Identification of Novel Therapeutic Targets Against Organophosphate‐Induced Axonal Transport Deficits

The chemicals known as the organophosphates (OPs) have a wide array of uses in industrial and agricultural settings, most notably as pesticides, but they have also been used on occasion as chemical warfare (nerve) agents. OPs are highly toxic and they have been associated with a variety of acute and long‐term neurologic deficits including impairments in cognition in humans and animal models. The mechanism of the acute toxicity of OPs, cholinesterase inhibition is well documented; however, the neurobiological basis for the long‐term effects of OPs, especially when the exposure levels were below the threshold for acute toxicity is less clear. It is imperative that the mechanism of these deleterious effects of OPs be elucidated so that effective therapeutic strategies can be developed. Previous research in our laboratory conducted both in vivo and in vitro indicated that deficits in axonal transport may represent one mechanism of the long‐term neurologic deficits associated with OPs. In the current series of experiments, we are analyzing post mortem brain tissues from OP‐exposed rats to identify non‐cholinesterase targets that might contribute to the OP‐related deficits in axonal transport. As the axonal transport‐related targets of OPs are identified post mortem, subsequent pharmacological experiments are being conducted in vitro to exploit these targets as a first step toward developing novel therapeutic strategies. In the first series of experiments in tissues collected from rats treated with the OP‐nerve agent, diisopropylfluorophosphate (DFP), 1.0 mg/kg every other day for 30 days, we have identified (using standard immunoblotting techniques) alterations in the phosphorylation of several signaling kinases (e.g., ERK, Akt, and GSKIIβ). We have also identified DFP‐related changes in post‐translational modifications of structural proteins that affect axonal transport through the regulation of microtubule dynamics and stability (e.g., Tau phosphorylation, Tubulin Acetylation). Using a live imaging technique in rat cortical neurons for evaluating fast axonal transport of fluorescent, (APPGFP‐labeled) membrane bound organelles, we have determined that compounds that target signaling kinases (e.g., GSKIIIβ), microtubule stability, and mitochondrial function, can attenuate the DFP‐related impairments in axonal transport. These data not only further elucidate potential non‐cholinesterase targets of OPs, but also provide an initial step toward the design of new therapeutic strategies against OP toxicity. Support or Funding Information This work was supported by the Congressionally Directed Medical Research Programs (CDMRP), specifically, the Gulf War Illness Research Program (GWIRP), grant number W81XWH‐12‐1‐0536. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .