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Ginsenoside compound K reduces ischemia/reperfusion-induced neuronal apoptosis by inhibiting PTP1B-mediated IRS1
1Department of Rehabilitation, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.
Background:
Ginsenoside compound K (CK) stimulated activation of the PI3K-Akt signaling is one of the major mechanisms in promoting cell survival after stroke. However, the underlying mediators remain poorly understood. This study aimed to explore the docking protein of ginsenoside CK mediating the neuroprotective effects.
Materials And Methods:
Molecular docking, surface plasmon resonance, and cellular thermal shift assay were performed to explore ginsenoside CK interacting proteins. Neuroscreen-1 cells and middle cerebral artery occlusion (MCAO) model in rats were utilized as in-vitro and in-vivo models.
Results:
Ginsenoside CK interacted with recombinant human PTP1B protein and impaired its tyrosine phosphatase activity. Pathway and process enrichment analysis confirmed the involvement of PTP1B and its interacting proteins in PI3K-Akt signaling pathway. PTP1B overexpression reduced the tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) after oxygen-glucose deprivation/reoxygenation (OGD/R) in neuroscreen-1 cells. These regulations were confirmed in the ipsilateral ischemic hemisphere of the rat brains after MCAO/R. Ginsenoside CK treatment reversed these alterations and attenuated neuronal apoptosis.
Conclusion:
Ginsenoside CK binds to PTP1B with a high affinity and inhibits PTP1B-mediated IRS1 tyrosine dephosphorylation. This novel mechanism helps explain the role of ginsenoside CK in activating the neuronal protective PI3K-Akt signaling pathway after ischemia-reperfusion injury.
Insights
Ginsenoside compound K (CK) protects neurons by inhibiting PTP1B, a protein that deactivates the PI3K-Akt survival pathway. This discovery clarifies CK
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Ginsenoside compound K (CK) activates the PI3K-Akt pathway, crucial for neuronal survival post-stroke.
- The specific mediators of CK's neuroprotective effects are not fully understood.
Purpose of the Study:
- To identify the protein that binds to ginsenoside CK and mediates its neuroprotective effects.
- To elucidate the mechanism by which CK exerts its neuroprotective actions.
Main Methods:
- Utilized molecular docking, surface plasmon resonance, and cellular thermal shift assay to identify CK-interacting proteins.
- Employed in vitro (Neuroscreen-1 cells) and in vivo (MCAO rat model) systems to study CK's effects.
Main Results:
- Ginsenoside CK directly binds to protein tyrosine phosphatase 1B (PTP1B), reducing its activity.
- CK treatment reversed PTP1B-mediated dephosphorylation of insulin receptor substrate 1 (IRS1) in both cell and animal models.
- CK attenuated neuronal apoptosis following ischemia-reperfusion injury.
Conclusions:
- Ginsenoside CK inhibits PTP1B, preventing IRS1 dephosphorylation and activating the PI3K-Akt signaling pathway.
- This interaction represents a novel mechanism for CK's neuroprotection against ischemia-reperfusion injury.
