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2.
Eur J Pharmacol ; 828: 9-17, 2018 Jun 05.
Article in English | MEDLINE | ID: mdl-29510124

ABSTRACT

Interest in brain-derived neurotrophic factor (BDNF) was greatly enhanced when it was recognized that its expression is reduced in neurodegenerative disorders, especially in Alzheimer's disease (AD). BDNF signaling through the TrkB receptor has a central role in promoting synaptic transmission, synaptogenesis, and facilitating synaptic plasticity making the BDNF-TrkB signaling pathway an attractive candidate for targeted therapies. Here we investigated the early effect of the small molecule TrkB agonist, 7,8 dihydroxyflavone (7,8-DHF), on AD-related pathology, dendritic arborization, synaptic density, and neurochemical changes in the 5xFAD mouse model of AD. We treated 5xFAD mice with 7,8-DHF for 2 months beginning at 1 month of age. We found that, in this model of AD, 7,8-DHF treatment decreased cortical Aß plaque deposition and protected cortical neurons against reduced dendritic arbor complexity but had no significant impact on the density of dendritic spines. In addition 7,8-DHF treatment protected against hippocampal increase in the level of choline-containing compounds and glutamate loss, but had no significant impact on hippocampal neurogenesis.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Flavones/pharmacology , Neuroprotective Agents/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Dendritic Spines/drug effects , Dendritic Spines/pathology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Mice , Peptide Fragments/metabolism
3.
Brain Res ; 1681: 34-43, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29277710

ABSTRACT

Gulf War Illness (GWI) is a chronic disease that affects the 1991 Gulf War (GW) veterans for which treatment is lacking. It has been hypothesized that drugs used to protect military personnel from chemical attacks and insects during the war: pyridostigmine bromide (PB),N, N-diethyl-m-toluamide (DEET), and permethrin (PER) together with stress may have contributed collectively and synergistically to generate GWI. There is a need to find markers of pathology to be used in pre-clinical trials. For this purpose we employed a previously validated mouse model of GWI evoked by daily exposure to PB (1.3 mg/kg), DEET (40 mg/kg), PER (0.13 mg/kg), and 5 min of restraint stress for 28 days to analyze behavior, brain pathology and neurochemical outcomes three months later. GWI-model mice were characterized by increased anxiety, decreased hippocampal levels of N-acetyl aspartate, GABA, the GABA-producing enzyme GAD-67 and microglial activation. We also observed that GWI model was sexually dimorphic on some measures: males had increased while females had decreased protein levels of the acetylcholine-synthesizing enzyme, choline acetyltransferase, in the septum and hippocampus and decreased levels of the receptor for brain-derived neurotrophic factor, TrkB140, in the hippocampus. Increased hippocampal levels of nerve growth factor were detected in males only. Together the data show behavioral and neuropathological abnormalities detected at 3 months post-exposure and that some of them are sexually dimorphic. Future preclinical studies for GWI may take advantage of this short latency model and should include both males and females as their response to treatment may differ.


Subject(s)
Acetylcholine/metabolism , Anxiety/complications , Disease Models, Animal , Encephalitis/complications , Persian Gulf Syndrome/etiology , gamma-Aminobutyric Acid/metabolism , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Brain/drug effects , Brain/metabolism , DEET/administration & dosage , Female , Male , Mice, Transgenic , Microglia/drug effects , Microglia/metabolism , Permethrin/administration & dosage , Persian Gulf Syndrome/metabolism , Pyridostigmine Bromide/administration & dosage , Stress, Psychological/complications
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