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: 8634855
• 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/8634855
• 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; 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; public health relevance; treatment strategy; young adult

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, it 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.

多发性硬化症（MS）在病理上以炎症和神经变性为特征。因为 当前对免疫调节剂MS的治疗方法不会预防神经元丧失和残疾， 已寻求神经保护疗法。脑衍生的神经营养因子（BDNF）是嗜营养素 具有神经保护特性的细胞因子已被研究为潜在治疗。在动物模型中 MS，实验性过敏性脑脊髓炎（EAE），BDNF由免疫细胞产生，并负责 减少轴突损失。 BDNF存在于MS病变中，可能在病变发病机理中起保护作用。 外源施用BDNF的研究受到其短血清半衰期和血液差的限制 障碍物（BBB）穿透，因此我们使用基因设计的骨髓干细胞进行了研究 在EAE中交付BDNF。 BDNF减少了炎症和神经变性，并且我们的观察已经 Linker等人（4）使用慢病毒递送系统确认。这些研究一起表明BDNF 治疗减少EAE中的炎症和神经退行性。 在2010年Jang等。报道7,8-二羟基氟烷（DHF）具有有效的BDNF激动剂活动，可以是 口服并容易跨越BBB。在培养的神经元中，它激活了BDNF，TRKB和 下游信号传导。它保护了野生型，但不能保护TRKB缺陷型神经元免受凋亡。 DHF激活 小鼠脑中的TRKB抑制了海藻酸诱导的神经毒性，在实验中减少了梗塞体积 以TRKB依赖性的方式鼠中风，并且在帕金森氏症动物模型中具有神经保护作用 疾病。并非所有DHF效应都依赖于TRKB：DHF具有依赖NFKB的抗炎活性 以及可能减少炎症损伤的抗氧化作用。我们在MOG诱导的C57BL/6中测试了DHF 小鼠并表明治疗也会导致临床和病理严重程度降低 被推迟到症状发作。这些结果共同支持了DHF的进一步研究 MS的治疗。 根据上面概述的结果，DHF至少有四种可能的机制 降低EAE的严重程度：它可以通过其抗氧化活性来减少炎症性损伤，可以减少 通过非TRKB介导的途径发炎，它可以通过TRKB介导的炎症来减少炎症 对炎症细胞的影响，或者可能对神经元细胞具有直接的TRKB介导的保护作用。我们 提出以下主要假设：DHF治疗MOG诱导的C57BL/6小鼠的EAE会减少 疾病的临床和病理严重程度。我们提出以下次要假设：DHF MOG诱导的C57BL/6小鼠的EAE的处理可通过TRKB依赖机制降低疾病的严重程度。 我们将通过完成以下特定目标来检验这些假设： 特定目标＃1：用MOG诱导的EAE优化C57BL/6小鼠的DHF剂量。 特定目的＃2：确定症状发作时启动DHF治疗的影响 C57BL/6小鼠中MOG诱导的EAE的炎症，免疫，脱髓鞘，轴突丧失和凋亡。 特定目的＃3：确定DHF治疗的影响在第50天开始对中枢神经系统发炎，免疫力， MOG诱导的C57BL/6小鼠中MOG诱导的EAE的脱髓鞘，轴突丢失和凋亡。 特定目标＃4：确定DHF在MOG诱导的C57BL/6小鼠中的效果是否为TRKB 通过确定TRKBF616A敲入C57BL/6小鼠对DHF对小鼠的影响的敏感性来依赖 具有和不运行trkb。 确认我们的假设将提供有关DHF治疗在A中影响的重要新信息 MS的模型，可以为MS患者的DHF研究提供基本原理。