NG291: A Stable B2 Kinin Receptor Agonist that Increases the Permeability of Normal Blood Brain Barrier: Possible Role in Organophosphate Poisoning Treatment

Abstract

Organophosphates are phosphorus containing compounds that inhibit acetylcholinesterase and generate a cholinergic crisis that is fatal if not treated. The classical antidotes prescribed are atropine and pralidoxime. They can protect peripherally, but cannot protect the central nervous system. Pralidoxime is the only FDA approved drug that re‐activates the acetylcholinesterase inhibited by organophosphate. Pralidoxime has limited neuroprotective potential because it is not able to cross the blood brain barrier (BBB) effectively. In order to increase this potential, our group is using a stable B2 kinin agonist NG291. This peptide can transiently open the normal blood brain barrier and increase the pralidoxime delivery to the brain after organophosphate poisoning. Sprague‐Dawley (SD) rats were subjected to NG291 treatment (50μg/Kg & 100μg/Kg) via intravenous (IV) route followed by 2% Evans Blue dye injection. 24 hours after the peptide injection the animals were perfused, and the amount of albumin‐Evans blue that reached the brain was qualitatively analyzed. To verify if the transient opening of blood brain barrier causes increase in the brain water content, controls (saline) and rats injected with the peptide NG291 were euthanized 24 hours after the peptide injection and the percentage of water content was measured. To assure that this transient opening is not causing damage to the brain, control and tests were submitted to analysis by histology using Fluoro Jade to verify the presence of dead neurons and glial fibrillary acidic protein (GFAP) to evaluate the astrocyte activation 72 hours after the injection of NG291. NG291‐treated animals have shown infiltration of Evans Blue to the brain parenchyma and accumulation in the ventricles showing increase of blood brain barrier permeation 24 hours after the injection. The water content of the brain did not increase with NG291 treatment. 72 hours after the treatment the histology using Fluoro Jade and GFAP did not show significant changes when compared to controls. We also determined for how long the BBB remains permeable following NG291 administration. In future studies, this peptide will be used to facilitate the delivery of pralidoxime into the brain and therefore increase the overall effect of this drug. This is done in hope to provide those currently exposed to organophosphates with an immediate treatment strategy.Support or Funding InformationUniversity of Puerto Rico Medical Sciences Campus RCMI‐8G12MD007600 Dr. Pedro Ferchmin and Dr. Vesna Eterovic, Universidad Central del CaribeThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.