Neuroprotective effects of allopregnenolone on hippocampal irreversible neurotoxicity in vitro.
1. The effects of allopregnenolone, a neurosteroid, endowed with GABAmimetic properties, were tested towards two models of irreversible hippocampal neurotoxicity: i) the irreversible depression produced by hypoxia on the CA1 evoked field potentials in rat hippocampal slices, and ii) glutamate-induced irreversible changes in intracellular calcium concentration in primary hippocampal cell coltures. 2. In control conditions during the reoxygenation period after the application of 15 min of hypoxia, the CA1 evoked field potentials were irreversibly suppressed in almost the 50% of the experiments. In the remaining experiments there were a significative (p<0.01) irreversible reduction of the magnitude of the CA1 population spike with respect with the pre-hypoxia values. Allopregnenolone (50-75 microM) perfused 30 min before, during and 30 min after hypoxia produced a significative (p<0.05) decrease both in the hypoxia-induced irreversible suppression of the CA1 PS and both in the irreversible decrease of the CA1 PS at the end of reoxygenation. 3. The exposition of the primary hippocampal cultured cells to glutamate 0.5 mM for 10 min was followed by a sustained elevation of [Ca2+]i, that persisted at 70-80% of maximal increase for the rest of the experiment (60 min). When a pretreatment with 10-50 microM allopregnanolone preceded Glu 0.5 mM application, [Ca2+]i increased to a maximal value during the glutamate application, after which a fast decrease to 50% was observed, followed by a slow recovery within about 30 min. 4. The results showed that the neurosteroid allopregnenolone, endowed with GABAmimetic properties, ameliorated the functional correlates of irreversible hippocampal neurotoxicity.
Frank
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Pharmacological Department, Istituto Superiore di Sanità Roma, Italy.
Sagratella
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D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control; D015220:Calcium Channels / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D011284:Pregnenolone / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D015220:Calcium Channels; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011284:Pregnenolone