Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer's disease

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 Aβ 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.

Amyloid�β and tau are involved in sleep disorder in Alzheimer's disease by orexin�A and adenosine A(1) receptor

“…In addition, a higher level of tau protein has been confirmed as a marker of rapid cognitive decline, while the abundance of neurofibrillary tangles was correlated with the severity of dementia (33,34). Previous studies (20)(21)(22) investigated neurocognitive function of the 5xFAD mice, using an AD animal model with a Morris water maze assay. In addition, in a study performed by Kang et al (10) suggested that the levels of soluble Aβ are positively associated with the time awake and negatively associated with the time asleep.…”

“…The animals were acclimatized to the laboratory environment for 1 week before the experiments. The AD mouse model was constructed as previously described in which 1-year old 5xFAD mice spontaneously exhibit AD-like pathological changes (20)(21)(22), and mice received cerebral injection of Aβ 25-35 (cat. no.…”

Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

“…In another related study using the fluid percussion injury (FPI) model, treatment with 7,8-DHF successfully restored TrkB signaling and memory function in the Barnes maze test [109]. 7,8-DHF also exhibited beneficial effects in the treatment of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) [110][111][112][113][114]. Recently, a derivative of 7,8-DHF, namely, BrAD-R13, was approved by the FDA for use in clinical trials for the treatment of mild to moderate AD.…”

The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis

“…The modulation of TrkB via small molecule drug formulations to enhance BDNF signaling also enhanced neuronal survival in degenerating neurons in vitro (Guerzoni et al, 2017) and improved motor function and motor neuron loss in ALS model mice (Korkmaz et al, 2014). BDNF potentiation has also been demonstrated to enhance MN survival in vitro (Tsai et al, 2013) and in other neurodegenerative diseases (Aytan et al, 2018). Additionally, transactivating TrkB by A 2 a receptors has also been reported to enhance survival of MNs in culture (Komaki et al, 2012).…”