Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures.
Altered glial function in the substantia nigra in Parkinson's disease may lead to the release of toxic substances that cause dopaminergic cell death or increase neuronal vulnerability to neurotoxins. To investigate this concept, we examined the effects of subjecting astrocytes to lipopolysaccharide (LPS)-induced activation alone or combined with L-buthionine-[S,R]-sulfoximine-induced glutathione depletion or inhibition of complex I activity by 1-methyl-4-phenylpyridinium (MPP+) on the viability of primary ventral mesencephalic neurones or susceptibility to MPP+ and 6-hydroxydopamine (6-OHDA) in co-cultures. LPS-activated astrocytes caused neuronal death in a time-dependent manner, but glutathione-depleted or complex I-inhibited astrocytes had no effect on neuronal viability. The neurotoxicity of LPS-activated astrocytes was inhibited by the inducible nitric oxide synthase inhibitor aminoguanidine, by the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and by reduced glutathione (GSH). MPP+-induced neuronal death was greater in ventral mesencephalic cultures previously cultured with LPS-activated, glutathione-depleted, or complex I-inhibited astrocytes compared with co-cultures containing normal astrocytes. The increased neuronal susceptibility to MPP+ caused by LPS-activated or complex I-inhibited astrocytes and glutathione-depleted astrocytes was inhibited by the NMDA/glutamate antagonist MK-801 and by GSH, respectively. Neuronal death caused by 6-OHDA was increased in ventral mesencephalic cultures previously cultured with LPS-activated and glutathione-depleted, but not complex I-inhibited astrocytes, compared with co-cultures containing normal astrocytes. Treatment of co-cultures with GSH prevented the increased neuronal susceptibility to 6-OHDA. These findings suggest that glial dysfunction may cause neuronal death or render neurones susceptible to toxic insults via a mechanism involving the release of free radicals and glutamate. Such a mechanism may play a role in the development or progression of nigrostriatal degeneration in Parkinson's disease.
McNaught
K S
KS
Neurodegenerative Disease Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, England.
Jenner
P
P
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000502:physiology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D008070:Lipopolysaccharides; D019328:Buthionine Sulfoximine; D016291:Dizocilpine Maleate; D016627:Oxidopamine; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine