Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation
Bermans J. Iskandar, … , Thomas D. Cook, Kirk J. Hogan
Bermans J. Iskandar, … , Thomas D. Cook, Kirk J. Hogan
Published April 26, 2010
Citation Information: J Clin Invest. 2010;120(5):1603-1616. https://doi.org/10.1172/JCI40000.
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Research Article

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

Abstract

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

Authors

Bermans J. Iskandar, Elias Rizk, Brenton Meier, Nithya Hariharan, Teodoro Bottiglieri, Richard H. Finnell, David F. Jarrard, Ruma V. Banerjee, J.H. Pate Skene, Aaron Nelson, Nirav Patel, Carmen Gherasim, Kathleen Simon, Thomas D. Cook, Kirk J. Hogan

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Figure 10

Dnmt agonist promotes, and Dnmt antagonist inhibits, the regeneration of injured sensory spinal axons into a peripheral nerve graft.

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Dnmt agonist promotes, and Dnmt antagonist inhibits, the regeneration of...
Spinal axonal regeneration was measured in the SCRM model on the “conditioned” side after i.p. treatment with a Dnmt agonist 3-ABA (15 mg/kg) or antagonist 5-AzaC (0.1 mg/kg) with and without FA at 80 μg/kg. Treatment with the antagonist suppresses the proregenerative effect of FA (A). Conversely, treatment with the agonist at this dose significantly improves spinal regeneration into a nerve graft in vivo. The effect of 3-ABA at 15 mg/kg is equivalent to the 60 μg/kg dose of FA (7) (B). n = 7 (FA); n = 9 (FA and 5-AzaC); n = 11 (vehicle control); n = 9 (3-ABA); n = 7 (FA); n = 9 (FA and 3-ABA). One-way ANOVA with Bonferroni’s correction; mean ± SEM; *P < 0.05.