title: 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration.
abstract: Many organophosphorous esters synthesized for applications in industry, agriculture, or warfare irreversibly inhibit acetylcholinesterase, and acute poisoning with these compounds causes life-threatening cholinergic overstimulation. Following classical emergency treatment with atropine, an oxime, and a benzodiazepine, surviving victims often suffer brain neurodegeneration. Currently, there is no pharmacological treatment to prevent this brain injury. Here we show that a cyclic diterpenoid, (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R) ameliorates the damage caused by diisopropylfluorophosphate (DFP) in the hippocampal area CA1. DFP has been frequently used as a surrogate for the warfare nerve agent sarin. In rats, DFP is lethal at the dose used to cause brain damage. Therefore, to observe brain damage in survivors, the death rate was reduced by pre-administration of the peripherally acting antidotes pyridostigmine and methyl atropine or its analog ipratropium. Pyridostigmine bromide, methyl atropine nitrate, and ipratropium bromide were dissolved in saline and injected intramuscularly at 0.1mg/kg, 20mg/kg, and 23mg/kg, respectively. DFP (9mg/kg) dissolved in cold water was injected intraperitoneally. 4R (6mg/kg) dissolved in DMSO was injected subcutaneously, either 1h before or 5 or 24h after DFP. Neurodegeneration was assessed with Fluoro-Jade B and amino cupric silver staining; neuroinflammation was measured by the expression of nestin, a marker of activated astrocytes. Forty-eight hours after DFP administration, 4R decreased the number of dead neurons by half when injected before or after DFP. 4R also significantly decreased the number of activated astrocytes. These data suggest that 4R is a promising new drug that could change the therapeutic paradigm for acute poisoning with organophosphorous compounds by the implementation of a second-stage intervention after the classical countermeasure treatment.
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA. Electronic address: ferchmin@gmail.com.
authors.forename: P A
authors.initials: PA
authors.lastname: Ferchmin
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Myrna
authors.initials: M
authors.lastname: Andino
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Reyes Salaman
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Janaina
authors.initials: J
authors.lastname: Alves
authors.affiliation: Department of Pharmacology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Velez-Roman
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Cuadrado
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Marimeé
authors.initials: M
authors.lastname: Carrasco
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Wilmarie
authors.initials: W
authors.lastname: Torres-Rivera
authors.affiliation: Department of Pharmacology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA.
authors.forename: Annabell
authors.initials: A
authors.lastname: Segarra
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Antonio Henrique
authors.initials: AH
authors.lastname: Martins
authors.affiliation: RTRN Data Coordinating Center, Jackson State University, Jackson, MI 39204, USA.
authors.forename: Jae Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe School of Medicine, Bayamón, PR 00960, USA.
authors.forename: Vesna A
authors.initials: VA
authors.lastname: Eterovic
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology; D016923:Cell Death; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D007531:Isoflurophate / Q000506:poisoning*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced
chemical_list: D002800:Cholinesterase Inhibitors; D004224:Diterpenes; D018696:Neuroprotective Agents; C544693:cembra-2,7,11-triene-4,6-diol; D007531:Isoflurophate; D000110:Acetylcholinesterase
keywords: (1S,2E,4R,6R,7E,11E)-Cembra-2,7,11-triene-4,6-diol; Cembranoid; Diisopropylfluorophosphate; Neurodegeneration; Neuroprotection