Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Int J Mol Sci. 2024 Jun 23;25(13):6893. doi: 10.3390/ijms25136893.
Peripheral nerve injuries (PNIs) represent a significant clinical challenge, particularly in elderly populations where axonal remyelination and regeneration are impaired. Developing therapies to enhance these processes is crucial for improving PNI repair outcomes. Glutamate carboxypeptidase II (GCPII) is a neuropeptidase that plays a pivotal role in modulating glutamate signaling through its enzymatic cleavage of the abundant neuropeptide N-acetyl aspartyl glutamate (NAAG) to liberate glutamate. Within the PNS, GCPII is expressed in Schwann cells and activated macrophages, and its expression is amplified with aging. In this study, we explored the therapeutic potential of inhibiting GCPII activity following PNI. We report significant GCPII protein and activity upregulation following PNI, which was normalized by the potent and selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In vitro, 2-PMPA robustly enhanced myelination in dorsal root ganglion (DRG) explants. In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA accelerated remyelination, as evidenced by increased myelin sheath thickness and higher numbers of remyelinated axons. These findings suggest that GCPII inhibition may be a promising therapeutic strategy to enhance remyelination and potentially improve functional recovery after PNI, which is especially relevant in elderly PNI patients where this process is compromised.
周围神经损伤 (PNI) 是一个重大的临床挑战，尤其是在老年人中，轴突髓鞘形成和再生受损。开发增强这些过程的治疗方法对于改善 PNI 修复结果至关重要。谷氨酸羧肽酶 II (GCPII) 是一种神经肽酶，通过酶切丰富的神经肽 N-乙酰天冬氨酸谷氨酸 (NAAG) 释放谷氨酸来调节谷氨酸信号转导，从而发挥关键作用。在周围神经系统中，GCPII 表达于施万细胞和激活的巨噬细胞中，其表达随年龄增长而放大。在这项研究中，我们探讨了抑制 PNI 后 GCPII 活性的治疗潜力。我们报告了 PNI 后 GCPII 蛋白和活性的显著上调，这一上调被强效和选择性 GCPII 抑制剂 2-(膦酰甲基）戊二酸 (2-PMPA) 所纠正。在体外，2-PMPA 可强有力地增强背根神经节 (DRG) 外植体的髓鞘形成。在体内，使用老年小鼠坐骨神经挤压损伤模型，2-PMPA 加速了髓鞘再生，表现为髓鞘厚度增加和更多的髓鞘再生轴突。这些发现表明，GCPII 抑制可能是一种有前途的治疗策略，可增强髓鞘再生，并可能改善 PNI 后的功能恢复，这在老年人 PNI 患者中尤为重要，因为这些患者的这一过程受损。
