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Research
Saidan Ding
Wenzhou Medical University First Affiliated Hospital
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairments. Thrombopoietin (TPO) has been shown to be neuroprotective. This study aimed to explore the therapeutic effect of Thrombopoietin receptor agonist eltrombopag (ELT) on MHE and the involvement of NRG1 signaling using primary rat neurons and a MHE rat model.
Methods
We explored the effects of ELT stimulation on NRG1/ErbB4 signaling and synapse formation in the primary rat neurons. Furthermore, we explored the cerebral TPO expression level and the effect of TPO replacement therapy in an MHE rat model.
Results
The results showed that ELT stimulation activated NRG1/ErbB4 signaling and enhanced synaptic protein expression in the primary rat neurons via sirtuin 1. An anti-NRG1 antibody, ErbB4 inhibitor, or knockdown of NRG1 or ErbB4 could significantly abolish ELT-induced upregulation of synaptic protein expression in the primary rat neurons. MHE rats had significantly decreased cerebral ELT expression compared with normal rats. ELT activated NRG1/ErbB4 signaling in MHE rat brains. Administration or overexpression of ELT or TPO promoted synapse formation and alleviated cognitive impairments in MHE rats.
Conclusions
These data suggest that ELT promotes synapse formation in vitro and in vivo via activating NRG1/ErbB4 signaling, serving as a promising therapeutic agent for MHE treatment.
Keywords
cognitive impairment, synapse, Thrombopoietin, eltrombopag, minimal hepatic encephalopathy
Figure 1
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Figure 3
Figure 4
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Figure 6
Figure 7
Figure 8
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.tif
(a) PHNs were treated with vehicle or ELT (0, 6.25, 12.5, 25 μM) for 24 h. Western blot analysis was performed to determine protein expression of NRG2 and NRG3. β-actin was used as an internal control. (b) Quantification of (a). Data are expressed as mean ± SD. NS, non-significant.
- FigureS2.tif
(a) PHNs were treated with vehicle or ELT (0, 6.25, 12.5, 25 μM) for 24 h. Western blot analysis was performed to determine protein expression of pErbB2 and total ErbB2. β-actin was used as an internal control. (b)The pErbB2/total ErbB2 ratio was quantified. Data are expressed as mean ± SD. NS, non-significant.
- FigureS3.tif
PHNs were transfected with 0.25 μg siRNA against NRG1, siRNA against ErbB4, or scrambled siRNA. (a, c) Western blot analysis was performed to determine protein expression of NRG1 and pErbB4. β-actin was used as an internal control. (b, d) Quantification of (a) and (c). Data are expressed as mean ± SD. **P < 0.01 vs. Scr siRNA. Scr, scrambled.
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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 23 Feb, 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
Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairments. Thrombopoietin (TPO) has been shown to be neuroprotective. This study aimed to explore the therapeutic effect of Thrombopoietin receptor agonist eltrombopag (ELT) on MHE and the involvement of NRG1 signaling using primary rat neurons and a MHE rat model.
Methods
We explored the effects of ELT stimulation on NRG1/ErbB4 signaling and synapse formation in the primary rat neurons. Furthermore, we explored the cerebral TPO expression level and the effect of TPO replacement therapy in an MHE rat model.
Results
The results showed that ELT stimulation activated NRG1/ErbB4 signaling and enhanced synaptic protein expression in the primary rat neurons via sirtuin 1. An anti-NRG1 antibody, ErbB4 inhibitor, or knockdown of NRG1 or ErbB4 could significantly abolish ELT-induced upregulation of synaptic protein expression in the primary rat neurons. MHE rats had significantly decreased cerebral ELT expression compared with normal rats. ELT activated NRG1/ErbB4 signaling in MHE rat brains. Administration or overexpression of ELT or TPO promoted synapse formation and alleviated cognitive impairments in MHE rats.
Conclusions
These data suggest that ELT promotes synapse formation in vitro and in vivo via activating NRG1/ErbB4 signaling, serving as a promising therapeutic agent for MHE treatment.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.tif
(a) PHNs were treated with vehicle or ELT (0, 6.25, 12.5, 25 μM) for 24 h. Western blot analysis was performed to determine protein expression of NRG2 and NRG3. β-actin was used as an internal control. (b) Quantification of (a). Data are expressed as mean ± SD. NS, non-significant.
- FigureS2.tif
(a) PHNs were treated with vehicle or ELT (0, 6.25, 12.5, 25 μM) for 24 h. Western blot analysis was performed to determine protein expression of pErbB2 and total ErbB2. β-actin was used as an internal control. (b)The pErbB2/total ErbB2 ratio was quantified. Data are expressed as mean ± SD. NS, non-significant.
- FigureS3.tif
PHNs were transfected with 0.25 μg siRNA against NRG1, siRNA against ErbB4, or scrambled siRNA. (a, c) Western blot analysis was performed to determine protein expression of NRG1 and pErbB4. β-actin was used as an internal control. (b, d) Quantification of (a) and (c). Data are expressed as mean ± SD. **P < 0.01 vs. Scr siRNA. Scr, scrambled.
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