BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR.
BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR.
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DOI：
10.1371/journal.pone.0149715
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Park J
中科院分区：
文献类型：
--
作者：
Makani V;Jang YG;Christopher K;Judy W;Eckstein J;Hensley K;Chiaia N;Kim DS;Park J
为了寻找治疗阿尔茨海默病（AD）等神经退行性疾病的有效药物，人们付出了巨大的努力。其中，再生神经元结构和增加神经元存活的神经营养肽在减缓神经变性方面显示出希望。然而，神经营养肽的血浆半衰期短和血脑屏障（BBB）渗透性差限制了其在体内的疗效。因此，寻找一种具有较长血浆半衰期和更好血脑屏障渗透性的替代神经营养剂。基于最近对神经保护多糖的研究发现，我们在被批准用于人体的天然多糖中寻找一种可渗透血脑屏障的神经保护多糖。然后，我们发现了midi-GAGR，一种可渗透血脑屏障，血浆半衰期长，强神经保护和神经营养的多糖。Midi-GAGR是一种低酰基结冷胶的4.7kD裂解产物，已被FDA批准用于人类。Midi-GAGR不仅可以保护啮齿动物皮层神经元免受共处理/后处理的自由基和Aβ42肽的病理浓度的影响，还可以保护激活的小胶质细胞。此外，中剂量gagr具有良好的神经营养作用；它促进了神经突的生长，增加了初级皮质神经元核中camp反应元件结合蛋白（pCREB）的磷酸化。此外，经鼻内给药的mid - gagr穿透血脑屏障，并在一次给药后24小时内在脑内发挥其神经营养作用。Midi-GAGR似乎激活成纤维细胞生长因子受体1 （FGFR1）及其下游神经营养信号通路，用于神经保护和CREB激活。此外，在3xTg-AD小鼠模型中，14天鼻内给药中- gagr不仅增加了神经元活性标记物，还降低了过度磷酸化的tau（神经原纤维缠结的前体）。综上所示，中- gagr具有血脑屏障通透性好、血浆半衰期长、神经保护和神经营养作用强的特点，在神经退行性疾病尤其是AD的治疗中具有很大的治疗潜力。
An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer’s disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aβ42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD.