Mechanism Of Improving Brain Development Of The Progeny With LT4 Treatment In Subclinical Hypothyroidism

Objective:Thyroid hormones（TH）are essential for normal brain development.Even modest degrees of TH disruption experienced in gestation mothers can result in neuropsychological deficits in children.Neurotrophins have been implicated in a host of brain cellular functions.The neurotrophin receptor p75^NTRTR has a well documented role in development and function of the nervous system.Studies have revealed that P75^NTRTR promote apoptosis of neurons and affected the JNK-p53-Bax pathway in intracerebral hemorrhage,in the brain of alzheimer’s disease the activation of p75^NTRTR mediated signaling pathways impact the expression of learning and memory proteins.However,There no evidence was available if p75^NTRTR mediated related signaling pathways play a key role on brain development under subclinical hypothyroidism during pregnancy.This review explore the expression and action of neurotrophins particularly p75^NTRTR mediated signaling pathways in offsprings’cortex,depending on the animal model of pregnant rat with subclinical hypothyroidism successfully established.we investigate the optimal intervention time of treatment with levothvroxin（L-T4）in maternal subclinical hypothyroidism（SCH）on the neural development of the progeny.Moreover we intend to investigate whether the treatment of subclinical hypothyroidism in pregnant rats can improve the brain development of mice by regulating the level of cell factors in related to p75^NTRTR signaling pathway.Methods:Ninty female adult Wistar rats were randomly divided into groups of hypothyroidism（OH）,SCH,SCH treated with levothyroxine at embryonic day 10（E10）,E13,E17,and normal control group（false thyroid surgery was carried out）.The expression of p75^NTR,Bax,p53,JNK,p-JNK was detected by western blotting in cortex at P7（postnatal day 7）the method of morris water test and the long time range enhancement（LTP）were conducted at at P40.Results:The SCH and OH groups had longer escape latencies（the first four days）during the learning process in the Morris water maze compared to the control group.In the fifth day,comparing with CON group,the times of the pups crossing the platform quadrant in the E10 and E13 group had no significant difference（P=0.688,P=0.688,P<0.05）,E17group existed obvious instinction（P=0.016）.The Long-term potentiation（LTP）test show that percentage of f-EPSP slope from SCH and OH groups were more reduced than CON group（P<0.05）,SCH group was slightly higher than OH group.In the intervention group,E10 and E13 group have little difference with CON group（P=0.1,P=0.1）,but significantly higher than that of SCH group（P<0.05）.E17 group showed lower than the CON group（P<0.05）,but have no obvious difference compared with SCH group（P=0.154）.Western blotting revealed that the level of p75^NTRTR expression was significantly higher in the E13 group,SCH group and OH group compared with CON group in pups’cortex at P7（P<0.05）,p75^NTRTR had no significant difference between the E10 group,E13 group and the CON group（P>0.05）.The expressions of p75^NTR,Bax,p53,and pJNK in the SCH and OH groups were higher than that in the CON group（P<0.05）,and the OH group was higher than the SCH group（P<0.05）.p75^NTR,Bax and p53 were lower than SCH group（P<0.05）in E10 group,while the number of p75^NTRand Bax in E13group and SCH group had no difference（P>0.05）,and E17 group was no different from the CON group（P>0.05）.Conclusion:Maternal SCH disturbs learning and memory performances of pups.This may be associated with increased expression of the p75^NTRTR and elevated the activation of the JNK-p53-Bax pathway.Before E10 levothyroxine treatment may reverse the ability of learning and memory in offsprings.