Department of Medicina Pubblica Clinica e Preventiva, Second University of Napoli, Napoli, Italy.
Biotechnol Adv. 2012 Jan-Feb;30(1):223-32. doi: 10.1016/j.biotechadv.2011.05.008. Epub 2011 May 18.
Peptidomimetics hold a great promise as therapeutic agents for neurodegenerative disorders. We previously described a Nerve Growth Factor (NGF)-like peptide, now named BB14, which was found to act as a strong TrkA agonist and to be effective in the sciatic nerve injury model of neuropathic pain. In this report we present the effects of BB14 in reducing reactive astrocytosis and reverting neuroplastic changes of the glutamate/GABAergic circuitry in the lumbar spinal cord following spared nerve injury (SNI) of the sciatic nerve. Immunohistochemical analysis of spinal cord sections revealed that SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) responses, indicative of reactive gliosis. These changes were paralleled by (i) decreased glial aminoacid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. A remarkable increase of the Glutamate/GABA ratio and the reduction of glutathione (GSH) levels were also indicative of modifications of glial function in neuroprotection. All these molecular changes were found to be linked to an alteration of endogenous NGF metabolism, as demonstrated by decreased levels of mature NGF, increase of proNGF and increased activity of NGF-degrading methallo-proteinases (MMPs). Biochemical alterations and SNI-related neuropathic behavior, characterized by allodynia and hyperalgesia, were reversed by 7-days i.t. administration of the NGF-like peptide BB14, as well as by increasing endogenous NGF levels by i.t. infusion of GM6001, a MMPs inhibitor. All together, while confirming the correlation between reactive astrogliosis and perturbation of synaptic circuitry in the SNI model of peripheral nerve injury, these data strongly support the beneficial effect of BB14 in reducing reactive astrogliosis and restoring synaptic homeostasis under pathological conditions linked to alteration of NGF availability and signaling, thereby suggesting a potential role of BB14 as a therapeutic agent.
肽模拟物作为神经退行性疾病的治疗药物具有很大的前景。我们之前描述了一种神经生长因子 (NGF)-样肽，现在命名为 BB14，它被发现是一种很强的 TrkA 激动剂，并且在坐骨神经损伤的神经性疼痛模型中有效。在本报告中，我们介绍了 BB14 在减少坐骨神经 spared 神经损伤 (SNI) 后脊髓中谷氨酸/GABA 能回路的神经可塑性变化和反应性星形胶质细胞增生中的作用。脊髓切片的免疫组织化学分析显示，SNI 与小胶质细胞 (Iba1) 和星形胶质细胞 (GFAP) 反应的增加有关，表明存在反应性神经胶质增生。这些变化与 (i) 胶质氨基酸转运体 (GLT1 和 GlyT1) 的减少和 (ii) 神经元谷氨酸转运体 EAAC1、(iii) 神经元囊泡 GABA 转运体 (vGAT) 和 (iv) GABA 能神经元标志物 GAD65/67 的增加平行。谷氨酸/GABA 比的显著增加和谷胱甘肽 (GSH) 水平的降低也表明了神经保护中胶质功能的改变。所有这些分子变化都与内源性 NGF 代谢的改变有关，这一点可以通过成熟 NGF 水平的降低、proNGF 的增加和 NGF 降解金属蛋白酶 (MMPs) 的活性增加来证明。生化改变和与 SNI 相关的神经病理性行为，表现为痛觉过敏和痛觉过敏，通过鞘内给予 NGF 样肽 BB14 7 天以及通过鞘内输注 MMPs 抑制剂 GM6001 增加内源性 NGF 水平来逆转。所有这些都证实了反应性星形胶质细胞增生与外周神经损伤的 SNI 模型中突触回路的紊乱之间的相关性，这些数据强烈支持 BB14 在减少反应性星形胶质细胞增生和在与 NGF 可用性和信号改变相关的病理条件下恢复突触平衡方面的有益作用，从而表明 BB14 作为治疗药物的潜在作用。
