Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury

Journal of Translational Medicine, 2024 · DOI: https://doi.org/10.1186/s12967-024-05436-9 · Published: July 3, 2024

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

This study investigates how metformin, a common diabetes drug, affects the repair process after spinal cord injury (SCI). It focuses on neural stem cells (NSCs), which can help regenerate damaged nerve tissue. The research explores whether metformin can boost the number of NSCs, help them turn into neurons (nerve cells), and protect them from ferroptosis, a type of cell death. The study also looks at the role of AMPK, a protein activated by metformin. The results suggest that metformin, by activating AMPK, can indeed promote NSC proliferation and neuronal differentiation, while also inhibiting ferroptosis. This leads to improved recovery of movement in rats with SCI.

Study Duration

56 days

Participants

98 female Wistar rats aged 6–8 weeks and 8 pregnant Wistar rats at gestational days 12–14

Evidence Level

Not specified

Key Findings

1
Metformin promotes the proliferation and neuronal differentiation of NSCs both in vitro and in vivo.
2
Metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology.
3
Metformin administration improved locomotor function recovery and histological outcomes following SCI in rats.

Research Summary

This study demonstrates that metformin enhances the proliferation and neuronal differentiation of neural stem cells (NSCs), both in vitro and in vivo. Metformin treatment reverses erastin-induced changes in the expression levels of GPX4, SLC7A11, and ACSL4 in NSCs. Metformin, dependent on AMPK activation, promotes the recovery of locomotor function after SCI by modulating the proliferation, differentiation fate, and inhibiting ferroptosis in endogenous NSCs.

Practical Implications

Therapeutic Potential

Metformin holds promise as a candidate for SCI repair by promoting nerve regeneration and neuroprotection.

Mechanism Elucidation

The study elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.

Clinical Translation

The findings support further investigation into the use of metformin as a therapeutic intervention for spinal cord injury, given its effects on NSCs and functional recovery.

Study Limitations

1
Lacking specific targeting, and thus unable to determine the roles of microglia/macrophages or other cells in the spinal cord repair process.
2
Focused only on the differentiation of neurons and astrocytes from neural stem cells; future experiments are needed to explore the differentiation direction and function of oligodendrocytes.
3
The potential off-target effects of erastin necessitates further investigation using additional ferroptosis inducers to establish a more robust and comprehensive NSC ferroptosis model.

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