BDNF agonist treatment in experimental allergic encephalomyelitis

BDNF 激动剂治疗实验性过敏性脑脊髓炎

• 批准号: 8815000
• 负责人: CHRISTOPHER T BEVER
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815000
• 关键词: Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Blood - brain barrier anatomy; Bone Marrow Stem Cell; Brain; Brain-Derived Neurotrophic Factor; Cells; Clinical; Complement; Demyelinations; Disease; Dose; Experimental Autoimmune Encephalomyelitis; Genetic Engineering; Half-Life; Health; Immune; Immunity; Infarction; Inflammation; Inflammatory; Injury; Kainic Acid; Knock-in Mouse; Lesion; Mediating; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; NF-kappa B; Nerve Degeneration; Neurologic; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Penetration; Play; Progress Reports; Property; Recovery of Function; Reporting; Role; Serum; Services; Severities; Severity of illness; Signal Transduction; Stroke; Subfamily lentivirinae; Symptoms; System; Testing; Time; Veterans; base; brain cell; care seeking; cytokine; design; disability; neuron apoptosis; neuron loss; neurotoxicity; prevent; protective effect; treatment strategy; young adult

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is characterized pathologically by inflammation and neurodegeneration. Because current treatments for MS, which are immune modulators, do not prevent neuronal loss and disability, neuroprotective treatments have been sought. Brain derived neurotrophic factor (BDNF) is a phleotrophic cytokine with neuroprotective properties that has been studied as a potential treatment. In an animal model of MS, experimental allergic encephalomyelitis (EAE), BDNF is produced by immune cells and is responsible for reducing axonal loss. BDNF is present in MS lesions and may play a protective role in lesion pathogenesis. Studies of exogenously administered BDNF have been limited by its short serum half-life and poor blood brain barrier (BBB) penetration so we conducted studies using genetically engineered bone marrow stem cells to deliver BDNF in EAE. BDNF reduced inflammation and neurodegeneration and our observations have been confirmed by Linker et al (4) using a lentivirus delivery system. Together these studies suggest that BDNF treatment reduces inflammation and neurodegeneration in EAE. In 2010 Jang et al. reported that 7,8-dihydroxyflavone (DHF) has potent BDNF agonist activity, can be given orally and readily crosses the BBB. In cultured neurons it activated the receptor for BDNF, TrkB, and downstream signaling. It protected wild-type, but not TrkB-deficient neurons from apoptosis. DHF activated TrkB in the mouse brain, inhibited kainic acid-induced neurotoxicity, decreased infarct volumes in experimental murine stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson's disease. Not all DHF effects are TrkB dependent: DHF has anti-inflammatory activity that is NFKB dependent and antioxidant effects that could reduce inflammatory injury. We tested DHF in MOG-induced EAE in C57Bl/6 mice and showed that treatment resulted in reduced clinical and pathological severity even when treatment was delayed until the onset of symptoms. Together these results support further studies of DHF as a possible treatment for MS. Based on the results outlined above, there are at least four possible mechanisms through with DHF could reduce the severity of EAE: It could reduce inflammatory injury through its antioxidant activity, i could reduce inflammation through a non-TrkB mediated pathway, it could reduce inflammation through a TrkB mediated effect on inflammatory cells or it could have a direct TrkB mediated protective effect on neuronal cells. We propose the following Primary Hypothesis: DHF treatment of MOG-induced EAE in C57Bl/6 mice reduces the clinical and pathological severity of disease. We propose the following Secondary Hypothesis: DHF treatment of MOG-induced EAE in C57Bl/6 mice reduces disease severity by a TrkB dependent mechanism. We will test these hypotheses by completing the following specific aims: Specific Aim #1: Optimize DHF dosing of C57Bl/6 mice with MOG-induced EAE. Specific Aim #2: Determine the effect of DHF treatment started at the time of symptom onset on CNS inflammation, immunity, demyelination, axonal loss and apoptosis in the MOG-induced EAE in C57Bl/6 mice. Specific Aim #3: Determine the effect of DHF treatment started on day 50 on CNS inflammation, immunity, demyelination, axonal loss and apoptosis in MOG-induced EAE in C57Bl/6 mice. Specific Aim #4: Determine whether the effect of DHF in MOG-induced EAE in C57Bl/6 mice is TrkB dependent by determining the sensitivity of the TrkBF616A knock-in C57Bl/6 mouse to the effects of DHF in mice with and without functioning TrkB. Confirming our hypotheses will provide important new information about the effects of DHF treatment in a model of MS and could provide a rationale for studies of DHF in MS patients.

