Effects of Huanglian Jiedu Decoction on Synaptic Plasticity in Rats with Vascular Dementia Through JNK/FoxO1 Signaling Pathway-Mediated Autophagy

OBJECTIVE  To investigate the effect of Huanglian Jiedu Decoction(HLJDD) on neuronal synaptic plasticit in rats with vascular dementia(VD) and its mechanism.

METHODS  Ten rats were randomly selected as the sham group. The remaining animals were used to establish the VD model via the modified method of cutting bilateral common carotid arteries method, and were randomly assigned to the model group, low-dose HLJDD group(1.5 g·kg^–1), high-dose HLJDD group(3.0 g·kg^–1), high-dose HLJDD(3.0 g·kg^–1)+JNK activator(Anisomycin, 5 mg·kg^–1) group, with 10 rats in each group. After 4 weeks of treatment, samples were collected. The escape latency and cross-platform times in each group were detected by Morris water maze test. The pathomorphological changes in the hippocampus were observed by Hematoxylin-eosin staining. Transmission electron microscope was used to detect the ultrastructural observation of neurons and synapses in rat hippocampus. The protein and mRNA relative expression levels of c-Jun N-terminal kinase(JNK), forkhead box protein O1(FoxO1), microtuble-associated protein light chain 3(LC3B), ubiquitin-binding protein p62(p62), myosin-like BCL2 interacting protein(Beclin1), autophagy related gene 7(Atg7), growth-associated protein 43(GAP43), postsynaptic dense protein95 (PSD95), N-methyl-D-aspartate receptor(NMDAR) subunit 2B(NR2B) and brain-derived neurotrophic factor(BDNF) in hippocampus was detected by Western blotting and Real-time quantitative polymerase chain reaction(RT-qPCR).

RESULTS  Compared with the model group, the intervention of HLJDD improved the learning and spatial memory abilities of model rats significantly(P<0.05 or P<0.01), alleviated pathological and morphological damage of hippocampal tissue, ameliorated the ultrastructure of neurons and synapses in hippocampus, decreased the number of autophagosomes, down-regulated the expression of JNK, FoxO1, LC3B, Beclin1, Atg7 proteins and mRNA(P<0.05 or P<0.01), up-regulated the expression of p62, GAP43, SYP, PSD95, NR2B, BDNF protein and mRNA simultaneously(P<0.05 or P<0.01). However, the co-treatment of Anisomycin partially reversed the therapeutic effects of HLJDD on synaptic plasticit.

CONCLUSION  HLJDD can improve synaptic plasticity in VD rats via regulating JNK/FoxO1-mediated autophagy.