Neuroinflammation and Glial ROS in Methamphetamine Neurotoxicity

甲基苯丙胺神经毒性中的神经炎症和胶质细胞活性氧

• 批准号: 7587112
• 负责人: M. KERRY O'BANION
• 金额: $ 33.72万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587112
• 关键词: Address; Adverse effects; Antioxidants; Applications Grants; Astrocytes; Behavioral; Biochemical; Blood; Bone Marrow; Brain Injuries; C57BL/6 Mouse; Cells; Central Nervous System Diseases; Chimera organism; Corpus striatum structure; Correlative Study; Data; Disease; Disease model; Dopamine; Dose; Drops; Drug usage; Encephalitis; Enzymes; Evaluation; Functional disorder; Genes; HIV; HIV Infections; HIV encephalitis; Health; Histologic; Illicit Drugs; Immunohistochemistry; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1; Interleukins; Measures; Messenger RNA; Methamphetamine; Microglia; Midbrain structure; Motor Activity; Mus; NADPH Oxidase; Nerve; Neurologic; Neuronal Injury; Neurons; Outcome; Oxidants; Oxidative Stress; Peripheral; Process; Production; Proteins; Protocols documentation; Reaction; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Rodent Model; Role; Signal Transduction; Substantia nigra structure; Symptoms; System; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Viral Vector; Work; attenuation; base; central nervous system injury; chemokine; cytokine; dopaminergic neuron; driving force; drug abuser; indexing; macrophage; methamphetamine abuse; methamphetamine exposure; monocyte; mouse model; neuroinflammation; neuronal cell body; neuropathology; neurotoxicity; nigrostriatal system; primary outcome; receptor; repaired; research study; response

Neurological symptoms with methamphetamine (METH) toxicity of the nigrostriatal system, both in rodent models and in drug abusers, are associated with neuroinflammation, a fundamental reaction to brain injury characterized by activated microglia and astrocytes, local expression of inflammatory mediators, and possible infiltration of peripheral cells such as monocytes. This prominent and local tissue response most likely represents an adaptive and restorative repair process. Yet reminiscent of many inflammatory conditions in peripheral diseases, neuroinflammation can also contribute to the pathophysiology of CNS disorders. Thus observations of neuroinflammation in the setting of METH neurotoxicity raise questions about the contribution of glial directed inflammation to neuronal damage as well as the possible mechanisms underlying this association. One such mechanism is oxidative stress, which is known to occur in both METH toxicity and neuroinflammation. Among HIV infected individuals, METH abuse is associated with significant enhancement of HIV encephalitis, greater neuropathology, and increased expression of inflammation-associated genes. Thus neuroinflammation represents a factor common to both METH exposure and CNS HIV infection that may underlie the enhanced disease and neuropathology seen when these two risk factors coexist. One of the major driving forces in CNS inflammation is the proinflammatory cytokine interleukin (IL)-1β, which is produced by activated microglia. Among its many actions, IL-1β promotes phenotypic activation of astrocytes leading to expression of other inflammatory mediators including chemokines, which facilitate CNS infiltration by monocytes and other blood-borne cells. Moreover, there is clear evidence that IL-1 is an important contributor to neuronal damage in several CNS injury and disease models. We have recently developed a transgenic mouse model that provides temporal and spatial control of sustained IL-1β expression. We propose using this mouse to test the hypothesis that coexistent neuroinflammation enhances METH-induced damage in the ventral midbrain dopaminergic system. A corollary hypothesis is that attenuation of neuroinflammation will protect against METH neurotoxicity. Finally, we hypothesize that one mechanism underlying the association between neuroinflammation and METH toxicity is production of microglial/ macrophage derived reactive oxygen species (ROS). To explore these hypotheses, we will: 1) quantify striatal dopaminergic nerve terminal toxicity elicited by METH exposure in the presence of sustained neuroinflammation; 2) determine whether abrogation of IL-1 signaling reduces neurotoxicity following METH exposure, and 3) characterize oxidant injury in METH and METH + neuroinflammation elicited neurotoxicity. By better understanding the role of neuroinflammation in METH-associated neurotoxicity, we may be able to develop strategies to curb the neurological side effects of METH abuse, particularly when associated with conditions like HIV where neuroinflammation is prominent.

在啮齿动物模型和药物滥用者中，黑质纹状体系统的甲基苯丙胺（METH）毒性的神经症状与神经炎症相关，神经炎症是对脑损伤的基本反应，其特征在于活化的小胶质细胞和星形胶质细胞、炎症介质的局部表达以及外周细胞（如单核细胞）的可能浸润。这种突出的局部组织反应很可能代表了适应性和恢复性修复过程。然而，与外周疾病中的许多炎性病症类似，神经炎症也可促成CNS病症的病理生理学。因此，在METH神经毒性环境中观察到的神经炎症引起了关于神经胶质定向炎症对神经元损伤的贡献以及这种关联的可能机制的问题。其中一种机制是氧化应激，这是已知的发生在METH毒性和神经炎症。在HIV感染者中，METH滥用与HIV脑炎的显著增强、更严重的神经病理学和炎症相关基因的表达增加有关。因此，神经炎症是METH暴露和CNS HIV感染的共同因素，可能是这两种危险因素共存时所见的增强的疾病和神经病理学的基础。CNS炎症的主要驱动力之一是由活化的小胶质细胞产生的促炎细胞因子白细胞介素（IL）-1β。在其许多作用中，IL-1β促进星形胶质细胞的表型活化，导致其他炎性介质（包括趋化因子）的表达，其促进单核细胞和其他血源性细胞的CNS浸润。此外，有明确的证据表明，IL-1是一个重要的贡献者在几个中枢神经系统损伤和疾病模型的神经元损伤。我们最近开发了一种转基因小鼠模型，可提供持续IL-1β表达的时间和空间控制。我们建议使用这只小鼠来测试共存的神经炎症增强腹侧中脑多巴胺能系统的MET诱导的损伤的假设。一个必然的假设是，神经炎症的衰减将防止METH神经毒性。最后，我们假设神经炎症和METH毒性之间相关的一种机制是产生小胶质细胞/巨噬细胞衍生的活性氧（ROS）。为了探索这些假设，我们将：1）量化在持续神经炎症存在下由METH暴露引起的纹状体多巴胺能神经末梢毒性; 2）确定IL-1信号传导的消除是否降低METH暴露后的神经毒性，和3）表征METH和METH +神经炎症引起的神经毒性中的氧化损伤。通过更好地了解神经炎症在METH相关神经毒性中的作用，我们可能能够制定策略来抑制METH滥用的神经副作用，特别是当与神经炎症突出的HIV等疾病相关时。