IPSIndian Journal of Pharmacology
Home  IPS  Feedback Subscribe Top cited articles Login 
Users Online : 8897 
Small font sizeDefault font sizeIncrease font size
Navigate Here
 »   Next article
 »   Previous article
 »   Table of Contents

Resource Links
 »   Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »   Citation Manager
 »   Access Statistics
 »   Reader Comments
 »   Email Alert *
 »   Add to My List *
 * Requires registration (Free)

 Article Access Statistics
    PDF Downloaded187    
    Comments [Add]    

Recommend this journal


Year : 1997  |  Volume : 29  |  Issue : 6  |  Page : 381-392

Neuroprotective effects of neurosteroids against hypoxic-neurotoxicity in naive and benzodiazepine inverse agonist FG 7142-treated mice

Correspondence Address:
D S Reddy

Login to access the Email id

Source of Support: None, Conflict of Interest: None

Rights and PermissionsRights and Permissions

Objective: The present study investigates the effects of various neorosteroids on hypoxic stress-induced neurotoxicity in naive and FG 7142-treated mice. Methods: The extent of neurotoxicity after the slow induction of hypoxic stress was estimated by measuring the latency for the onset of tremors and convulsions followed by death. Results: Treatment with FG 7142 (5-20 mg/kg, i.p.), a benzodiazepine (BZD) inverse agonist, augmented the hypoxic neurotoxicity. Pretreatment with neurosteroid allopregnanolone (AP) offered a significant protection in both naive and FG 7142- treated mice. Dehydroepiandrosterone sulphate (DHEAS) had no protective effect. In contrast, pregnenolone sulphate (PS) at high doses significantly protected naive but not FG 7142-treated mice, while low doses are ineffective. Progesterone (PROG), aneurosteroid precursor, and 4' chlordiazepam (4'-CD), a mitochondrial diazepam binding inhibitor receptor (MDR) agonist, produced a dose-dependent protection of both naive and FG 7142-treated mice. The neuro-protective effects of AP, PROG and 4'-CD against hypoxic neurotoxicity were blocked by picrotoxin, a GABA-A chloride channel antagonist, but not by flumazenil, a selective BZD antagonist. However, picrotoxin failed to reverse the PS-induced hypoxic neuroprotection. The 4'-CD elicited protection was, however, reversed by PK11195, a partial MDR antagonist. In addition, triazolam, a short acting BZD, nifedipine, a calcium channel blocker, and dizocilpine, a non-competitive NMDA receptor blocker, also dose-dependently protected the mice from hypoxic neurotoxicity. Combined exposure of nifedipine and PS resulted in a significant additive effect in protecting the hypoxic neurotoxicity. Similarly, combined administration of nifedipine with PROG, 4'-CD or dizocilpine markedly augmented the protective effect of nifedipine. Further, the dizocilpine induced neuroprotection was blocked by DHEAS. Conclusion: These results show that neurosteroids AP, PS and PROG, and MDR ligand 4'-CD possess neuroprotective activity in hypoxic stress models. Further, the present study suggests a role for GABA-A and mitochondrial DBI receptors in the neurosteroidal alleviation of hypoxic neurotoxicity, and thus may have therapeutic implications in cerebral ischemia and neurodegenerative disorders.


Print this article     Email this article

Site Map | Home | Contact Us | Feedback | Copyright and Disclaimer | Privacy Notice
Online since 20th July '04
Published by Wolters Kluwer - Medknow