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Kinase and Mitochondrial Targets for Reversing the Adverse Effects of Organophosphates on Axonal Transport

Organophosphates (OPs) represent a class of chemicals with a wide range of uses in industrial and agricultural settings as pesticides, but they have also been associated with a variety of adverse health effects in humans including deficits in cognition. While the acute toxicity of OPs is associated with the inhibition of cholinesterase enzymes, our laboratory has previously demonstrated that repeated exposures to levels of OPs below the threshold for acute toxicity can negatively affect non‐cholinesterase targets (i.e., effects that might contribute to the cognitive defects). These negative effects of OPs include deficits in the axonal transport of membrane bound organelles (MBOs) as well as alterations in both the transport and morphology of mitochondria. Postmortem analyses of brain tissues of rats treated with the OP diisopropylfluorophosphate (DFP) and in vitro phenotypic screening assays revealed that targeting specific signaling kinases that regulate axonal transport and approaches to improve mitochondrial function might represent rational therapeutic strategies to reverse the negative effects of OPs. These hypotheses were validated in live cell imaging studies in vitro, where DFP‐induced impairments in both anterograde and retrograde AXT were attenuated in a dose‐dependent manner with the glycogen synthase kinase (GSKIIIβ) inhibitor, lithium chloride. Similarly, the mitochondrial‐targeting antioxidant methylene blue also attenuated the negative effects of DFP on anterograde and retrograde axonal transport in a dose dependent manner. Studies are in progress to determine the effects of these potential therapeutic agents on specific components of the axonal transport process (e.g., number of stationary particles, directional changes, pauses, etc.).