Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/ NRF2 pathway in spinal cord injury accompanied by diabetes

Redox Biology, 2024 · DOI: https://doi.org/10.1016/j.redox.2024.103104 · Published: February 28, 2024

Spinal Cord Injury Endocrinology Neurology

Simple Explanation

This study investigates how diabetes worsens spinal cord injury (SCI) outcomes due to increased neuronal oxidative stress. The research focuses on the role of Mammalian sterile 20-like kinase (MST1) in this process, particularly its impact on neuronal oxidative stress in SCI patients with diabetes. The study demonstrates that inhibiting MST1 can significantly improve neurological function in SCI mice with diabetes by activating antioxidant properties via the GSK3β/β-TrCP/NRF2 pathway.

Study Duration

Not specified

Participants

Mice, PC12 cell line

Evidence Level

Not specified

Key Findings

1
Diabetes upregulates MST1, leading to excessive neuronal apoptosis and weakened motor function in SCI mice, while inhibiting MST1 restores antioxidant properties and promotes neuronal survival.
2
In vitro, AGEs worsen mitochondrial dysfunction and increase cellular oxidative stress, but MST1 inhibition restores NRF2 accumulation and antioxidant enzyme transcription, preventing ROS generation.
3
MST1 over-activation hinders neuroprotective AKT1, fostering NRF2 ubiquitination and degradation via the GSK3β/β-TrCP pathway.

Research Summary

This study investigates the role of MST1 in exacerbating spinal cord injury (SCI) in diabetic mice, finding that diabetes induces excessive MST1 activation, impairing motor function and neuronal apoptosis. The research demonstrates that inhibiting MST1 can alleviate mitochondrial dysfunction and reduce oxidative damage by facilitating the NRF2-mediated antioxidant defense system. The study identifies that the protective effect of MST1 inhibition is mediated by the GSK3β/β-TrCP/NRF2 pathway, suggesting MST1 as a potential therapeutic target for SCI patients with diabetes.

Practical Implications

Therapeutic Target Identification

MST1 may be a promising pharmacological target for treating spinal cord injury patients with diabetes.

Treatment Strategies

Targeting MST1 inhibition could improve neurological function and reduce neuronal apoptosis in SCI patients with diabetes.

Clinical Attention to Metabolic Regulation

Clinical attention to metabolic regulation in spinal cord injury patients with SCI is important.

Study Limitations

1
Use of PC12 cell line instead of mature primary neurons.
2
Other regulatory mechanisms besides MST1 knockdown may contribute to motor function recovery.
3
Not specified

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