Folic acid supplementation enhances repair of the adult central nervous system

Abstract

Folic acid supplementation has proved to be extremely effective in reducing the occurrence of neural tube defects (NTDs) and other congenital abnormalities in humans, suggesting that folic acid can modulate key mechanisms for growth and differentiation in the central nervous system (CNS). To prevent NTDs, however, supplemental folate must be provided early in gestation. This suggests that the ability of folic acid to activate growth and differentiation mechanisms may be confined to the early embryonic period. Here, we show that folic acid can enhance growth and repair mechanisms even in the adult CNS. Using lesion models of CNS injury, we found that intraperitoneal treatment of adult rats with folic acid significantly improves the regrowth of sensory spinal axons into a grafted segment of peripheral nerve in vivo. Regrowth of retinal ganglion cell (RGC) axons into a similar graft also was enhanced, although to a smaller extent than spinal axons. Furthermore, folic acid supplementation enhances neurological recovery from a spinal cord contusion injury, showing its potential clinical impact. The results show that the effects of folic acid supplementation on CNS growth processes are not restricted to the embryonic period, but can also be effective for enhancing growth, repair, and recovery in the injured adult CNS.

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

“…In addition, we have previously shown that the combination of peripheral nerve injury and i.p. FA supplementation is additive or synergistic, increasing the number of regenerating axons on the conditioned side nearly 10-fold (7). Accordingly, the SCRM results reported in this study refer to the conditioned side of the spinal cord.…”

“…The SCRM model of spinal cord axonal regeneration combines a sharp bilateral cervical dorsal column transection with a unilateral "conditioning" sciatic nerve injury (spinal cord and sciatic nerve injury [SCSN]) (7,13). Injuring the peripheral axon of the dorsal root ganglia (DRG) enhances growth of both the peripheral (sciatic) and central (dorsal column) components of the DRG (13).…”

“…Absence of glia from the culture medium indicates that axonal regeneration is independent of the glial microenvironment. Sharp transection injuries were subsequently administered to the optic nerve and cervical dorsal columns of Folr1 +/-and WT mice, and a sciatic nerve graft was attached to the optic or spinal cord injury sites respectively, as previously reported (7,13,18). After an interval of time adequate for growth of axons a distance of at least 1 cm into the graft (i.e., 2 weeks in the spinal model and 2 months in the optic model), the end of the graft was backfilled with a fluorescent tracer, and the corresponding cell bodies in the retina and DRG were counted.…”

“…First, periconceptional FA supplementation markedly reduces the incidence of neural tube and other malformations (5,6). Furthermore, we have shown that parenteral FA produces up to a 10-fold, dose-dependent improvement in axon regrowth and functional recovery after injury to the adult CNS, an effect well in excess of other interventions (7). Corresponding efforts to improve neurological function through folate administration in neurodevelopmental diseases, including autism and depression, and other neuropsychiatric disorders are underway (8).…”

“…Herein, we report the consequences of specific interventions on enzymatic steps that comprise the folate pathway from cellular entry to methylation on axonal regeneration in the adult CNS after sharp injury. For this purpose, we use the spinal cord regeneration model (SCRM), which combines a bilateral dorsal column transection with a conditioning left sciatic nerve injury (7,13). As depicted in a folate pathway schematic diagram (Figure 1), we show that agonists and antagonists of sequential reactions in folate metabolism exhibit dose-dependent inhibition and promotion of CNS repair, respectively, and that axonal regeneration relies upon the integrity of DNA methylation pathways.…”