PROTECTION AGAINST ORGANOPHOSPHATE NEUROTOXINS BY TOBACCO CEMBRANOIDSThe long term objective of this project is to develop a novel antidote against the organophosphate nervetoxins like soman and sarin. The increased awareness of terrorist threats prompted the development ofstrategies for protection against nerve toxin attacks. The most likely nerve toxins to be used are theorganophosphate (OP) neurotoxins that have been used before against military and civilian populations.OPs inhibit the acetylcholinesterase (AChE) in brain and peripheral nerves, causing a cholinergic crisis thatis fatal if untreated. The classic antidotes now in use protect against a wide spectrum of neural injury anddramatically decrease mortality. They fail, however, to target neuronal apoptosis initiated by the toxic OPallowing for long term neurological impairment. Here we propose to test a novel neuroprotective compoundthe (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R). 4R neuroprotection is mediated by a nicotinicantiapoptotic mechanism found effective in in vitro and in vivo models. 4R is not toxic and has a favorablepharmacological profile with antiapoptotic and antiinflammatory properties. Since the use of war neurotoxinsis impractical in the early stages of antidotes development the neuroprotective efficacy of 4R will be testedagainst two less toxic analogues, paraoxon (POX) and diisopropylfluorophosphate (DFP). The first objectiveproposed here is to test 4R in an in vitro model against POX and DFP. The in vitro neuroprotective activity of4R will be tested alone and in combination with the classical antidotes. The model to be used for the in vitrostudies is the hippocampal slice. The damage inflicted by the toxins will be determined byelectrophysiological and histological methods.
The second aim will address the efficacy of 4R against bothtoxins in vivo using a rat model. 4R in several combinations with classical antidotes will be tested againstvarious doses of POX and DFP. Behavioral, physiological, and histological determinations will be used todetermine the efficacy of 4R. In the third aim the window of therapeutical opportunity for 4R neuroprotectionwill be investigated in various combinations with the classical antidotes. The variables to asses the toxiceffect of the organophosphates and of 4R neuroprotection will be as in aim 2.From the public health perspective any improvement in the treatment of OPs poisoning of military or civilianpopulation would be of great value in human suffering and costs involved. The risk of OPs exposure is notrestricted to war scenario or terrorist attacks but includes industrial leaks of insecticides, accidentalpoisonings and chronic occupational exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS063555-01
Application #
7696144
Study Section
Special Emphasis Panel (ZNS1-SRB-R (33))
Project Start
2008-09-15
Project End
2011-05-31
Budget Start
2008-09-15
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$669,887
Indirect Cost
Name
Universidad Central Del Caribe
Department
Type
DUNS #
090534694
City
Bayamon
State
PR
Country
United States
Zip Code
00960
Ferchmin, P A; Pérez, Dinely; Cuadrado, Brenda L et al. (2015) Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices. Neurochem Res 40:2143-51
Martins, Antonio H; Hu, Jing; Xu, Zhenfeng et al. (2015) Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia. Neuroscience 291:250-259
Vélez-Carrasco, Wanda; Green, Carol E; Catz, Paul et al. (2015) Pharmacokinetics and Metabolism of 4R-Cembranoid. PLoS One 10:e0121540
Ferchmin, P A; Andino, Myrna; Reyes Salaman, Rebeca et al. (2014) 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration. Neurotoxicology 44:80-90
Torres-Rivera, W; Pérez, D; Park, K-Y et al. (2013) Kinin-B2 receptor exerted neuroprotection after diisopropylfluorophosphate-induced neuronal damage. Neuroscience 247:273-9
Eterovi?, Vesna A; Del Valle-Rodriguez, Angelie; Pérez, Dinely et al. (2013) Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: preliminary structure-activity relationship and pharmacophore modeling. Bioorg Med Chem 21:4678-86
Ferchmin, P A; Pérez, Dinely; Castro Alvarez, William et al. (2013) ?-Aminobutyric acid type A receptor inhibition triggers a nicotinic neuroprotective mechanism. J Neurosci Res 91:416-25
Rodriguez-Mercado, Rafael; Ford, Gregory D; Xu, Zhenfeng et al. (2012) Acute neuronal injury and blood genomic profiles in a nonhuman primate model for ischemic stroke. Comp Med 62:427-38
Martins, Antonio H; Alves, Janaina M; Perez, Dinely et al. (2012) Kinin-B2 receptor mediated neuroprotection after NMDA excitotoxicity is reversed in the presence of kinin-B1 receptor agonists. PLoS One 7:e30755
Eterovi?, Vesna A; Pérez, Dinely; Martins, Antonio H et al. (2011) A cembranoid protects acute hippocampal slices against paraoxon neurotoxicity. Toxicol In Vitro 25:1468-74

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