The differential effects of pathway- versus target-derived glial cell line-derived neurotrophic factor on peripheral nerve regeneration

Abstract

Object: Glial cell line-derived neurotrophic factor (GDNF) has potent survival effects on central and peripheral nerve populations. The authors examined the differential effects of GDNF following either a sciatic nerve crush injury in mice that overexpressed GDNF in the central or peripheral nervous systems (glial fibrillary acidic protein [GFAP]-GDNF) or in the muscle target (Myo-GDNF).

Methods: Adult mice (GFAP-GDNF, Myo-GDNF, or wild-type [WT] animals) underwent sciatic nerve crush and were evaluated using histomorphometry and muscle force and power testing. Uninjured WT animals served as controls.

Results: In the sciatic nerve crush, the Myo-GDNF mice demonstrated a higher number of nerve fibers, fiber density, and nerve percentage (p < 0.05) at 2 weeks. The early regenerative response did not result in superlative functional recovery. At 3 weeks, GFAP-GDNF animals exhibit fewer nerve fibers, decreased fiber width, and decreased nerve percentage compared with WT and Myo-GDNF mice (p < 0.05). By 6 weeks, there were no significant differences between groups.

Conclusions: Peripheral delivery of GDNF resulted in earlier regeneration following sciatic nerve crush injuries than that with central GDNF delivery. Treatment with neurotrophic factors such as GDNF may offer new possibilities for the treatment of peripheral nerve injury.

Fig. 1

Bar graphs. Histomorphometry was performed on harvested sciatic nerves following crush injury. Compared with WT and GFAP-GDNF mice, Myo-GDNF demonstrated a statistically significantly higher total number of nerve fibers (A), fiber density (C), and nerve percentage (D) at 2 weeks after sciatic nerve crush injury. At the 3-week time point Myo-GDNF demonstrated a significantly higher total number of nerve fibers, fiber width, fiber density, and nerve percentage compared with GFAP-GDNF mice. The GFAP-GDNF animals demonstrated a delayed regenerative response; at 4 weeks they had significantly more total nerve fibers and fiber density than WT controls. At 6 weeks, there was no statistical difference between any of the groups or measured parameters. Asterisks denote statistical differences (p < 0.05) between measurements.

Fig. 2

Bar graphs showing the distribution of fiber width as a percentage of the total fibers. At each time point following sciatic nerve crush, fiber width data were stratified according to animal genotype. Stratification data are represented as a percentage of the total mean fiber width within each genotype. A: In uninjured control animals, there are statistical differences in fiber width distribution of smaller-diameter fibers. B: At 2 weeks after nerve crush, WT animals show a statistically significant increase in 4–5-μm fibers. C and D: The GFAP-GDNF animals show an increase in small-diameter fibers at 3 weeks (C), with significantly lower numbers of larger-diameter fibers compared with both WT and GFAP-GDNF. E: By 6 weeks, there are no differences between fiber distributions between genotypes. Asterisks denote statistical differences (p < 0.05) between measurements.

Fig. 3

Bar graphs. Functional motor recovery following crush injury was assessed through an in situ measurement of maximum specific tetanic force production and normalized peak power production in the EDL muscle. Left: The Myo-GDNF mice demonstrated a greater recovery of specific force production compared with GFAP-GDNF mice at 2 weeks postoperatively, equivalent to WT mice. Right: At a similar time point, recovery of power production in Myo-GDNF and GFAP-GDNF mice was indistinguishable, although both Myo-GDNF and GFAP-GDNF mice demonstrated a lower power production than WT mice.