Abstract:
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.
摘要:
周围神经损伤(PNI)是一个重大的临床挑战,特别是在轴突髓鞘再生和再生受损的老年人群。开发增强这些过程的疗法对于改善PNI修复结果至关重要。谷氨酸羧肽酶II(GCPII)是一种神经肽酶,通过其酶切丰富的神经肽N-乙酰基天冬氨酰谷氨酸(NAAG)释放谷氨酸来调节谷氨酸信号传导中起关键作用。在PNS内,GCPII在施万细胞和活化的巨噬细胞中表达,其表达随着衰老而扩增。在这项研究中,我们探索了PNI后抑制GCPII活性的治疗潜力.我们报道了PNI后GCPII蛋白和活性的显著上调,其通过有效和选择性的GCPII抑制剂2-(膦酰基甲基)-戊二酸(2-PMPA)进行归一化。体外,2-PMPA强烈增强背根神经节(DRG)外植体的髓鞘形成。在体内,在老年小鼠中使用坐骨神经挤压损伤模型,2-PMPA加速髓鞘再生,髓鞘厚度增加和髓鞘再生轴突数量增加。这些发现表明,GCPII抑制可能是一种有希望的治疗策略,以增强髓鞘再生并可能改善PNI后的功能恢复。这在该过程受损的老年PNI患者中尤其重要。