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4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration.

Neurotoxicology (2014-06-15)
P A Ferchmin, Myrna Andino, Rebeca Reyes Salaman, Janaina Alves, Joyce Velez-Roman, Brenda Cuadrado, Marimeé Carrasco, Wilmarie Torres-Rivera, Annabell Segarra, Antonio Henrique Martins, Jae Eun Lee, Vesna A Eterovic
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
o-Xylene, anhydrous, 97%
Sigma-Aldrich
o-Xylene, puriss. p.a., ≥99.0% (GC)
Sigma-Aldrich
Acetylthiocholine iodide, ≥98% (TLC), powder or crystals
Supelco
o-Xylene, analytical standard
Sigma-Aldrich
o-Xylene, reagent grade, ≥98.0%
Sigma-Aldrich
Diisopropylfluorophosphate
Sigma-Aldrich
Acetylthiocholine iodide, ≥99.0% (AT)
Supelco
o-Xylene, suitable for HPLC, 98%
Sigma-Aldrich
Pyridostigmine bromide
Sigma-Aldrich
2-Nitrobenzoic acid, 95%, Contains 3- and 4-isomers
Supelco
o-Xylene, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ipratropium bromide monohydrate, ≥98% (TLC), powder
USP
Pyridostigmine bromide, United States Pharmacopeia (USP) Reference Standard
Pyridostigmine bromide, European Pharmacopoeia (EP) Reference Standard

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