GM1 and GD3 Gangliosides Attenuate NGF-TrkA and BDNF-TrkB Signaling Dysfunction Associated with Acute Diisopropylfluorophosphate Exposure in Mouse Brain

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single toxic dose of the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, seven days of repeated intranasal administration of gangliosides GM1 or GD3 24 hours after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 can prevent the organophosphate-related alterations in those brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological deficits associated with a class of poisons that endangers millions of people worldwide. Highlights O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/646417v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@edf17dorg.highwire.dtl.DTLVardef@1895982org.highwire.dtl.DTLVardef@538e99org.highwire.dtl.DTLVardef@1b700d3_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIA single exposure to DFP, which causes cognitive deficits, dysregulates NGF and BDNF signaling C_LIO_LIGM1 or GD3 24 hours after DFP injection prevents the alteration of the neurotrophin signaling C_LIO_LIIntranasal ganglioside treatment provides neuroprotective effects against persistent organophosphate toxicity C_LI