描述（由申请人提供）： 多发性硬化症（MS）的病理特征是炎症和神经变性。由于目前多发性硬化症的治疗方法是免疫调节剂，不能防止神经元损失和残疾，因此人们一直在寻求神经保护治疗。脑源性神经营养因子（BDNF）是一种具有神经保护特性的嗜热细胞因子，已被研究作为一种潜在的治疗方法。在多发性硬化症、实验性过敏性脑脊髓炎 (EAE) 动物模型中，BDNF 由免疫细胞产生，负责减少轴突损失。 BDNF 存在于 MS 病变中，可能在病变发病机制中发挥保护作用。外源性施用 BDNF 的研究因其血清半衰期短和血脑屏障 (BBB) 渗透性差而受到限制，因此我们使用基因工程骨髓干细胞在 EAE 中递送 BDNF 进行了研究。 BDNF 减少炎症和神经退行性变，Linker 等人 (4) 使用慢病毒递送系统证实了我们的观察结果。这些研究共同表明 BDNF 治疗可减少 EAE 中的炎症和神经退行性变。 2010 年，Jang 等人。据报道，7,8-二羟基黄酮 (DHF) 具有有效的 BDNF 激动剂活性，可以口服且易于穿过 BBB。在培养的神经元中，它激活 BDNF、TrkB 和下游信号传导的受体。它可以保护野生型神经元免于凋亡，但不能保护 TrkB 缺陷型神经元。 DHF 激活小鼠大脑中的 TrkB，抑制红藻氨酸诱导的神经毒性，以 TrkB 依赖性方式减少实验性小鼠中风中的梗塞体积，并对帕金森病动物模型具有神经保护作用。并非所有 DHF 作用都依赖于 TrkB：DHF 具有依赖 NFKB 的抗炎活性和可以减少炎症损伤的抗氧化作用。我们在 C57Bl/6 小鼠中测试了 MOG 诱导的 EAE 中的 DHF，结果表明，即使治疗延迟到症状出现，治疗也能减轻临床和病理严重程度。这些结果共同支持了 DHF 作为 MS 可能治疗方法的进一步研究。 基于上述结果，DHF 至少有四种可能的机制可以减轻 EAE 的严重程度：它可以通过其抗氧化活性减少炎症损伤，可以通过非 TrkB 介导的途径减少炎症，它可以通过 TrkB 介导的对炎症细胞的作用减少炎症，或者它可以对神经元细胞产生直接的 TrkB 介导的保护作用。我们提出以下主要假设：C57Bl/6 小鼠中 MOG 诱导的 EAE 的 DHF 治疗可降低疾病的临床和病理严重程度。我们提出以下次要假设：C57Bl/6 小鼠中 MOG 诱导的 EAE 的 DHF 治疗可通过 TrkB 依赖性机制降低疾病严重程度。我们将通过完成以下具体目标来测试这些假设：具体目标#1：优化 MOG 诱导的 EAE 的 C57Bl/6 小鼠的 DHF 剂量。具体目标#2：确定症状出现时开始的 DHF 治疗对 C57Bl/6 小鼠 MOG 诱导的 EAE 中中枢神经系统炎症、免疫、脱髓鞘、轴突丢失和细胞凋亡的影响。 具体目标#3：确定第 50 天开始的 DHF 治疗对 C57Bl/6 小鼠 MOG 诱导的 EAE 中 CNS 炎症、免疫、脱髓鞘、轴突丢失和细胞凋亡的影响。 具体目标#4：通过确定 TrkBF616A 敲入 C57Bl/6 小鼠对具有或不具有 TrkB 功能的小鼠中 DHF 影响的敏感性，确定 DHF 对 C57Bl/6 小鼠 MOG 诱导的 EAE 的影响是否依赖于 TrkB。 证实我们的假设将提供有关 DHF 治疗在 MS 模型中的作用的重要新信息，并可为 MS 患者的 DHF 研究提供依据。