title: Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.
abstract: Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality.
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Jishnu K S
authors.initials: JKS
authors.lastname: Krishnan
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Peethambaran
authors.initials: P
authors.lastname: Arun
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Abhilash P
authors.initials: AP
authors.lastname: Appu
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Nivetha
authors.initials: N
authors.lastname: Vijayakumar
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Taíza H
authors.initials: TH
authors.lastname: Figueiredo
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Maria F M
authors.initials: MFM
authors.lastname: Braga
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: Sudikshya
authors.initials: S
authors.lastname: Baskota
authors.affiliation: Biostatistics Consulting Center, USUHS Bethesda, MD, United States.
authors.forename: Cara H
authors.initials: CH
authors.lastname: Olsen
authors.affiliation: Section on Metrology, NIST, Gaithersburg, MD, United States.
authors.forename: Natalia
authors.initials: N
authors.lastname: Farkas
authors.affiliation: Section on Metrology, NIST, Gaithersburg, MD, United States.
authors.forename: John
authors.initials: J
authors.lastname: Dagata
authors.affiliation: Center for Memory & Aging, Regions Hospital, Health Partners Institute for Education and Research, St. Paul, MN, United States.
authors.forename: William H
authors.initials: WH
authors.lastname: Frey
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Moffett
authors.affiliation: Department of Anatomy, Physiology and Genetics, and Neurosciences Program, USUHS, Bethesda, 20814 MD, United States. Electronic address: anamboodiri@usuhs.edu.
authors.forename: Aryan M A
authors.initials: AMA
authors.lastname: Namboodiri
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002493:Central Nervous System Diseases / Q000209:etiology / Q000517:prevention & control*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D008297:Male; D009768:Obidoxime Chloride / Q000627:therapeutic use*; D062025:Organophosphate Poisoning / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D011220:Pralidoxime Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D002801:Cholinesterase Reactivators; D011220:Pralidoxime Compounds; D014316:Tritium; D009768:Obidoxime Chloride; D000110:Acetylcholinesterase; C028797:pralidoxime
keywords: Acetylcholinesterase; Excitotoxicity; Fluoro-jade; Neuropathology; Racine scale; Status Epilepticus