title: 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.affiliation: Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Garrett
authors.forename: Kaushal
authors.initials: K
authors.lastname: Joshi
authors.forename: Christine M
authors.initials: CM
authors.lastname: Rapp
authors.forename: Molly
authors.initials: M
authors.lastname: Chapleau
authors.forename: David R
authors.initials: DR
authors.lastname: Cool
authors.forename: John J
authors.initials: JJ
authors.lastname: Schlager
authors.forename: James B
authors.initials: JB
authors.lastname: Lucot
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009943:Organophosphorus Compounds / Q000633:toxicity; D012524:Sarin / Q000506:poisoning*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D015431:Weight Loss / Q000187:drug effects
chemical_list: D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D017366:Serotonin Receptor Agonists; C528900:glial fibrillary astrocytic protein, mouse; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012524:Sarin; D002802:Cholinesterases
keywords: 5-HT(1A) agonist; Chemical warfare agent; Neuroinflammation; Organophosphate; Protection; Sarin