title: Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs.
abstract: To explore the efficacy of paraoxonase 1 (PON1) as a catalytic bioscavenger, we evaluated human recombinant PON1 (rePON1) expressed in Trichoplusia ni larvae against sarin and soman toxicity using microinstillation inhalation exposure in guinea pigs. Animals were pretreated intravenously with catalytically active rePON1, followed by exposure to 1.2 X LCt₅₀ sarin or soman. Administration of 5 units of rePON1 showed mild increase in the blood activity of the enzyme after 30 min, but protected the animals with a significant increase in survival rate along with minimal signs of nerve agent toxicity. Recombinant PON1 pretreated animals exposed to sarin or soman prevented the reduction of blood O₂ saturation and pulse rate observed after nerve agent exposure. In addition, rePON1 pretreated animals showed significantly higher blood PON1, acetylcholinesterase (AChE), and butyrylcholinesterase activity after nerve agent exposure compared to the respective controls without treatments. AChE activity in different brain regions of rePON1 pretreated animals exposed to sarin or soman were also significantly higher than respective controls. The remaining activity of blood PON1, cholinesterases and brain AChE in PON1 pretreated animals after nerve agent exposure correlated with the survival rate. In summary, these data suggest that human rePON1 protects against sarin and soman exposure in guinea pigs.
authors.affiliation: Closed-Head Injury Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Manojkumar
authors.initials: M
authors.lastname: Valiyaveettil
authors.forename: Yonas
authors.initials: Y
authors.lastname: Alamneh
authors.forename: Peter
authors.initials: P
authors.lastname: Rezk
authors.forename: Michael W
authors.initials: MW
authors.lastname: Perkins
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000517:prevention & control*; D000818:Animals; D043303:Aryldialkylphosphatase / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood; D006168:Guinea Pigs; D006801:Humans; D019570:Inhalation Exposure; D007275:Injections, Intravenous; D007322:Instillation, Drug; D053208:Kaplan-Meier Estimate; D008136:Longevity / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012524:Sarin / Q000633:toxicity*; D012999:Soman / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D012999:Soman; D012524:Sarin; D002802:Cholinesterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D010100:Oxygen