Lacto-N-fucopentaose-III (LNFPIII) ameliorates acute aberrations in hippocampal synaptic transmission in a Gulf War Illness animal model

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

“…Behavioral testing began 8 months post GWI exposure and 1 month post LNFPIII treatment initiation. After behavioral testing completion, a subset of mice underwent hippocampal electrophysiology assessment ( Brown et al, 2021a , Brown et al, 2021b ) while the remaining mice received bromodeoxyuridine 3 weeks prior to euthanasia for post-mortem evaluation of hippocampal neurogenesis. Additionally, the brains from these mice were processed for immunohistochemistry and qPCR, for which some results have been published elsewhere ( Brown et al, 2021a , Brown et al, 2021b ).…”

“…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 ).…”

“…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 ).…”

Exposing the latent phenotype of Gulf War Illness: examination of the mechanistic mediators of cognitive dysfunction

“…One anti-inflammatory compound that has shown promise in preclinical GWI studies is Lacto-N-fucopentaose III (LNFPIII), an immunomodulatory glycan found in human breast milk ( 175 ). Treating a mouse model of GWI with LNFPIII either 7 months or 11 months post-exposure decreased hippocampal levels of IL-6 and increased hippocampal levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) ( 172 ). Additionally, the same group of investigators found that LNFPIII ameliorates the deficits in hippocampal synaptic plasticity and transmission observed in their mouse model ( 172 , 176 ).…”

“…Treating a mouse model of GWI with LNFPIII either 7 months or 11 months post-exposure decreased hippocampal levels of IL-6 and increased hippocampal levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) ( 172 ). Additionally, the same group of investigators found that LNFPIII ameliorates the deficits in hippocampal synaptic plasticity and transmission observed in their mouse model ( 172 , 176 ). Another family of compounds that have shown anti-inflammatory effects in GWI studies are activators of nuclear factor [erythroid-derived 2]-like 2 (Nrf2), which is a transcription factor that regulates antioxidant responses.…”