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NOVEL SYNTHETIC SDG TO TREAT TRAUMA-INDUCED INFLAMMATION

治疗创伤引起的炎症的新型合成 SDG

基本信息

批准号：
8984869
负责人：
Melpo Christofidou-Solomidou
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984869
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 Models Biological Response Modifier Therapy Blood - brain barrier anatomy Botanicals Cells Clinical Clinical Research Coculture Techniques Development Diet Engineering Ensure Environment Etiology Exhibits Flax Formulation GLAST Protein Gene Expression Gene Proteins Glial Fibrillary Acidic Protein Glutamate Transporter Goals Growth Healed Health Human Hypersensitivity Immunoblotting In Vitro Infiltration Inflammation Inflammatory Injury Lignans Low Back Pain Measures Methodology Methods Microglia Modeling Mus Natural Products 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 glial activation glutamatergic signaling healing improved in vivo in vivo Model injured insight macrophage mouse model neuroinflammation neuroprotection neurotoxicity neurotransmission novel oxidative damage pain symptom prevent receptor relating to nervous system response secoisolariciresinol success sugar tissue trauma transcription factor vanillin

项目摘要

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（由申请人提供）：神经组织创伤是一种常见的临床综合征，其症状包括麻痹、麻木和疼痛。神经根创伤是脊髓损伤、椎管狭窄或椎间盘突出引起神经根病的主要原因。神经根病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。我们的啮齿动物神经根压迫模型会导致持续的行为缺陷、沃勒氏变性和损伤部位的炎症。疼痛的根受压会引起局部和脊柱的伤害和炎症改变，包括神经肽、生长因子和细胞因子的表达改变，以及神经胶质活化、巨噬细胞浸润、