Enhancing Remyelination in Aging Peripheral Nerve Injury Through GCPII Inhibition

Peripheral nerve injuries (PNIs) pose a significant clinical challenge, particularly in aging populations, where impaired remyelination and axonal regeneration limit recovery. This study investigates the therapeutic potential of inhibiting glutamate carboxypeptidase II (GCPII), a neuropeptidase that catalayzes the hydrolysis of N-acetylaspartylglutamate (NAAG) to glutamate, to promote remyelination after PNI. Our findings reveal a significant upregulation of GCPII activity post-injury in nerve, which was normalized using the selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) (7464 ± 626 vs. 10,047 ± 440 vs. 1504 ± 89 fmol/mg/h; p < 0.05, n = 3). Immunofluorescence identified increased GCPII expression predominantly in activated macrophages and repair Schwann cells. In vitro, 2-PMPA treatment significantly enhanced myelination in dorsal root ganglion (DRG) explants, indicated by a substantial increase in myelin segments (17.67 ± 3.48 vs. 72.67 ± 4.37; p < 0.05, n = 3). In vivo, 2-PMPA accelerated remyelination in a sciatic nerve crush injury model in both young and aged mice, demonstrated by a reduced g-ratio (0.90 ± 0.01 vs. 0.73 ± 0.05; p < 0.05, n = 3) and a higher proportion of remyelinated axons (28.1 ± 2.1 vs. 82.5 ± 7.2%; p < 0.05, n = 3) in aged mice. Additionally, dendrimer-conjugated 2-PMPA, which selectively targets macrophages and Schwann cells, significantly reduced compound muscle action potential (CMAP) latency after 10 weeks of treatment in aged PNI mice (4.04 ± 0.11 vs. 3.23 ± 0.13 ms; p < 0.01, n = 5). These findings underscore the potential of GCPII inhibition as a promising therapeutic strategy to enhance remyelination and recovery in aging populations with compromised PNI repair. This work was supported by NIH R01-AG078181 (to BSS), R01-AG068130 (to BSS), R01-NS093416 (to BSS), and Johns Hopkins Merkin PNNR center 90093312 (to YS). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.