4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration.
Enviado por Annabell Segarra el
Título | 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Autores | Ferchmin, PA, Andino, M, Salaman, RReyes, Alves, J, Velez-Roman, J, Cuadrado, B, Carrasco, M, Torres-Rivera, W, Segarra, A, Martins, AHenrique, Lee, JEun, Eterović, VA |
Journal | Neurotoxicology |
Volume | 44 |
Pagination | 80-90 |
Date Published | 2014 Sep |
ISSN | 1872-9711 |
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. |
DOI | 10.1016/j.neuro.2014.06.001 |
Alternate Journal | Neurotoxicology |
PubMed ID | 24928201 |
PubMed Central ID | PMC4176603 |
Grant List | 1U54NS083924-01 / NS / NINDS NIH HHS / United States 8G12MD007583 / MD / NIMHD NIH HHS / United States G12 MD007583 / MD / NIMHD NIH HHS / United States NINDS5U01NS063555 / NS / NINDS NIH HHS / United States U01 NS063555 / NS / NINDS NIH HHS / United States U54MD008149 / MD / NIMHD NIH HHS / United States |