A BBB-permeable neurotrophic polysaccharide, midi-GAGR

已经进行了巨大的努力来寻找用于治疗以下疾病的有效治疗剂： 神经退行性疾病如阿尔茨海默氏病，而改善疾病的治疗 尚未找到。与传统治疗相比，神经营养肽似乎 能够通过再生神经元结构和增加神经元数量来减缓神经变性 生存然而，短的血浆半衰期和差的血脑屏障（BBB）渗透性， 神经营养肽降低它们的体内功效。因此，研究人员寻找了一种 在某些实施方案中，所述神经营养剂是具有较长血浆半衰期和较好BBB渗透性的神经营养剂。最近的研究 表明多糖的一个子集可以保护神经元免受自由基的氧化损伤。 活性自由基和淀粉样肽，提高了它们用于治疗 神经退行性疾病然而，其BBB渗透性未得到证实。这 这种可能性促使我们寻找一种可透过血脑屏障的神经营养多糖。我们的努力 发现了血脑屏障渗透性、神经保护性和神经营养性多糖，midi-GAGR。 Midi-GAGR是低酰基结冷胶的裂解产物，其在人体内具有很少的副作用， 已经被FDA批准用于人类食品添加剂。在我们的研究中，midi-GAGR（1 μ M） 保护啮齿动物皮层神经元免受共处理或后处理的病理浓度的损伤。 处理的自由基和A β 42肽。Midi-GAGR还保护啮齿动物皮质 神经元从激活的小胶质细胞。此外，midi-GAGR显示出强烈的神经营养作用， 它增强了神经突的生长，并增加了磷酸化的cAMP反应性。 元件结合蛋白（pCREB）在原代皮层神经元的核。重要的是，内- 鼻内给药的midi-GAGR通过BBB进入脑，发挥其神经营养作用， 一次给药后，其结构完整性保持>12 h。我们也 发现midi-GAGR与成纤维细胞生长因子受体1（FGFR 1）强烈结合， 神经营养受体综上所述，midi-GAGR是一种很好的候选药物，用于治疗 神经退行性疾病，因为它具有良好的BBB渗透性，强的神经保护作用， 神经营养作用和>12小时血浆半衰期。我们研究的目标是 确定midi-GAGR神经保护和神经营养作用的机制 并检测其在减缓动物神经变性中的功效。这场 研究将为midi-GAGR的临床开发提供坚实的临床前基础。

There have been enormous efforts to find an effective therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease while a disease-modifying treatment is not found yet. Compared to the conventional treatments, neurotrophic peptides appear to be able to slow neurodegeneration by regenerating neuronal structures and increasing neuron survival. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides lower their in vivo efficacy. Thus, researchers have searched for a neurotrophic agent that has longer plasma half-life and better BBB-permeability. Recent studies showed that a subset of polysaccharides could protect neurons from the oxidative insults of free reactive radicals and amyloid peptide, raising the possibility of their use for the treatment of neurodegenerative diseases. However, their BBB-permeability was not demonstrated. This possibility prompted us to search for a BBB-permeable neurotrophic polysaccharide. Our effort discovered the BBB-permeable, neuroprotective, and neurotrophic polysaccharide, midi-GAGR. Midi-GAGR is a cleavage product of low acyl gellan gum that has few side effects in human and is already approved by FDA for human use as food additive. In our study, midi-GAGR (1 M) protected rodent cortical neurons from the pathological concentrations of co-treated or post- treated free reactive radicals and A42 peptide. Midi-GAGR also protected rodent cortical neurons from activated microglial cells. Moreover, midi-GAGR showed a strong neurotrophic property; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Importantly, intra- nasally administered midi-GAGR entered the brain through the BBB, exerted its neurotrophic effects, and maintained its structural intactness for >12 h after one-time administration. We also found that midi-GAGR strongly bound to fibroblast growth factor receptor 1 (FGFR1), a known neurotrophic receptor. Taken together, midi-GAGR is a good drug candidate for the treatment of neurodegenerative diseases since it has good BBB-permeability, strong neuroprotective and neurotrophic effects, and >12 h plasma half-life. The goals of our proposed research are to identify the mechanism underlying the neuroprotective and neurotrophic effects of midi-GAGR and to examine its efficacy in slowing neurodegeneration in animal. The outcome of this research will provide a solid pre-clinical basis for the clinical development of midi-GAGR.