Lacto-N-fucopentaose-III ameliorates acute and persisting hippocampal synaptic plasticity and transmission deficits in a Gulf War Illness mouse model

Evaluation of delayed LNFPIII treatment initiation protocol on improving long-term behavioral and neuroinflammatory pathology in a mouse model of Gulf War Illness

“…In this study ( Brown et al, 2021a ), we found that basal synaptic transmission was increased at 48 h, had no change at 7 months, and decreased at 11 months post-PB/DEET/CORT/DFP exposure. Similar results were seen at 11 months when long-term potentiation was evaluated; these delayed reductions were consistent with a delayed onset of hippocampal neuroinflammation (IL-6) at this time point ( Brown et al, 2021a ). However, the long-term behavioral consequences in this GWI model remain unknown.…”

“…LNFPIII, when conjugated to a dextran carrier, activates CD14/TLR-4 signaling for extracellular signal-regulated kinase (ERK)-dependent production of anti-inflammatory mediators to skew the inflammatory balance of the innate immune system in an anti-inflammatory direction ( Atochina et al, 2008 ; Bhargava et al, 2012 ; Carpenter et al, 2020 , 2021 ; Srivastava et al, 2014 ; Tundup et al, 2015 ; Zhu et al, 2012 ). Of note, in utilizing the PB/DEET/CORT/DFP and the pyridostigmine bromide/permethrin (PB/PM) GWI models, we demonstrated that LNFPIII was beneficial in restoring acute monoaminergic disbalance and neuroinflammation (both models) as well as long-term behavioral deficits (PB/PM model), neuroinflammation, and hippocampal synaptic plasticity impairments after these chemical exposures ( Brown et al, 2021a , 2021b ; Carpenter et al, 2020 , 2021 ). In non-immune cells, ERK-activation (LNFPIII target) is important for neurogenesis ( Hao et al, 2004 ; Ma et al, 2013 ).…”

“…Additionally, acute widespread monoaminergic disbalance, i.e., increases in the utilization of serotonin (nucleus accumbens and ventral hippocampus) and dopamine (nucleus accumbens, dorsal hippocampus, and ventral hippocampus), was evident ( Carpenter et al, 2020 ). Further, detailed time-course characterization of this model at 48 h, 7-, and 11-months post GWI chemicals exposure termination provided insights into the progression of hippocampal impairments, particularly in regard to synaptic plasticity and transmission ( Brown et al, 2021a ). In this study ( Brown et al, 2021a ), we found that basal synaptic transmission was increased at 48 h, had no change at 7 months, and decreased at 11 months post-PB/DEET/CORT/DFP exposure.…”

“…Further, detailed time-course characterization of this model at 48 h, 7-, and 11-months post GWI chemicals exposure termination provided insights into the progression of hippocampal impairments, particularly in regard to synaptic plasticity and transmission ( Brown et al, 2021a ). In this study ( Brown et al, 2021a ), we found that basal synaptic transmission was increased at 48 h, had no change at 7 months, and decreased at 11 months post-PB/DEET/CORT/DFP exposure. Similar results were seen at 11 months when long-term potentiation was evaluated; these delayed reductions were consistent with a delayed onset of hippocampal neuroinflammation (IL-6) at this time point ( Brown et al, 2021a ).…”

“…Considering the immune dysfunction in GWI, recent preclinical studies have explored the efficacy of several immune-targeted compounds that have shown some promising results ( Joshi et al, 2018 ; Kodali et al, 2018a ; Ribeiro et al, 2020 ; Shetty et al, 2020 ). In our studies, we have focused on one potent immunomodulatory and anti-inflammatory treatment, Lacto-N-fucopentaose III (LNFPIII), that may be an advantageous treatment option for GWI as demonstrated in two, chemically distinct GWI models ( Brown et al, 2021a , 2021b ; Carpenter et al, 2020 , 2021 ; Mote et al, 2020 ). LNFPIII is a Lewis(X)-containing immunomodulatory glycan found in human breast milk and on parasitic helminths that, to date, has had no documented adverse effects ( Atochina et al, 2008 ; Bhargava et al, 2012 ; Srivastava et al, 2014 ; Tundup et al, 2015 ; Zhu et al, 2012 ).…”