The effects of 8-OH-DPAT on neuroinflammation after sarin exposure in mice.

Abstract

Poisoning by organophosphate nerve agents can induce seizures which rapidly become refractory to treatment and result in brain damage. Current therapies have only a narrow time frame for effective administration after poisoning. 5-HT1A agonists were tested for efficacy in mice against a seizure-producing combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP) and sarin, producing an LD20-40. Administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased glial fibrillary acidic protein (GFAP) staining in mice when administered 1min after CBDP and sarin while other 5-HT1A agonists buspirone and S-14506 were not effective. The reduction in GFAP staining by 8-OH-DPAT remained significant when a single dose was administered 2h after the toxic challenge. In addition, 8-OH-DPAT reversed the increase in the inflammatory factor IL-1β in the dentate gyrus and amygdala but did not reduce positive TUNEL staining in the dentate gyrus. Due to the failure of the two other agonists to provide protection, the 5-HT1A antagonist WAY-100635 was tested. WAY-100635 was found to neither reverse the neuroprotective effects of 8-OH-DPAT nor worsen the damage when given alone, making a role for this receptor unlikely. The neuroprotective effects of 8-OH-DPAT appear to lie within its secondary pharmacology.

• Authors: Teresa L Garrett, Kaushal Joshi, Christine M Rapp, Molly Chapleau, David R Cool, John J Schlager, James B Lucot
• Journal: Toxicology (Toxicology) Vol. 310 Pg. 22-8 (Aug 09 2013) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 23692952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Glial Fibrillary Acidic Protein
• Interleukin-1beta
• Nerve Tissue Proteins
• Neuroprotective Agents
• Organophosphorus Compounds
• Serotonin Receptor Agonists
• glial fibrillary astrocytic protein, mouse
• 2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Sarin
• Cholinesterases

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (administration & dosage, pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Behavior, Animal (drug effects)
• Brain (drug effects, enzymology, immunology, pathology)
• Cholinesterases (metabolism)
• Dose-Response Relationship, Drug
• Glial Fibrillary Acidic Protein
• Immunohistochemistry
• Interleukin-1beta (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (metabolism)
• Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
• Neurotoxicity Syndromes (enzymology, immunology, pathology, prevention & control)
• Organophosphorus Compounds (toxicity)
• Sarin (poisoning)
• Serotonin Receptor Agonists (administration & dosage, pharmacology, therapeutic use)
• Survival Analysis
• Weight Loss (drug effects)