Jose Luis Marrero Valentin¹, Rivera-Moctezuma F. G.¹, ³, Sorangely Vázquez Alicia.¹, ⁴, Dinely Perez ²,

Pedro A. Ferchmin ⁵, Nadezhda Sabeva ¹

1 Department of Neuroscience, Universidad Central del Caribe, Bayamon, PR

2 Department of Biochemistry, Universidad Central del Caribe, Bayamon, PR

3 Polytechnic University, San Juan, PR

4 University of Puerto Rico, Bayamon, PR

5 Neuroprotection for Life, Carmel, IN


Organophosphate (OP) compounds have been widely used as agricultural and household pesticides, jet engine lubricants, and warfare nerve agents. Therefore, the general population and military personnel could be exposed to OPs not only during combat or terroristic attacks but also during routine military, industrial or private activities. Delayed neuronal damage of OP intoxication is thought to contribute to neuronal death and various neurological illnesses. Gulf War Illness (GWI) is one of them.

GWI is a currently untreatable multi-symptom disorder experienced by more than 250,000 veterans from the Persian Gulf War (1990-1991). The distinctive hallmark of GWI includes chronic fatigue, migraine, muscle and joint pain, gastrointestinal problems, and cognitive disturbances such as depression and anxiety. Various studies have consistently linked these symptoms to exposure to pyridostigmine, DEET, permethrin, and traces of sarin (the most commonly used nerve agent).

There is no effective cure for the GWI or the chronic effect of other neurotoxicants. Our group demonstrated ex vivo that exposure to diisopropylfluorophosphate (DFP, a surrogate of sarin) and the above-mentioned neurotoxicants reduce the number of functionally active neurons in hippocampal slices. This loss of neuronal functionality can be reversed by the application of a 4Rcembranotrienes- diol (4R), a cyclic diterpenoid with anti-inflammatory and anti-apoptotic properties. The cembranoid is not toxic and reaches higher concentrations in the brain than plasma.

We took advantage of our ex vivo GWI model (rat hippocampal slices) to investigate whether 4R has a protective effect on synaptic integrity and neuronal survival in the presence of DFP. We combined electrophysiological recordings with molecular analysis on acute hippocampal slices.

Our results suggest that 4R protects neuronal functionality and activates AKT/PI3K cell survival pathway. Thus, this cembranoid is a promising compound to protect the nervous system against neurotoxicants.

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