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.