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）的病理特征是炎症和神经变性。因为 目前用于MS的治疗是免疫调节剂，不能预防神经元损失和残疾， 一直在寻求神经保护治疗。脑源性神经营养因子（脑源性神经营养因子）是一种静脉营养因子 具有神经保护特性的细胞因子，已被研究为潜在的治疗方法。的动物模型中 MS，实验性变态反应性脑脊髓炎（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，并可能在病变发病机制中起保护作用。 外源性给予BDNF的研究受到其血清半衰期短和血脑功能差的限制 因此，我们使用基因工程骨髓干细胞进行研究， 在EAE中递送BDNF。BDNF减少炎症和神经退行性变，我们的观察结果表明， Linker等人（4）使用慢病毒递送系统证实。这些研究表明，BDNF 治疗减少了EAE中的炎症和神经变性。 2010年，Jang等报道了7，8-二羟基黄酮（DHF）具有有效的BDNF激动剂活性，可用于治疗脑源性神经营养不良。 口服给药并容易穿过BBB。在培养的神经元中，它激活了BDNF受体，TrkB， 下行信号。它可以保护野生型神经元免受细胞凋亡，但不能保护TrkB缺陷神经元免受细胞凋亡。DHF已激活 TrkB在小鼠脑中，抑制海人酸诱导的神经毒性，减少实验性脑梗死体积， 在帕金森病动物模型中具有神经保护作用 疾病并非所有DHF效应都是TrkB依赖性的：DHF具有NF κ B依赖性的抗炎活性 和抗氧化作用，可以减少炎症损伤。我们在C57 B1/6小鼠中检测了DHF在MOG诱导的EAE中的作用 并显示治疗导致临床和病理学严重程度降低，即使治疗 直到症状出现才被发现总之，这些结果支持DHF的进一步研究， 治疗MS。 根据上述结果，DHF至少有四种可能的机制， 减轻EAE的严重程度：它可以通过其抗氧化活性减轻炎症损伤， 通过非TrkB介导的途径减少炎症，它可以通过TrkB介导的途径减少炎症。 它可以对炎性细胞具有直接的TrkB介导的保护作用，或者它可以对神经元细胞具有直接的TrkB介导的保护作用。我们 我提出了以下初步假设：DHF治疗C57 Bl/6小鼠MOG诱导的EAE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：DHF 在C57 B1/6小鼠中治疗MOG诱导的EAE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：优化患有MOG诱导EAE的C57 Bl/6小鼠的DHF给药。 具体目标#2：确定症状发作时开始DHF治疗对CNS的影响 炎症、免疫、脱髓鞘、轴突损失和细胞凋亡在MOG诱导的C57 B1/6小鼠EAE中的作用。 具体目标#3：确定第50天开始DHF治疗对CNS炎症、免疫力 在C57 B1/6小鼠中MOG诱导的EAE中的脱髓鞘、轴突损失和细胞凋亡。 具体目标#4：确定DHF在C57 Bl/6小鼠中MOG诱导的EAE中的作用是否为TrkB 通过测定TrkBF 616 A敲入C57 B1/6小鼠对DHF在小鼠中的作用的敏感性， 有和没有TrkB功能。 证实我们的假设将提供有关DHF治疗在一个特定疾病中的作用的重要新信息。 MS的模型，并可以提供的理由，DHF在MS患者的研究。