Acute and Long-Term Benefits of Methylene blue Intervention after TBI on Neuroinflammation, Glial Dysfunction, and Neuropsychiatric Complications

TBI 后亚甲蓝干预对神经炎症、神经胶质功能障碍和神经精神并发症的短期和长期益处

• 批准号: 9512139
• 负责人: Jonathan P Godbout
• 金额: $ 46.67万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9512139
• 关键词: Acute; Address; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Astrocytes; Attenuated; Behavior; Behavioral; Blood - brain barrier anatomy; Chronic; Clinical; Coculture Techniques; Cognition; Cognitive; Craniocerebral Trauma; Data; Deterioration; Development; Diffuse; Dose; Feedback; Functional disorder; Goals; Health; Immune; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Injury; Intervention; Intravenous; Ischemia; Link; Longevity; Mediating; Mental Depression; Messenger RNA; Methylene blue; Microglia; Modeling; Morphology; Mus; Neuroglia; Neurons; Pathology; Phenotype; Process; Protocols documentation; Quality of life; Recovery; Recovery of Function; Secondary to; Sepsis; Sorting - Cell Movement; Syndrome; Techniques; Time; Traumatic Brain Injury; Traumatic Brain Injury recovery; Work; axon growth; axon injury; base; cognitive ability; comparative efficacy; depressive symptoms; experience; fluid percussion injury; glial activation; glial cell development; improved; in vivo; innovation; insight; mRNA Expression; memory recall; myelination; nano-string; negative affect; neuroinflammation; neuropathology; neuroprotection; neuropsychiatry; novel; prevent; relating to nervous system; repaired; response

PROJECT SUMMARY/ABSTRACT: Traumatic brain injury (TBI) leads to secondary neuropsychiatric complications that develop and persist years after injury and negatively affect health span. Mounting evidence indicates that neuroinflammatory processes advance after the initial head injury and worsen with time. The ongoing inflammatory processes after TBI are mediated by microglia and astrocytes. In fact, these glia are the primary inflammatory responders to the injury. Therefore, it is important to identify interventions that can be provided immediately after TBI to reduce glial- mediated inflammation and facilitate recovery. It is also critical that immediate interventions prevent the development of TBI-related long-term complications in behavior, cognition, and pathology. New data are provided to show that immediate intervention with methylene blue (MB), an antioxidant and anti-inflammatory agent, reduces neuroinflammation in mice after moderate and diffuse TBI, improves functional recovery, and limits the development of primed and reactive microglia 1 month after injury. Development of a primed microglial phenotype is relevant because it represents an increased state of inflammation. These primed glia are highly reactive to subsequent immune challenges, which trigger the development of neuropsychiatric complications. Overall, we show that there are both acute and long-term benefits of immediate MB intervention after TBI. MB is used clinically in sepsis, ischemia, and vasoplegic syndrome but it has not been used clinically for TBI. MB is safe, crosses the blood brain barrier, and is administered intravenously. Therefore, our goal is to determine the degree to which MB intervention shifts the activation profile of microglia and astrocytes and protects against secondary complications following TBI including cognitive decline, glia-mediated inflammation, and glial reactivity to immune challenge. To address this, three objectives are proposed using a midline fluid percussion injury model of TBI in mice. In Aim-1 we will ascertain if MB intervention after TBI promotes a neuroprotective “repair” profile of microglia and astrocytes. We will use unique approaches to determine the effects of TBI and MB intervention specifically on microglia and astrocyte mRNA expression, morphological profiles, and ex vivo interactions with neurons. In Aim-2 we will determine if MB intervention (immediate or delayed) prevents or reverses glia-mediated inflammation and cognitive deterioration months after TBI. Cognitive ability will be assessed for 6 m after TBI. Parallel to these assessments, glial inflammatory states and associated axonal injury and myelination changes will be determined 1, 3, and 6 m after TBI. In Aim-3, we will determine if immediate MB intervention prevents TBI-induced immune-reactivity of microglia and the development of neuropsychiatric complications. To address this, mice will receive an immune challenge 1 m after TBI and glial profiles and depressive-like behavior will be determined. Collectively, completion of these aims will provide new insight into TBI-induced glial priming and immune-reactivity and will address the efficacy and long-term benefit of methylene blue intervention.

项目总结/摘要： 创伤性脑损伤（TBI）导致继发性神经精神并发症， 受伤后，对健康产生负面影响。越来越多的证据表明神经炎症过程 在最初的头部损伤后进展，并随着时间的推移而恶化。TBI后持续的炎症过程是 由小胶质细胞和星形胶质细胞介导。事实上，这些神经胶质细胞是对损伤的主要炎症反应。 因此，重要的是要确定可以在TBI后立即提供的干预措施，以减少胶质细胞， 介导炎症并促进恢复。同样至关重要的是，立即采取干预措施， 在行为、认知和病理学方面发生TBI相关的长期并发症。新数据 提供了一种抗氧化剂和抗炎剂亚甲蓝（MB）的即时干预， 药物，减轻中度和弥漫性TBI后小鼠的神经炎症，改善功能恢复， 限制了损伤后1个月引发和反应性小胶质细胞的发育。开发一种引发 小胶质细胞表型是相关的，因为它代表了炎症的增加状态。这些神经胶质细胞 对随后的免疫挑战具有高度反应性，从而引发神经精神疾病的发展。 并发症总体而言，我们表明，立即进行MB干预既有急性益处，也有长期益处 脑外伤后。MB在临床上用于脓毒症、缺血和血管麻痹综合征，但尚未用于临床 对于TBI。MB是安全的，可以穿过血脑屏障，并通过静脉注射给药。因此，我们的目标是 以确定MB干预改变小胶质细胞和星形胶质细胞活化特征的程度， 防止TBI后的继发性并发症，包括认知能力下降，神经胶质介导的炎症， 和神经胶质对免疫攻击的反应性。为了解决这个问题，提出了三个目标，使用中线流体 撞击伤模型。在Aim-1中，我们将确定创伤性脑损伤后MB干预是否会促进 小胶质细胞和星形胶质细胞的神经保护性“修复”特征。我们将使用独特的方法来确定 TBI和MB干预对小胶质细胞和星形胶质细胞mRNA表达、形态学 概况以及与神经元的离体相互作用。在目标-2中，我们将确定是否进行MB干预（立即或 延迟）预防或逆转胶质介导的炎症和TBI后数月的认知退化。 认知能力将在TBI后6个月进行评估。与这些评估平行，神经胶质炎症状态 并在TBI后1、3和6 m确定相关的轴突损伤和髓鞘形成变化。在目标3中，我们 将确定是否立即MB干预防止TBI诱导的小胶质细胞的免疫反应性， 神经精神并发症的发展。为了解决这个问题，小鼠将接受免疫挑战1 m TBI后，将确定神经胶质特征和抑郁样行为。总的来说，完成这些 目的将提供新的洞察TBI诱导的神经胶质启动和免疫反应性，并将解决疗效 以及亚甲蓝干预的长期益处。