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Saidan Ding
Wenzhou Medical University First Affiliated Hospital
Corresponding Author
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Background: Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. The mechanism underlying the effects of thrombopoietin receptor agonist eltrombopag (ELT) on synaptic activity and formation involved in MHE pathogenesis remains unclear.
Methods: The effect of ELT on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model.
Results: We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the inhibition of inflammatory response and upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons.
Conclusions: These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.
Keywords
cognitive impairment, synapse, Thrombopoietin, eltrombopag, insulin resistance
Figure 1
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Figure 7
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.tif
Figure S1. MPL expression was decreased in MHE rats (a,b) Analysis of MPL mRNAs of cortical lysates from MHE rats by RT-PCR (a) and Q-PCR (b). (c,d) Analysis of MPL mRNAs of hippocampal lysates from MHE rats by RT-PCR (c) and Q-PCR (d). Data are shown as mean± SD. *P <0.05, **P <0.01 vs Con group. Scale bar, 25 μm. MRGD, merged image. Con, control.
- FigureS2.tif
Figure S2. ELT prevented memory impairment in MHE rats (a) Spontaneous alternation percentage (SA%) in YM of MHE rats administered with two dose (5, 25mg) of ELT. (b) Results of WFT (EL, entry latency; CL, contacting latency; DL, drinking latency) of MHE rats administered with two dosages (5, 25mg) of ELT. Data are shown as mean± SD. *P <0.05, **P <0.01 vs Con. #P <0.05, ##P <0.01 vs MHE model group. Con, control.
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Saidan Ding
Wenzhou Medical University First Affiliated Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 19 Mar, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. The mechanism underlying the effects of thrombopoietin receptor agonist eltrombopag (ELT) on synaptic activity and formation involved in MHE pathogenesis remains unclear.
Methods: The effect of ELT on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model.
Results: We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the inhibition of inflammatory response and upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons.
Conclusions: These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.tif
Figure S1. MPL expression was decreased in MHE rats (a,b) Analysis of MPL mRNAs of cortical lysates from MHE rats by RT-PCR (a) and Q-PCR (b). (c,d) Analysis of MPL mRNAs of hippocampal lysates from MHE rats by RT-PCR (c) and Q-PCR (d). Data are shown as mean± SD. *P <0.05, **P <0.01 vs Con group. Scale bar, 25 μm. MRGD, merged image. Con, control.
- FigureS2.tif
Figure S2. ELT prevented memory impairment in MHE rats (a) Spontaneous alternation percentage (SA%) in YM of MHE rats administered with two dose (5, 25mg) of ELT. (b) Results of WFT (EL, entry latency; CL, contacting latency; DL, drinking latency) of MHE rats administered with two dosages (5, 25mg) of ELT. Data are shown as mean± SD. *P <0.05, **P <0.01 vs Con. #P <0.05, ##P <0.01 vs MHE model group. Con, control.
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