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  4. Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

The Journal of Clinical Investigation, 2010 · DOI: 10.1172/JCI40000 · Published: May 1, 2010

Regenerative MedicineNeurologyGenetics

Simple Explanation

This research investigates how folate (vitamin B9) affects nerve repair in the central nervous system (CNS) of rodents after injury. They found that folate promotes nerve regeneration through a process called DNA methylation. The study revealed that after spinal cord and nerve damage, the body increases production of a specific folate receptor (Folr1). This receptor helps cells absorb more folate, which is then used in DNA methylation, a key process for nerve repair. The researchers also discovered that the amount of folate given affects nerve regeneration in a biphasic manner. Too little or too much folate isn't as effective as the optimal dose, which closely relates to how much DNA methylation occurs.

Study Duration
Not specified
Participants
Rodents (rats and mice)
Evidence Level
Not specified

Key Findings

  • 1
    Spinal cord and peripheral nerve injury induces the expression of the high-affinity folate receptor Folr1, but not the low-affinity reduced folate carrier Rfc1.
  • 2
    Dhfr bioactivation of FA is essential for folate-mediated CNS regeneration; blocking Dhfr with methotrexate inhibits axonal regeneration.
  • 3
    Combined spinal cord and peripheral nerve injury suppresses spinal cord DNA methylation, and FA restores methylation levels in a biphasic fashion.

Research Summary

This study investigates the mechanisms by which folate promotes CNS axon regeneration after injury in rodents, focusing on the role of DNA methylation. The research demonstrates that injury induces Folr1 expression, which facilitates folate uptake and subsequent DNA methylation, essential for axonal regeneration. The dose-dependent effects of folate on nerve regeneration correlate with global and gene-specific DNA methylation and the expression of de novo DNA methyltransferases.

Practical Implications

Therapeutic potential of folate

Folic acid and other nontoxic dietary methyl donors may be useful in clinical interventions to promote brain and spinal cord healing.

Epigenetic-based therapies

The findings suggest possible avenues for new pharmacologic approaches to treating CNS injuries by promoting endogenous axonal regeneration through epigenetic mechanisms.

Optimizing folate dosage

Understanding the biphasic dose response to folate is crucial for maximizing its therapeutic benefits in CNS repair.

Study Limitations

  • 1
    The exact mechanisms underlying the biphasic dose response to folate remain unclear.
  • 2
    The study is conducted in rodents, and further research is needed to confirm these findings in humans.
  • 3
    The long-term effects of folate supplementation on CNS regeneration require further investigation.

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