Dehydroepiandrosterone sulphate prevents oxygen-glucose deprivation-induced injury in cerebellar granule cell culture.
Decreased levels of dehydroepiandrosterone sulphate have been hypothesized to contribute to increased vulnerability of the ageing or stressed human brain to ischemia. To help to address the question of whether of dehydroepiandrosterone sulphate has a possible neuroprotective effect against ischemic neuronal injury, we tested its effect on the neurodegeneration induced by oxygen-glucose deprivation in rat cultured cerebellar granule cells. Dehydroepiandrosterone sulphate added to the medium after injury demonstrated a neuroprotective effect with a median inhibitory concentration of 0.5 microM. At 10 microM concentration almost full neuroprotection was observed. Even more pronounced neuroprotective effect was found when dehydroepiandrosterone sulphate was added for 48h before injury. Furthermore, partial neuroprotection of dehydroepiandrosterone sulphate was also found against 1-methyl-4-phenylpyridinium, colchicine, glutamate and N-methyl-D-aspartate-induced toxicity. Further analysis demonstrated that dehydroepiandrosterone sulphate eliminated the apoptotic features of the oxygen-glucose deprivation-induced neuronal death: DNA fragmentation and nuclear condensation/fragmentation.Thus, our data suggest that dehydroepiandrosterone sulphate may have therapeutic potential in the prevention and treatment of ischemic/hypoxic neuronal damage. The neuroprotective action of dehydroepiandrosterone sulphate was inhibited by both a GABA(A) receptor-linked chloride channel agonist and an antagonist, pentobarbital and picrotoxin, respectively. It seems that GABA(A) receptor-mediated neuronal inhibition as well as neuronal excitation can reduce the neuroprotective action of dehydroepiandrosterone sulphate.
Kaasik
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Department of Pharmacology, University of Tartu, 18 Ylikooli Street, 50090, Tartu, Estonia.
Kalda
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Jaako
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Zharkovsky
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D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D015687:Cell Hypoxia / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003078:Colchicine / Q000633:toxicity; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D020925:Hypoxia-Ischemia, Brain / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism
D015655:1-Methyl-4-phenylpyridinium; D003078:Colchicine; D019314:Dehydroepiandrosterone Sulfate; D016291:Dizocilpine Maleate; D018757:GABA Modulators; D005947:Glucose; D018698:Glutamic Acid; D018696:Neuroprotective Agents; D010424:Pentobarbital; D010852:Picrotoxin; D011280:Pregnanolone; D011963:Receptors, GABA-A