Heparin mimetics: Novel non-anticoagulant compounds to promote CNS repair.

众所周知，大脑和脊髓（统称为中枢神经系统; CNS）的损伤很难修复。在诸如多发性硬化症的疾病中，神经过程失去其保护性绝缘包裹（变得“脱髓鞘”，导致神经信号传导错误）并且在组织中形成瘢痕（称为“星形胶质细胞增生”，其阻止神经再生）。目前的治疗方法往往只关注引起损伤的免疫反应的改变，而不关注其他组织的变化。修复是多因素的，非常复杂，需要抑制免疫反应和瘢痕组织形成，以及促进再绝缘（髓鞘形成）和神经生长。位于损伤部位周围的专门的糖分子，称为硫酸乙酰肝素（HS），对修复所需的许多细胞功能进行调节。HS在其表面上具有不同的硫酸基团模式，凭借它们在分子上的数量和位置，可以使神经细胞执行不同类型的功能。为了研究HS如何工作，我们使用称为肝素模拟物（mHeps）的HS化学模拟物。这些mHep是血液稀释药物肝素的改良形式，但可以通过改变硫酸基团的数量和位置来化学制备。在皮氏培养皿中使用几种测定，我们发现具有少量硫酸盐基团的mHep促进髓鞘再生、神经突起生长并抑制瘢痕形成反应。我们也有一些证据表明，它们可以在疾病的动物模型中产生有益的影响，特别是促进髓鞘再生，调节免疫反应以及一般健康（动物体重减轻较少）。出于这个原因，我们现在的目标是使用脱髓鞘的动物模型对低硫酸化mHep的修复功效进行详细的实验。我们的目的是：i）确认mHep 7的剂量、浓度和最佳分子量形式。ii）确认mHep 7（比较两种MW形式）可以促进经典地用于研究CNS损伤的两种临床前动物模型中的修复的初步数据。它们的作用机制），重点是免疫反应（它可以进入中枢神经系统和损伤细胞），体重增加（mHep似乎促进中枢神经系统修复，动物看起来更健康，体重减轻较少）和血脑屏障（BBB）的完整性。血脑屏障阻止血液中的物质进入大脑。在疾病中，这可能是泄漏的，并允许免疫系统进入大脑，这可能是有害的。总体而言，我们的目标是表明，低硫酸化mHep是潜在的新药物，通过对损伤/疾病后诱导的几个关键细胞特性具有多模式效应，以促进CNS修复。

Damage to the brain and spinal cord (together known as the central nervous system; CNS) is notoriously difficult to repair. In a disease such as multiple sclerosis damage occurs in which nerve processes lose their protective insulation wrapping (becoming "demyelinated", leading to faulty nerve signalling) and scarring forms in the tissue (called "astrogliosis", which prevents nerve regrowth). Current therapeutics tend to focus solely on altered immune responses, which cause damage, but not on other tissue changes. Repair is multifactorial and very complex, requiring a damping down of the immune response and scar tissue formation, as well as the promotion of re-insulation (myelination) and nerve outgrowth. Specialised sugar molecules that reside around the injury site, known as heparan sulphates (HS), carry out the regulation of many cellular functions required for repair. HS has varied patterns of sulphate groups on their surface, which by virtue of their number and position on the molecule can make neural cells carry out different types of functions. To study how HS works, we use chemical mimics of HS called heparin mimetics (mHeps). These mHeps are modified forms of the blood-thinning drug heparin but can be made chemically with altered amounts and positions of the sulphate groups. Using several assays in a Petri dish we have found that mHeps with a low number of sulphate groups promote remyelination, nerve process outgrowth and dampen down the scarring reactions. We also have some evidence that they can have a beneficial effect in animal models of disease, especially promoting remyelination, modulation of the immune response as well as general health (with less animal weight loss). For this reason, we now aim to carry out detailed experiments on the repair efficacy of a low sulphated mHep using an animal model of demyelination. We aim to:i) Confirm dosage, concentration and optimal molecular weight form of mHep7.ii) Confirm preliminary data that mHep7 (comparing two MW forms) can promote repair in two pre-clinical animal models classically used to study CNS injury.iii) Identify how the compounds work (ie. their mechanism-of-action), focusing on the immune response (which can enter the CNS and damage cells), weight gain (mHeps appear to promote CNS repair and animals appear healthier with less weight loss) and the integrity of the blood-brain barrier (BBB). The BBB prevents materials from the blood entering the brain. In disease, this can be leaky and allow the immune system to enter the brain, which can be harmful.Overall we aim to show that low sulphated mHeps are potential new drugs to promote CNS repair by having a multi-modal effect on several key cellular properties induced after injury/disease.