Abstract

Gradual loss of neuronal structure and function due to impaired blood–brain barrier (BBB) and neuroinflammation are important factors in multiple sclerosis (MS) progression. Our previous studies demonstrated that the C16 peptide and angiopoietin 1 (Ang-1) compound (C + A) could modulate inflammation and vascular protection in many models of MS. In this study, nanotechnology and a novel nanovector of the leukocyte chemotactic peptide N-formyl-methionyl-leucyl–phenylalanine (fMLP) were used to examine the effects of C + A on MS. The acute experimental autoimmune encephalomyelitis (EAE) model of MS was established in Lewis rats. The C + A compounds were conjugated to control nano-carriers and fMLP-nano-carriers and administered to animals by intravenous injection. The neuropathological changes in the brain cortex and spinal cord were examined using multiple approaches. The stimulation of vascular injection sites was examined using rabbits. The results showed that all C + A compounds (C + A alone, nano-carrier C + A, and fMLP-nano-carrier C + A) reduced neuronal inflammation, axonal demyelination, gliosis, neuronal apoptosis, vascular leakage, and BBB impairment induced by EAE. In addition, the C + A compounds had minimal side effects on liver and kidney functions. Furthermore, the fMLP-nano-carrier C + A compound had better effects compared to C + A alone and the nano-carrier C + A. This study indicated that the fMLP-nano-carrier C + A could attenuate inflammation-related pathological changes in EAE and may be a potential therapeutic strategy for the treatment of MS and EAE.

摘要

由于血脑屏障（BBB）受损和神经炎症导致神经元结构和功能逐渐丧失，是多发性硬化症（MS）进展的重要因素。我们之前的研究表明，C16 肽和血管生成素 1 (Ang-1) 化合物 (C + A) 可以在许多 MS 模型中调节炎症和血管保护。在本研究中，采用纳米技术和白细胞趋化肽 N-甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸 (fMLP) 的新型纳米载体来研究 C + A 对 MS 的影响。采用Lewis大鼠建立MS急性实验性自身免疫性脑脊髓炎（EAE）模型。C+A化合物与对照纳米载体和fMLP-纳米载体缀合，并通过静脉注射施用于动物。使用多种方法检查大脑皮层和脊髓的神经病理学变化。使用兔子检查血管注射部位的刺激。结果表明，所有 C + A 化合物（单独的 C + A、纳米载体 C + A 和 fMLP-纳米载体 C + A）均可减少神经元炎症、轴突脱髓鞘、神经胶质增生、神经元凋亡、血管渗漏和 BBB 损伤EAE诱发。此外，C+A化合物对肝肾功能的副作用极小。此外，fMLP-纳米载体C+A复合物比单独的C+A和纳米载体C+A具有更好的效果。本研究表明，fMLP-纳米载体C+A可以减轻炎症相关的病理变化可能是治疗 MS 和 EAE 的潜在治疗策略。