scL-2PAM: A Novel Countermeasure That Ameliorates Neuroinflammation and Neuronal Losses in Mice Exposed to an Anticholinesterase Organophosphate

Abstract

Due to their inhibition of acetylcholinesterase, organophosphates are among the most toxic of chemicals. Pralidoxime (a.k.a 2-PAM) is the only acetylcholinesterase reactivator approved in the U.S., but 2-PAM only poorly traverses the blood–brain barrier. Previously, we have demonstrated that scL-2PAM, a nanoformulation designed to enter the brain via receptor-mediated transcytosis, is superior to unencapsulated 2-PAM for reactivating brain acetylcholinesterase, ameliorating cholinergic crisis, and improving survival rates for paraoxon-exposed mice. Here, we employ histology and transcriptome analyses to assess the ability of scL-2PAM to prevent neurological sequelae including microglial activation, expression of inflammatory cytokines, and ultimately loss of neurons in mice surviving paraoxon exposures. Levels of the mRNA encoding chemokine ligand 2 (CCL2) were significantly upregulated after paraoxon exposures, with CCL2 mRNA levels in the brain correlating well with the intensity and duration of cholinergic symptoms. Our nanoformulation of 2-PAM was found to be superior to unencapsulated 2-PAM in reducing the levels of the CCL2 transcript. Moreover, brain histology revealed that scL-2PAM was more effective than unencapsulated 2-PAM in preventing microglial activation and the subsequent loss of neurons. Thus, scL-2PAM appears to be a new and improved countermeasure for reducing neuroinflammation and mitigating brain damage in survivors of organophosphate exposures.