1 Department of Pathology and Immunology, Geneva Medical Faculty, Geneva University Hospitals, Centre Médical Universitaire , Geneva, Switzerland .
Antioxid Redox Signal. 2014 Jun 10;20(17):2815-37. doi: 10.1089/ars.2013.5703. Epub 2014 Jan 16.
There is increasing evidence that the generation of reactive oxygen species (ROS) in the central nervous system (CNS) involves the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Controlled ROS generation appears necessary for optimal functioning of the CNS through fine-tuning of redox-sensitive signaling pathways, while overshooting ROS generation will lead to oxidative stress and CNS disease.
NOX enzymes are not only restricted to microglia (i.e. brain phagocytes) but also expressed in neurons, astrocytes, and the neurovascular system. NOX enzymes are involved in CNS development, neural stem cell biology, and the function of mature neurons. While NOX2 appears to be a major source of pathological oxidative stress in the CNS, other NOX isoforms might also be of importance, for example, NOX4 in stroke. Globally speaking, there is now convincing evidence for a role of NOX enzymes in various neurodegenerative diseases, cerebrovascular diseases, and psychosis-related disorders.
The relative importance of specific ROS sources (e.g., NOX enzymes vs. mitochondria; NOX2 vs. NOX4) in different pathological processes needs further investigation. The absence of specific inhibitors limits the possibility to investigate specific therapeutic strategies. The uncritical use of non-specific inhibitors (e.g., apocynin, diphenylene iodonium) and poorly validated antibodies may lead to misleading conclusions.
Physiological and pathophysiological studies with cell-type-specific knock-out mice will be necessary to delineate the precise functions of NOX enzymes and their implications in pathomechanisms. The development of CNS-permeant, specific NOX inhibitors will be necessary to advance toward therapeutic applications.
越来越多的证据表明，活性氧（ROS）在中枢神经系统（CNS）中的产生涉及烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）家族。受控的 ROS 生成似乎是通过微调氧化还原敏感信号通路来使中枢神经系统最佳运作所必需的，而过度的 ROS 生成将导致氧化应激和 CNS 疾病。
NOX 酶不仅限于小胶质细胞（即脑吞噬细胞），而且在神经元、星形胶质细胞和神经血管系统中也有表达。NOX 酶参与 CNS 发育、神经干细胞生物学和成熟神经元的功能。虽然 NOX2 似乎是 CNS 中病理性氧化应激的主要来源，但其他 NOX 同工酶也可能很重要，例如在中风中 NOX4。总的来说，现在有令人信服的证据表明 NOX 酶在各种神经退行性疾病、脑血管疾病和与精神病相关的疾病中起作用。
在不同的病理过程中，特定 ROS 来源（例如，NOX 酶与线粒体；NOX2 与 NOX4）的相对重要性需要进一步研究。缺乏特异性抑制剂限制了研究特定治疗策略的可能性。非特异性抑制剂（例如，apocynin、二苯基碘）和验证不足的抗体的不加批判的使用可能导致误导性的结论。
需要使用细胞类型特异性敲除小鼠进行生理和病理生理研究，以描绘 NOX 酶的精确功能及其在发病机制中的意义。需要开发 CNS 穿透性、特异性的 NOX 抑制剂，以推进治疗应用。
