Taurine Promotes Short-term And Long-term Brain Development In Fetal Rats With Growth Restriction

Background:Fetal growth restriction(FGR)is one of the main causes of short-term and long-term neurodevelopmental disorders in children.The short-term damage of FGR brain development is characterized by decreased proliferation and differentiation of neural stem cells(NSCs),abnormal cell composition,synaptic connection and brain metabolism.The long-term damage is presented as motor learning disorder and abnormal neurobehavior.Fetal NSC differentiation is the basis of brain development.Hippocampus is the key area of learning and cognition.The effect of taurine on impoving FGR fetal brain development via protein kinase A(PKA)-cyclic adenosine monophosphate response binding protein(CREB)pathway need to be futher studied.At the same time,the long-term effects of taurine on hippocampal nerve cells,metabolic function,synaptic development,cognition development are not clear.In this study,the NSC model of FGR fetal rats in vitro and FGR infant rats in vivo were established.Molecular biology,MRS and functional evaluation were used.The major contents consist of the mechanism of taurine promoting the differentiation of FGR fetal rat NSC,the effect on protecting the normal proportion of nerve cells to improve cell metabolic function,and promoting cognitive development through increasing the number of hippocampal synapses.To explore the mechanism of taurine on the short-term and long-term neurodevelopment of FGR rats,the study provides theoretical basis for clinical application of taurine to promote FGR brain development.Methods:The fetal rat model of FGR was established by diet restriction of pregnant rats during pregnancy.The subependymal tissue of fetal rats was dissociated and cultured into neurospheres.After neurospheres passage,the NSCs were divided into the control group,the FGR group,the FGR+taurine(taurine)group,the FGR +H89(H89)group and the FGR+taurine+H89(taurine+H89)group.The proliferation of NSCs was detected by CCK8 method and optical counting.The differentiated Tuj-1(+)neurons and GFAP(+)astrocytes were detected by immunofluorescence.The mRNA and protein expressions of PKA,CREB and BDNF were detected by RT-PCR and Western blot(WB)respectively.The 14 day old pups FGR model was established.The newborn rats were randomly divided into the control group,the FGR group,the FGR+prenatal taurine(FAT)group(FGR pregnant rats received taurine supplementation from the 7th day of pregnancy to natural childbirth)and the FGR+postnatal taurine(FPT)group(FGR newborn rats were supplemented with taurine for 14 days).Metabolism of hippocampal neural cells of 14 day rats were detected by MRS,which was consist of metabolic characteristics of NAA,Gln,Cho,ml and Cr.The composition of neurons in hippocampus was observed by immunohistochemistry and WB method.The 28 day old pups of FGR model was established.The sensory motor ability of the young rats was tested last for 14 days.The expression of synaptophysin(Syn)in hippocampus was detected after test.At the same time,the correlation between the sensory motor ability of the young rats and the expression of Syn in hippocampus was analyzed.Results:The proliferation and differentiation ability of FGR NSCs was lower.Furthermore,the proportion of differentiated Tuj-1(+)neurons was lower than that in control group(p<0.05),but the proportion of GFAP(+)astrocytes was higher(p<0.05).Taurine increased the proportion of Tuj-1(+)neurons and decreased the proportion of GFAP(+)glial cells,by promoting the mRNA and protein expression of the major signaling factors in PKA-CREB-BDNF signaling way.The expression of NAA/Cr,Gln/Cr and NeuN protein in the hippocampus of FGR young rats(14 day old)decreased,while the expression of Cho/Cr,mI/Cr and GFAP protein increased.Prenatal taurine supplementation increased the expression of NAA/Cr and NeuN protein in the the hippocampus of FGR young rats,which was close to that of the control group(p>0.05),and the above value of postnatal taurine supplementation was lower than that of the control group(p<0.05).Prenatal and postnatal supplementation could reduce the expression of CHO/Cr,mI/Cr and GFAP protein(p>0.05).There existed a positive correlation between NAA/Cr and NeuN protein,mI/Cr and GFAP protein in hippocampus(p<0.05).3)On the 28th day,the suspension and balance beam test scores in the FGR group were lower than those in the control group(p<0.001),the test scores in the FAT group were close to those in the control group(p>0.05),but those in the FPT group were lower(p<0.05).The scores of suspension test and balance beam test and the protein expression of Syn in the hippocampus were decreased.Prenatal taurine supplementation increased the test scores and Syn protein expression,which were close to those in the control group(p>0.05),but the above value of postnatal supplementation were still lower than those in the control group(p<0.05).The score of functional test was positively correlated with the expression of Syn protein in the hippocampus of young rats(p<0.05).Conclusion:Taurine promoted the proliferation and differentiation of FGR fetal brain NSCs,and improved the neuron/glial ratio,via activating PKA-CREB-BDNF signaling pathway.Prenatal taurine supplementation improved hippocampal metabolism by increasing the ratio of neurons to glial cells in the hippocampus of FGR young rats.At the same time,prenatal taurine also promoted synaptic development,sensory motor ability and cognitive development through increasing the expression of syn in the hippocampus of young FGR rats.