The Role Of Cognitive Impairment And MTOR Pathway In TSH Inhibition Therapy After Total Thyroidectomy In Rats

Objective: This study aimed to investigate the effect of thyroid-stimulating hormone(TSH)suppression therapy on cognitive function in rats after total thyroidectomy and the underlying role of the mammalian target of rapamycin(mTOR)signaling pathway.Methods: Forty Wistar rats were randomized into the sham operation control(OC),total thyroidectomy(TD),thyroxine replacement therapy(TR),and TSH suppression therapy(TS)groups.After total thyroidectomy,1.4?g/100g*d L-thyroxine(L-T4)and 1.6?g/100g*d L-T4 were subcutaneously injected in the TR and TS groups.Serum T3,T4,and TSH levels were measured by ELISA.Spatial learning and memory were assessed by the Morris water maze assay.Hippocampal histopathology was detected by HE staining,and Western blot was performed to detect the hippocampal mTOR-related proteins.Results: Compared to the OC group,the TD group showed significantly decreased serum T3(P=0.000)and T4(P=0.000)levels and increased serum TSH(P=0.000)levels.No significant differences were detected in the serum T3(P=0.253)and TSH(P=0.934)levels in the TR group as compared to OC group,but serum T4 levels were slightly higher(P=0.000).The serum T3 levels in the TS group were not altered as compared to the OC group(P=0.068),but serum T4 levels were increased and the TSH content was significantly decreased(P=0.000).Compared to the OC group,escape latency on 1–4 days was significantly prolonged in the TD(P=0.000,P=0.000,P=0.000,P=0.000)and TS(P=0.036,P=0.000,P=0.000,P=0.000,P=0.000)groups,and the number of rats crossing the virtual platform was significantly reduced in the TD(P=0.000)and TS(P=0.002)groups.In the TD,TR,and TS groups,the residence time in the target quadrant was significantly decreased(P=0.000,P=0.016,P=0.000),while the activity distance in the target quadrant in the TD group was significantly decreased compared with OC group(P=0.010).In the TD and TS groups,the pyramidal cells in the hippocampal CA1 region showed a disordered arrangement.The cytoplasm was lightly stained,the cells were swollen and round,and spotty liquefaction necrosis could be observed.Compared to the OC group,hippocampal p-mTOR and p-p70s6 k levels were significantly decreased in the TDgroup(P=0.017,P=0.002),while no significant changes were detected in the TR group(P=0.126,P=0.379).Hippocampal p-mTOR and p-p70s6 k amounts in the TS group were significantly increased compared with OC group(P=0.008,P=0.004).Conclusion: TSH suppression therapy after total thyroidectomy in rats might impair cognitive function,which is related to the activation of the mTOR signaling pathway and the damage and necrosis of hippocampal neurons.