和厚朴酚调节BDNF-TrkB-CREB信号通路对脑出血小鼠神经损伤和认知功能的影响OA北大核心CSTPCD

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. Conclusions Honokiol may alleviate hippocampal neuronal apoptosis and damage,and improve cognitive dysfunction in ICH mice by activating the BDNF-TrkB-CREB signaling pathway.