NOVEL SYNTHETIC SDG TO TREAT TRAUMA-INDUCED INFLAMMATION

治疗创伤引起的炎症的新型合成 SDG

• 批准号: 8824322
• 负责人: Melpo Christofidou-Solomidou
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824322
• 关键词: Adult; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Astrocytes; Attenuated; Axon; Back; Behavioral; Biochemical; Biocompatible Materials; Biological Assay; Biological Factors; Biological Models; Biological Response Modifier Therapy; Blood - brain barrier anatomy; Botanicals; Cells; Clinical; Clinical Research; Coculture Techniques; Cytokine Activation; Development; Diet; Drug Formulations; Engineering; Ensure; Environment; Etiology; Exhibits; Flax; GLAST Protein; Gene Expression; Gene Proteins; Glial Fibrillary Acidic Protein; Glutamate Transporter; Goals; Growth Factor; Healed; Health; Human; Hypersensitivity; Immunoblotting; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Lignans; Low Back Pain; Macrophage Activation; Measures; Methodology; Methods; Microglia; Modeling; Mus; Neck; Neck Pain; Nerve; Nerve Degeneration; Nerve Regeneration; Nerve Root Compressions; Neuraxis; Neuroglia; Neuronal Injury; Neurons; Neuropeptides; Nociception; Non-Steroidal Anti-Inflammatory Agents; Numbness; Oral; Outcome; Oxidative Stress; Pain; Paralysed; Pathology; Pathway interactions; Plant Roots; Population; Prevalence; Property; Public Health; Radiculopathy; Reactive Oxygen Species; Research Design; Response Elements; Rodent Model; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Ganglia; Spinal Injuries; Spinal cord injury; Spondylosis; Stenosis; Stimulus; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transgenic Mice; Trauma; Wallerian Degeneration; Western Blotting; Wild Type Mouse; addiction; cell injury; cytokine; disability; effective therapy; experience; glutamatergic signaling; healing; improved; in vivo; in vivo Model; injured; insight; mouse model; neuroinflammation; neuroprotection; neurotoxicity; neurotransmission; novel; oxidative damage; prevent; public health relevance; receptor; relating to nervous system; response; secoisolariciresinol; success; sugar; tissue trauma; transcription factor; vanillin

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.

描述（申请人提供）：神经组织创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。神经根创伤是脊柱损伤、狭窄或椎间盘突出引起的神经根病的主要原因。神经根病会导致颈部和腰痛，影响 12-71% 的成年人，并带来沉重的经济负担。我们的神经根受压啮齿动物模型会导致持续的行为缺陷、沃勒变性和损伤部位的炎症。疼痛的根部压迫会引起局部和脊髓伤害性和炎症变化，包括神经肽、生长因子和细胞因子表达的改变，以及神经胶质活化、巨噬细胞浸润、 和神经元过度兴奋。尽管神经根病临床普遍存在，但仍然缺乏有效的治疗方法。亚麻籽是一种全谷物，作为促进健康的天然产品越来越受欢迎，具有有效的抗氧化和抗炎特性，并且富含抗氧化剂木酚素开环异落叶松树脂醇二葡萄糖苷 (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) 途径增强内源性抗氧化防御，并表现出有效的抗炎活性。 SDG 在木酚素提取物制剂中的临床效用已在全球许多临床研究中得到证实。 SDG 可以穿过血/脑屏障并进入中枢神经系统，使其成为治疗创伤引起的炎症的有吸引力的候选者。 SDG 具有促进受损轴突愈合的潜力，同时还可以调节已知与氧化神经元损伤、炎症和伤害感受有关的神经炎症级联反应。我们建议评估由香草醛和糖化学合成的 SDG 作为一种新型生物制剂，因为从全谷物中提取的方法产量低，价格昂贵，并且无法产生动物或人体测试所需的量。合成 SDG 与天然提取的 SDG 具有显着的抗氧化相似性。我们假设新型合成 SDG 既可以作为神经保护性抗氧化剂又可以作为抗炎剂，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，它是一种潜在的新型生物疗法，有助于神经元炎症/氧化损伤的愈合。拟议研究的主要目标是深入了解 SDG 作为此类药物的有用性，并通过评估炎症和氧化细胞损伤来阐明其作用机制。目标 1 在使用野生型和 Nrf2-/- 转基因小鼠的体内模型中，与抗炎 NSAID 治疗相比，研究 SDG 对神经组织损伤和广泛炎症的潜在缓解作用。目标 2 使用原代神经元-胶质细胞共培养物来鉴定 SDG 调节 EAR 激活、胶质细胞激活和伤害性信号传导的细胞和生物分子机制。研究将确定一种重要的新型生物疗法，具有高度潜在的临床实用性，可改善神经元愈合、减少炎症和减轻神经损伤后的症状。