Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons.

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Shirakawa H, Katsuki H, Kume T, Kaneko S, Akaike A

Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons.

Br J Pharmacol. 2006 Apr;147(7):729-36.

PubMed ID

16474421 [ View in PubMed

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Abstract

Aminoglutethimide is a clinically available drug that suppresses steroid biosynthesis by inhibiting enzymes such as cytochrome P450scc and aromatase. Because several members of neurosteroids regulate glutamate receptors, we investigated the effect of aminoglutethimide on cell death induced by overactivation of glutamate receptors in CNS neurons. Long-term pretreatment of organotypic cerebrocortical slice cultures with aminoglutethimide (100-1000 microM) for 6 days or over resulted in concentration-dependent suppression of neuronal cell death induced by NMDA. Aminoglutethimide (1000 microM) also inhibited neurotoxicity of AMPA and kainate, but not of ionomycin or staurosporine. The protective effect of aminoglutethimide against NMDA cytotoxicity was not mimicked by other steroid synthesis inhibitors including trilostane and exemestane, and was not reversed by concurrent application of steroids such as pregnenolone, estrone, 17beta-estradiol and estriol. In dissociated rat cerebrocortical cell cultures, long-term treatment with aminoglutethimide (10-1000 microM) attenuated NMDA receptor-mediated glutamate cytotoxicity but produced no significant effect on glutamate-induced increases in intracellular Ca2+. Brief as well as long-term pretreatment with aminoglutethimide (30-1000 microM) prevented NMDA receptor-dependent ischemic neuronal injury in organotypic cerebrocortical slice cultures, which was associated with suppression of glutamate release during the ischemic insult. These results indicate that aminoglutethimide, irrelevant to its actions on neurosteroid synthesis, protects CNS neurons from excitotoxic and ischemic injuries. Development of aminoglutethimide analogs possessing neuroprotective properties may be of therapeutic value.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Aminoglutethimide	Cytochrome P450 19A1	Protein	Humans	Yes	Inhibitor	Details