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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Dhir, Ashish Rogawski, Michael A. |
| Description | Author Affiliation: Dhir A ( Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.) |
| Abstract | BACKGROUND AND PURPOSE: Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA(A) receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA(A) receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. EXPERIMENTAL APPROACH: Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test. KEY RESULTS: Midazolam (500-5000 µg·kg(-1) , i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5 -reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11ß-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg(-1) ) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO. CONCLUSION AND IMPLICATIONS: Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 8 |
| Volume Number | 165 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2012-04-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Anticonvulsants Therapeutic Use Midazolam Neurotransmitter Agents Metabolism Receptors, GABA Seizures Drug Therapy 5-alpha Reductase Inhibitors Pharmacology Animals Clonazepam Convulsants Disease Models, Animal Finasteride GABA Antagonists Isoquinolines Mice Pentylenetetrazole Chemically Induced |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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