Neuroinflammation and Glial ROS in Methamphetamine Neurotoxicity

在啮齿动物模型和吸毒者中，黑质纹状体系统的甲基苯丙胺毒性的神经学症状与神经炎症、以小胶质细胞和星形胶质细胞激活为特征的脑损伤的基本反应、炎症介质的局部表达以及可能的单核细胞等外周细胞的渗透有关。这种突出的局部组织反应很可能代表了一种适应性和恢复性的修复过程。然而，与周围疾病中的许多炎症状态相似，神经炎症也可能导致中枢神经系统疾病的病理生理学。因此，在冰毒的背景下观察到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联系的可能机制的问题。其中一个机制是氧化应激，众所周知，氧化应激既发生在冰毒中，也发生在神经炎症中。在艾滋病毒感染者中，滥用冰毒与艾滋病毒脑炎显著增加、神经病理加重以及炎症相关基因表达增加有关。因此，神经炎症是冰毒暴露和中枢神经系统HIV感染的共同因素，当这两个危险因素并存时，可能是疾病和神经病理增强的基础。促炎症细胞因子IL-1β是中枢神经系统炎症的主要驱动力之一，它是由激活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活化，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渗透。此外，有明确的证据表明，在几种中枢神经系统损伤和疾病模型中，IL-1是导致神经元损伤的重要因素。我们最近开发了一种转基因小鼠模型，可以在时间和空间上控制持续的IL-1β表达。我们建议用这只小鼠来检验这一假说，即共存的神经炎症增强了冰毒诱导的腹侧中脑多巴胺能系统的损伤。一个推论是，神经炎症的减轻将防止冰毒的神经毒性。最后，我们假设神经炎症和冰毒之间存在联系的一个机制是产生小胶质细胞/巨噬细胞衍生的活性氧(ROS)。为了探索这些假说，我们将：1)量化在存在持续性神经炎症的情况下冰毒暴露引起的纹状体多巴胺能神经末梢毒性；2)确定取消IL-1信号是否降低冰毒暴露后的神经毒性；3)表征冰毒和冰毒+神经炎症引起的氧化损伤引起的神经毒性。通过更好地了解神经炎症在冰毒相关神经毒性中的作用，我们或许能够开发出遏制冰毒滥用的神经副作用的策略，特别是在与艾滋病毒等神经炎症突出的疾病相关的情况下。

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.