title: Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs.
abstract: Human paraoxonase 1 (PON1) has been portrayed as a catalytic bioscavenger which can hydrolyze large amounts of chemical warfare nerve agents (CWNAs) and organophosphate (OP) pesticides compared to the stoichiometric bioscavengers such as butyrylcholinesterase. We evaluated the protective efficacy of purified human and rabbit serum PON1 against nerve agents sarin and soman in guinea pigs. Catalytically active PON1 purified from human and rabbit serum was intravenously injected to guinea pigs, which were 30 min later exposed to 1.2 × LCt₅₀ sarin or soman using a microinstillation inhalation exposure technology. Pre-treatment with 5 units of purified human and rabbit serum PON1 showed mild to moderate increase in the activity of blood PON1, but significantly increased the survival rate with reduced symptoms of CWNA exposure. Although PON1 is expected to be catalytic, sarin and soman exposure resulted in a significant reduction in blood PON1 activity. However, the blood levels of PON1 in pre-treated animals after exposure to nerve agent were higher than that of untreated control animals. The activity of blood acetylcholinesterase and butyrylcholinesterase and brain acetylcholinesterase was significantly higher in PON1 pre-treated animals and were highly correlated with the survival rate. Blood O₂ saturation, pulse rate and respiratory dynamics were normalized in animals treated with PON1 compared to controls. These results demonstrate that purified human and rabbit serum PON1 significantly protect against sarin and soman exposure in guinea pigs and support the development of PON1 as a catalytic bioscavenger for protection against lethal exposure to CWNAs.
authors.affiliation: Closed Head Injury Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. m.valiyaveettil@amedd.army.mil
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: Lionel
authors.initials: L
authors.lastname: Biggemann
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: D000818:Animals; D043303:Aryldialkylphosphatase / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D020134:Catalytic Domain / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D020011:Protective Agents / Q000494:pharmacology; D011817:Rabbits; D012524:Sarin / Q000633:toxicity*; D012999:Soman / Q000633:toxicity*
chemical_list: D016166:Free Radical Scavengers; D020011:Protective Agents; D012999:Soman; D012524:Sarin; D043303:Aryldialkylphosphatase