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

• Published in: International journal of molecular sciences Vol. 25; no. 14; p. 7539
• Main Authors: Moghe, Manish, Kim, Sang-Soo, Guan, Miaoyin, Rait, Antonina, Pirollo, Kathleen F, Harford, Joe B, Chang, Esther H
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2024
• Subjects: Acetylcholine; Acetylcholinesterase - metabolism; Animals; Apoptosis; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain damage; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Cholinesterase Inhibitors - pharmacology; Cytokines; Gases, Asphyxiating and poisonous; Genes; Hazardous substances; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - metabolism; nanotherapeutic; Nerve gas; neuroinflammation; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - metabolism; neuronal loss; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuropathology; organophosphate; Organophosphates - pharmacology; Paraoxon - toxicity; Poisoning; pralidoxime; Toxicity; Tumor necrosis factor-TNF; War use; Japan; nanotherapeutic; organophosphate; neuroinflammation; neuronal loss; pralidoxime
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25147539

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 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 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.