Neuroinflammation and Glial ROS in Methamphetamine Neurotoxicity

在啮齿类动物模型和药物滥用者中，与甲基苯丙胺（METH）黑质纹状体系统毒性有关的神经系统症状与神经炎症有关，神经炎症是脑损伤的基本反应，其特征是小胶质细胞和星形胶质细胞活化，炎症介质局部表达，以及周围细胞（如单核细胞）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，与周围疾病中的许多炎症状况类似，神经炎症也可以促进中枢神经系统疾病的病理生理。因此，在甲基安非他明神经毒性环境下观察到的神经炎症提出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，已知在冰毒中毒和神经炎症中都会发生。在艾滋病毒感染者中，冰毒滥用与艾滋病毒脑炎的显著增强、更大的神经病理学和炎症相关基因的表达增加有关。因此，神经炎症是甲基苯丙胺暴露和中枢神经系统HIV感染的共同因素，当这两种风险因素共存时，可能会导致疾病和神经病理学的增强。中枢神经系统炎症的主要驱动力之一是促炎细胞因子白细胞介素(IL)-1β，它是由活化的小胶质细胞产生的。在其众多作用中，IL-1β促进星形胶质细胞的表型激活，导致包括趋化因子在内的其他炎症介质的表达，从而促进单核细胞和其他血源性细胞对中枢神经系统的浸润。此外，有明确的证据表明，IL-1在几种中枢神经系统损伤和疾病模型中是神经元损伤的重要贡献者。我们最近开发了一种转基因小鼠模型，提供持续IL-1β表达的时间和空间控制。我们建议用这只小鼠来验证共存的神经炎症增强甲基苯丙胺诱导的腹侧中脑多巴胺能系统损伤的假设。一个必然的假设是，神经炎症的衰减将防止冰毒神经毒性。最后，我们假设神经炎症和甲基安非他明毒性之间关联的一个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)量化甲基安非他明暴露在持续神经炎症存在下引起的纹状体多巴胺能神经末梢毒性；2)确定IL-1信号的消除是否会降低甲基安非他明暴露后的神经毒性，3)表征甲基安非他明和甲基安非他明+神经炎症引起的神经毒性的氧化损伤。通过更好地了解神经炎症在冰毒相关神经毒性中的作用，我们可能能够制定策略来抑制冰毒滥用的神经副作用，特别是当与艾滋病毒等神经炎症突出的疾病相关时。

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.