NOVEL SYNTHETIC SDG TO TREAT TRAUMA-INDUCED INFLAMMATION

描述(申请人提供)：神经组织损伤是一种常见的临床综合征，具有一系列症状，包括瘫痪、麻木和疼痛。神经根损伤是脊柱损伤、椎管狭窄或椎间盘突出所致神经根病的主要原因。神经根病会导致颈部和下背部疼痛，影响12%-71%的成年人，并造成沉重的经济负担。我们的神经根受压的啮齿动物模型会导致持续性的行为缺陷、沃勒变性和损伤部位的炎症。痛性根压迫可引起局部和脊髓的伤害性和炎症性改变，包括神经肽、生长因子和细胞因子的表达改变，以及神经胶质细胞的激活，巨噬细胞的浸润， 以及神经元的过度兴奋性。尽管神经根病在临床上很常见，但仍然缺乏有效的治疗方法。亚麻籽是一种全谷物，作为一种促进健康的天然产品越来越受欢迎，具有强大的抗氧化和抗炎特性，并含有丰富的抗氧化剂木脂素二葡萄糖苷(SDG)。我们已经证明，膳食SDG配方通过诱导Nrf2和内源性抗氧化反应(EAR)途径来增强内源性抗氧化防御，并显示出强大的抗炎活性。SDG在木脂素提取物制剂中的临床应用正在全球许多临床研究中得到证实。SDG可以穿过血/脑屏障进入中枢神经系统，使其在创伤诱导的炎症背景下具有吸引力。SDG具有促进损伤轴突愈合的潜力，同时也调节已知的与氧化性神经元损伤、炎症和伤害性感受有关的神经炎性级联反应。我们建议评估从香草醛和糖化学合成的SDG作为一种新的生物制剂，因为从全谷物中提取的方法产量低，昂贵得令人望而却步，而且不能产生动物或人类试验所需的量。合成的SDG与天然提取的SDG有显著的抗氧化相似之处。我们假设新的合成SDG既是神经保护性抗氧化剂又是抗炎剂，并通过激活内源性抗氧化途径来减轻创伤相关的神经毒性和炎症。因此，它是一种潜在的促进神经元炎症/氧化损伤愈合的新型生物疗法。拟议研究的主要目标是通过评估炎症和氧化细胞损伤来深入了解SDG作为此类药物的有效性，并阐明其作用机制(S)。目的1研究SDG对野生型和Nrf2/-转基因小鼠体内神经组织损伤和广泛炎症的潜在缓解作用，并与抗炎非甾体抗炎治疗进行比较。目的2采用原代神经元-神经胶质共培养的方法，鉴定SDG调节耳部激活、神经胶质激活和伤害性信号传导的细胞和生物分子机制。研究将确定一种具有高度临床应用潜力的重要的新型生物疗法，以促进神经元愈合，减少炎症，减轻神经创伤后的症状。

DESCRIPTION (provided by applicant): Neural tissue trauma is a common clinical syndrome with a range of symptoms including paralysis, numbness and pain. Nerve root trauma is a leading cause of radiculopathy from spinal injury, stenosis, or disc herniation. Radiculopathy leads to neck and low back pain, which affects between 12-71% of adults, and imposes high financial burdens. Our rodent model of nerve root compression induces persistent behavioral deficits, Wallerian degeneration, and inflammation at the injury site. Painful root compression induces local and spinal nociceptive and inflammatory changes including altered expression of neuropeptides, growth factors, and cytokines, as well as glial activation, macrophage infiltration, and neuronal hyperexcitability. Despite the clinical prevalence of radiculopathy, effective treatments are still lacking. Flaxseed, a wholegrain that has gained increasing popularity as a health-promoting natural product, has potent antioxidant and anti-inflammatory properties and is rich in the antioxidant lignan secoisolariciresinol diglucoside (SDG). We have shown that dietary SDG formulations boost endogenous antioxidant defenses via induction of the Nrf2 and the Endogenous Antioxidant Response (EAR) pathways and exhibit potent anti-inflammatory activity. The clinical utility of SDG in lignan extract formulations is being confirmed in many clinical studies globally. SDG can cross the blood/brain barrier and enter the CNS, making it an attractive candidate in the context of trauma-induced inflammation. SDG has the potential to promote healing of injured axons, while also modulating the neuroinflammatory cascades known to be involved in oxidative neuronal damage, inflammation, and nociception. We propose to evaluate SDG that is chemically synthesized from vanillin and sugar as a novel biologic agent since extraction methods from the wholegrain have low yield, are prohibitively expensive, and are not capable of generating amounts needed for animal or human testing. Synthetic SDG shares remarkable antioxidant similarities to the natural, extracted SDG. We hypothesize that novel synthetic SDG acts as both a neuroprotective antioxidant and anti-inflammatory agent and mitigates trauma-associated neurotoxicity and inflammation by activating endogenous antioxidant pathways. As such, it is a potential novel biologic therapy facilitating healing in neuronal inflammation/oxidative damage. The major goal of proposed studies is to provide insights into the usefulness of SDG as such an agent and to elucidate its mechanism(s) of action by evaluating inflammation and oxidative cell damage. Aim 1 investigates the potential mitigating effects of SDG on neural tissue damage and widespread inflammation in an in vivo model using wild type and Nrf2-/- transgenic mice compared to anti-inflammatory NSAID treatment. Aim 2 uses primary neuronal-glial co-cultures to identify the cellular and biomolecular mechanisms by which SDG modulates EAR activation, glial activation and nociceptive signaling. Studies will identify an important novel biologic therapy with a high degree of potential clinical utility to improve neuronal healing, reduce inflammation and attenuate symptoms after neural trauma.