Objective
To investigate the effects of honokiol on neurological injury and
cognitive function in mice with intracerebral hemorrhage (ICH) and its
mechanism.
Methods C57BL/6J mice were randomly grouped into the
sham operation group, the model group, the low, medium, and high dose honokiol
groups, and the honokiol+inhibitor group. Except for the sham operation group,
ICH models were established by injecting autologous blood into the right basal
ganglia in other groups. At 15 min before ICH and 1 h after ICH, the low,
medium, and high dose honokiol groups were intraperitoneally injected with 10
mg/kg, 20 mg/kg, and 40 mg/kg honokiol, respectively. The honokiol+inhibitor group
was intraperitoneally injected with 40 mg/kg honokiol and 5 μg/kg brain derived neurotrophic
factor (BDNF)-tyrosine kinase receptor B (TrkB)-cyclic adenosine monophosphate
response element binding protein (CREB) signaling pathway inhibitor K252a. The
sham operation group and the model group were intraperitoneally injected with
equal amounts of dimethyl sulfoxide and physiological saline. The modified
neurological severity score (mNSS) was applied to assess the neurological
function of mice. The Morris water maze experiment was applied to evaluate the
spatial learning and memory abilities of mice by calculating the escape
latency, the number of times of crossing the original platform, and the
percentage of residence time in the target quadrant. Hematoxylin-eosin (HE)
staining was applied to observe the pathological changes in hippocampal
neurons. Terminal-deoxynucleotidyl transferase-mediated dUTP-biotin nick end
labeling (TUNEL) staining was applied to detect the apoptotic rate of
hippocampal neurons. Enzyme-linked immunosorbent assay (ELISA) was applied to
detect serum levels of BDNF and TrkB. Western blot was applied to detect the
expression of BDNF, TrkB, CREB, and phosphorylated CREB (p-CREB) proteins in
the hippocampus.
Results Compared with the sham operation group, the
mNSS and apoptotic rate of hippocampal neurons in the model group increased,
the escape latency prolonged, the number of times of crossing the original
platform decreased, the percentage of residence time in the target quadrant
decreased, and the levels of BDNF, TrkB in serum and BDNF, TrkB, p-CREB/CREB in
the hippocampus decreased (all P<0.001). The structure
of hippocampal neurons was blurred, the arrangement was disordered, the number
was reduced, the volume was smaller, and the nucleus was shrunk. Compared with
the model group, the mNSS (all P<0.01) and apoptotic
rate of hippocampal neurons (all P<0.001) in mice in
the low, medium, and high dose honokiol groups decreased successively, the
escape latency (all P<0.001) shortened successively,
the number of times of crossing the original platform (P=0.007, P<0.001, P<0.001) increased
successively, the percentage of residence time in the target quadrant (P=0.004, P<0.001, P<0.001)
increased successively, and the levels of BDNF (all P<0.001),
TrkB (P=0.001, P<0.001, P<0.001) in serum and BDNF (P=0.008, P<0.001, P<0.001), TrkB (P=0.001, P<0.001, P<0.001),
p-CREB/CREB (all P<0.001) in the hippocampus increased
successively, the damage of hippocampal neurons was improved. Compared with the
high dose honokiol group, the mNSS and apoptotic rate of hippocampal neurons in
the honokiol+inhibitor group were increased, the escape latency was prolonged,
and the number of times of crossing the original platform was decreased, the
percentage of residence time in the target quadrant was decreased, and the
levels of BDNF, TrkB in serum and BDNF, TrkB, and p-CREB/CREB in the
hippocampus were decreased (all P<0.001), and the
damage of hippocampal neurons was aggravated.
Conclusion
s Honokiol may alleviate hippocampal neuronal
apoptosis and damage, and improve cognitive dysfunction in ICH mice by
activating the BDNF-TrkB-CREB signaling pathway.
