Mechanism of action of Liuwei Dihuang Pill on sodium valproate-induced neonatal rat model of autism spectrum disorder based on BDNF/TrkB/CREB pathway
Objective To explore the mechanism of action of Liuwei Dihuang Pill(LWDHP)on the neonatal rats with autism spectrum disorder(ASD)induced by sodium valproate(VPA)based on the brain-derived neurotrophic factor(BDNF)/tyrosine kinase receptor B(TrkB)/cAMP response element binding protein(CREB)pathway.Methods Thirteen SD pregnant rats were randomly divided into two groups,with 10 pregnant rats receiving intraperitoneal injection of VPA solution(600 mg·kg-1)on the day 12.5th as the VPA group,and the other 3 pregnant rats receiving injection of equal volume of normal saline as the control group.Behavioral tests were carried out on the male neonatal rats of two groups on the 21th day,then 30 male neonatal rats conforming to the ASD disease model were selected and randomized into model group(equal volume of normal saline),vitamin D group(1 480 IU·kg-1),as well as high-(3 g·kg-1),medium-(1.5 g·kg-1),and low-dose(0.75 g·kg-1)LWDHP groups,with six rats in each group.And six normal male neonatal rats were set as blank group(equal volume of normal saline).The neonatal rats in each group were given the corresponding medicine by gavage once a day,for continual 14 days,and behavioral tests were carried out again after administration.The morphological changes of hippocampal neurons in neonatal rats of each group were observed using Nissl staining;the content of glutamic acid(GLU)and gamma-aminobutyric acid(GABA)in the hippocampal tissue was measured by colorimetry;the mRNA relative expressions of BDNF,TrkB,and CREB in the hippocampal tissue were determined by qRT-PCR.Results Compared with the control group,the VPA group had smaller body weight,body length,and tail length(P＜0.05).Compared with the blank group,the model group showed significant symptoms of social disorders(P＜0.01),anxiety disorders(P＜0.01),and increased repetitive stereotyped behaviors(P＜0.05 or P＜0.01),structural damage of hippocampal neurons,increased GLU content(P＜0.01),decreased GABA content(P＜0.01),as well as reduced mRNA expressions of BDNF,TrkB,and CREB(P＜0.05 or P＜0.01).Compared with model group,the social ability of neonatal rats in vitamin D group and medium-and low-dose LWDHP groups was enhanced(P＜0.05 or P＜0.01),anxiety disorder was alleviated(P＜0.05 or P＜0.01),repetitive and stereotyped behaviors were reduced(P＜0.01 or P＜0.05),the structures of hippocampal neurons were significantly restored,GLU content was decreased(P＜0.01),and the mRNA expressions of BDNF,TrkB,and CREB were higher(P＜0.05 or P＜0.01).Additionally,GABA content was elevated in medium-and low-dose LWDHP groups(P＜0.05 or P＜0.01).Conclusion LWDHP can significantly improve the behavioral outcome of VPA-induced ASD neonatal rats,and enhance the regeneration and repair of hippocampal neurons.The mechanism may be related to the balance of GLU and GABA levels as well as up-regulation of BDNF/TrkB/CREB expression in the hippocampal tissue.
万方数据
维普
