Introduction
Systemic inflammation often promotes
central neuroinflammation by up-regulating pro-inflammatory cytokines,
increasing the permeability of the blood-brain barrier and further
causing neuroinflammation in the central nervous system(Adetuyi &
Farombi, 2021; Zhan, Stamova, & Sharp, 2018), which further activates
the inflammatory signaling pathway, that triggers synaptic plasticity
changes and neuronal apoptosis , ultimately leading to cognitive
dysfunction and neurodegenerative diseases(Li et al., 2020; H. Zhang et
al., 2020; Zhao et al., 2019). For example, systemic infection which
occurs with surgery(Cibelli et al., 2010; Wan et al., 2007), can trigger
systemic and hippocampal inflammation resulting in cognitive
decline(Barrientos et al., 2009).
The brain-derived neurotrophic factor (BDNF) is the main neurotrophin
growth factor that participates in mediating synaptic plasticity and
neuronal survival, differentiation, as well as neurogenesis(Leal,
Bramham, & Duarte, 2017; von Bohlen und Halbach & von Bohlen und
Halbach, 2018). BDNF exerts its biological functions mainly through
binding to tyrosine kinase B (TrkB) receptors(Bekinschtein, Cammarota,
& Medina, 2014; Lu, Nagappan, & Lu, 2014) and the BDNF-TrkB signaling
pathway is involved in the formation of dendritic spines. Furthermore,
activation of TrkB receptors promotes activations of downstream cascades
including the ERK1/2, CaMK2, CREB, GluR1 and the mechanism of apoptosis
which are related to regulating learning and memory(Y. J. Yang et al.,
2014). The ERK1/2, a member of the mitogen-activated protein kinase
superfamily, is involved in regulating cell proliferation, survival, and
apoptosis(Morella, Hallum, & Brambilla, 2020). The CaMK2 is essential
for synaptic plasticity and memory formation(Kool et al., 2019). The
CREB, a transcription factor, is one of the main downstream
transcription factors of ERK1/2 and plays significant roles in neuronal
plasticity, learning and memory(B. Zhang et al., 2020). The GluR1 is
also necessary for learning and memory processing and mediates neuronal
plasticity(Xiao, Liu, Li, Ruan, & Wang, 2019). Therefore, the reduction
of BDNF expression in the brain is associated with impairment of
synaptic plasticity and learning and memory failures.
7,8- Dihydroxyflavone (7,8-DHF), a member of the flavonoid derivative,
has been identified as an
effective agonist of the TrkB receptor which mimics the properties of
BDNF(Bollen et al., 2013; Castello et al., 2014; Zhang et al., 2014).
7,8-DHF can penetrate the blood-brain barrier and plays neuroprotective
roles including increasing dendritic spine density and exerting
neurotrophic effects, via activating the BDNF-TrkB signaling pathway and
its downstream cascades. ANA12 is a small molecule antagonist of TrkB
and crosses the blood-brain barrier in order to exert its antagonism
effect(Giuliani, 2019). In the current research, we mainly investigated
the roles of the BDNF-TrkB signaling pathway and its downstream cascades
on neuroinflammation-induced learning and memory impairments and whether
7,8-DHF could alleviate these disorders in mice.