Neuroprotective action of synthetic steroids with oxygen bridge. Activity on GABAA receptor.
Allopregnanolone (A) and pregnanolone (P) are able to modify neural activities acting through the GABAA receptor complex. This capacity makes them useful as anticonvulsant, anxiolytic, or anti-stress compounds. In this study, the performance of seven synthetic steroids (SS) analogous of A or P containing an intramolecular oxygen bridge was evaluated using different assays. Competition assays showed that compounds 1, 5, 6 and 7 affected the binding of specific ligands for the GABAA receptor in a way similar to that of A and P, whereas compounds 3 and 4 stimulated [(3)H]-flunitrazepam and reduced [(35)S]-TBPS binding. The enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) produces the precursor for A and P, and its activity is regulated by steroids. The action of several SS on 3β-HSD activity was tested in different tissues. All SS analyzed inhibit its activity, but compound 5 was the least effective. Finally, the neuroprotective role of two SS was evaluated in cerebral cortex and hippocampus cultures subjected to hypoxia. Glial fibrillary acidic protein (GFAP) increase was prevented by A, P, and compounds 3 and 5. Only A, P and compound 5 prevented neurofilament (NF160/200) decrease in hippocampus cultures, whereas A and compound 5 partially prevented NF200 and NF160 decreases respectively in cerebral cortex cultures. A prevented microtubule associated protein (MAP 2b) decrease in cerebral cortex cultures, while in hippocampus cultures only compounds 3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions.
Laboratorio de Neurobiología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina.
Mariana
M
Rey
María Sol
MS
Kruse
Lautaro D
LD
Alvarez
Alberto A
AA
Ghini
Adriana S
AS
Veleiro
Gerardo
G
Burton
Héctor
H
Coirini
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013256:Steroids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D013256:Steroids; D010100:Oxygen
3β-HSD; Cerebellum; Hippocampus; Hypothalamus; Hypoxia; Neurosteroids