Keywords
D-allose; Gal-3; TLR4 signaling; neuroinflammation; ischemic stroke;
neurological dysfunction
Introduction
D-allose (PubChem CID: 439507), a C-3 epimer of D-glucose which
originally isolated from some plants, is an important typical rare
monosaccharide safe for consumption by human beings1.
Growing evidence showed that D-allose has an inhibitory effect on the
production of reactive oxygen species (ROS) in inflammatory reactions in
leukocytes2, an activation effect on programmed cell
apoptosis in tumor cells3, an anti-inflammatory effect
to protect the kidney4, liver5 and
retina6 from ischemia/reperfusion(I/R) injury. Our
previous study initially explored the anti-inflammatory effects of
D-allose in a model of focal cerebral I/R injury in
rats7. However, it remains unclear to date the
mechanism of D-allose neuroprotective effect after ischemic stroke (IS)
by simultaneously reducing neuroinflammation damage and neuron-specific
apoptosis.
Globally, IS is one of the leading causes of death and long-term
disability at present and is associated with the shortage of effective
treatments despite numerous clinical trials, because the pathophysiology
of various cells in injured brain tissue is not yet well
understood8-10. Lots of experimental results have
indicated that inflammatory response has a direct negative impact on
ischemic neurons, a brain function executor, leading to the collapse of
organelle structure and the release of pro-apoptotic proteins, and
ultimately causes cerebral apoptosis and
necrosis11-14. Therefore, protecting neurons from
inflammatory damage and apoptosis could be a rational and efficient
measure for ameliorating the neurological dysfunction of IS patients.
Galectin-3 (Gal-3), is an important member of β-galactoside-
binding lectin family
and was first recognized in murine immune cells, and thereafter found in
microglial cells, astrocytes and neurons, which was demonstrated to be a
novel inflammatory factor participating in the process of inflammation,
oxidative stress, cellular proliferation, cell apoptosis and
pyroptosis15-19. Given evidence showed that the effect
of Gal-3 in neuroinflammation of neurodegeneration and central nerve
system (CNS) injury is contentious20. Some studies’
results showed that deletion of the Galectin-3 gene attenuates
experimental through decreased expression level of inflammatory
cytokines in C57Bl/6 mice during autoimmune encephalomyelitis
progression21. The other research indicated that Gal-3
deficiency in microglial cells and astrocytes of C57Bl/6 mice enhanced
inflammatory response in Wallerian degeneration
(WD)22. Nevertheless, the function of Gal-3 in the
apoptotic process is somewhat controversial. Wesley et al reported that
Gal-3 in neuro-vascular protection and functional recovery after IS
through upregulation of the cerebral blood vessel density and
downregulation of neuron apoptotic death23,24. On the
contrary, Fukumori T et al showed that tumor cells’ secreted Gal-3
induces T-cells’ apoptosis, which in turn enhanced the effect of Gal-3
anti-apoptosis of tumor cells25. In summary, the
potential injury or protective mechanism of Gal-3 on inflammation
damage-induced neuronal apoptosis post-IS are largely unknown to date.
Secondary neuroinflammation can occur after acute ischemic stroke.
Immune-mediated pro-inflammatory signals rapidly activate various types
of inflammatory cells, causing them to infiltrate into areas of ischemia
and exacerbate brain damage26. Among all the
inflammatory-related proteins and signaling pathways, Toll-like receptor
4 (TLR4) and TLR4-dependent PI3K/AKT signaling are one of the crucial
inflammatory pathways found at present, which is related to the
pathogenesis and development of many neuroinflammatory diseases,
especially protecting the brain from I/R-induced
injury27-32.
Mietto
BS et al observed that a lack of Gal-3 increased both RNA and protein
levels for the pro-inflammatory cytokines, as well as for TLR2 and TLR4,
which ultimately contributed to the prognosis of WD22.
Conversely, Liu et al reported recently that TD139, a specific inhibitor
of Gal-3, alleviates TLR4 and MyD88 of microglia in autoimmune
uveitis33. Therefore, the relationship between the
TLR4/PI3K/AKT signaling axis and Gal-3 in inflammatory damage of neurons
induced by IS is unknown. Moreover, like TD139, whether D-allose plays
an anti-inflammatory role via inhibiting the expression of the Gal-3 and
TLR4 signaling pathway in IS is also unclear.
Taken together, the aims of this study were (1) to determine whether
D-allose pretreatment alleviates the inflammation damage and ischemic
neuronal apoptosis induced by brain I/R injury; and, if so, (2) to
evaluate the involved underlying mechanisms of down-regulation Gal-3 via
TLR4/ PI3K/AKT signaling in mediating the protective mechanisms of
D-allose.