrial function, or neuronal survival. Intercellular dye transfer analyses revealed extensive astrocyte‐astrocyte coupling but no astrocyte‐neuron or neuron‐neuron coupling in the mixed cultures. Studies of pure astrocyte cultures and microscope analyses of neurons in mixed cultures showed that the increased oxidative stress and cell death in GA‐treated cultures occurred only in neurons and not in astrocytes. Antioxidants (propyl gallate and glutathione) blocked the death of neurons exposed to FeSO 4 /GA. Elevations of neuronal intracellular calcium levels ([Ca 2+ ] i ) induced by FeSO 4 were enhanced in neurons in mixed cultures exposed to GA. Removal of extracellular Ca 2+ and the L‐type Ca 2+ channel blocker nimodipine prevented impairment of mitochondrial function and cell death induced by FeSO 4 and GA, whereas glutamate receptor antagonists were ineffective. Finally, GA exacerbated kainate‐ and FeSO 4 ‐induced injury to pyramidal neurons in organotypic hippocampal slice cultures. The data suggest that interastrocytic gap junctional communication decreases neuronal vulnerability to oxidative injury by a mechanism involving stabilization of cellular calcium homeostasis and dissipation of oxidative stress.