In a previous study, we demonstrated that
F. mume extracted using hot water mitigates the spatial memory impairments induced by chronic BCCAo via the restoration of abnormal microglial activation and altered signaling of extracellular signal-regulated kinases (ERKs) or nuclear factor-κB (NF-κB) in the hippocampus [
26]. Our present study demonstrated a neuroprotective effect of
F. mume extracted using 70% EtOH on chronic cerebral hypoperfusion-induced brain dysfunction through inhibiting MBP degradation, activation of microglia and astrocytes, increased proinflammatory mediator expression, and stimulation of TLR4 and p38 MAPK signaling.
F. mume has long been used as a traditional medicine in Asian contries. The efficacy of
F. mume has been known to include anti-bacterial [
30], anti-inflammatory [
14], and anti-diabetic properties [
31]. According to HPLC analysis, the 70% EtOH extract of
F. mume had benzyl-O-β-D-glucopyranoside, benzyl-O-α-L-arabinopyranosyl-β-D-glycopyranoside, benzyl-O-β-D-xylopyranosyl-β-D-glycopyranoside, prunasin, α-hydroxy-benzeneacetamide, and 5-hydroxymethyl-2-furaldehyde (Additional file
1: Figure S1).
White matter, which is generally composed of glial cells and myelinated axons, is vulnerable to chronic cerebral hypoperfusion [
32]. White matter lesions are detected in the brains of AD and VaD patients with chronic cerebral hypoperfusion as a result of glial cell activation and myelin sheath degradation [
5]. Also, to study the relationship between demyelination and inflammation in the injured brain after hypoxia-ischemia, MBP expression and glial cell activation have been measured, since demyelination was accompanied with neuroinflammtion, such as activation of glial cells and release of proinflammatory cytokines [
33,
34].
In the present study, MBP expression, a marker of myelin sheath structure, was significantly decreased in the white matter of rats subjected to chronic BCCAo, but this reduction was alleviated by administration of
F. mume. This result indicates that
F. mume can protect the brain from chronic cerebral hypoperfusion-induced white matter lesions by restoring the decrease in MBP expression. Inflammatory events play a crucial role in the pathogenesis of neurological diseases, including AD and VaD [
35]. Chronic cerebral hypoperfusion-induced inflammation is characterized by activation of glial cells and overexpression of inflammatory mediators, such as TNF-α and IL-1β [
8,
11,
36]. Therefore, inhibition of these inflammatory responses is important for protecting the brain injury induced by chronic cerebral hypoperfusion. Microglia and astrocytes are activated by various events, such as ischemia, infection, and inflammation, which subsequently stimulate the release of cytotoxic agents, including cytokines, matrix metallo proteinases, nitric oxide, and reactive oxygen species [
12]. We found that
F. mume significantly attenuates microglial and astrocytic activation in the white matter and hippocampus in rats subjected to chronic BCCAo. In addition, treatment with
F. mume alleviates the increase in hippocampal COX-2, IL-1β, and IL-6 expression in chronic BCCAo rats. Toll-like receptors (TLRs) play a pivotal role in the initiation of innate immune responses. Among the identified TLRs, TLR4 is expressed on microglia and astrocytes and participates in activation of these cells induced by hypoxia in the brain [
22,
37,
38]. Several studies have reported that TLR4-dependent activation of microglia and astrocytes is involved in neurodegenerative diseases [
35,
38]. We have previously demonstrated that
F. mume inhibits the stimulation of IKK/NF-κB signaling induced by chronic BCCAo in the rat hippocampus [
26]. Moreover, the phosphorylation of MAPK-related signaling molecules, such as ERKs, c-Jun amino-terminal kinases (JNKs), and p38 MAPK, is important for the production of proinflammatory mediators, including TNF-α, IL-1β, and IL-6, in microglia and astrocytes [
20,
28]. It has been reported that specific inhibition of p38 MAPK using SB203580 attenuated the increase in expression of TNF-α, IL-1β, and IL-6 in the hippocampus activated by mitogenic factor-induced inflammation [
39]. In the present study, we demonstrated that activation of TLR4/MyD88 signaling and p38 MAPK signaling is suppressed by treatment with
F. mume in rats subjected to chronic BCCAo.