Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Free Radic Biol Med. 2017 Jul;108:668-682. doi: 10.1016/j.freeradbiomed.2017.04.026. Epub 2017 Apr 20.
The strict energetic demands of the brain require that nutrient supply and usage be fine-tuned in accordance with the specific temporal and spatial patterns of ever-changing levels of neuronal activity. This is achieved by adjusting local cerebral blood flow (CBF) as a function of activity level - neurovascular coupling - and by changing how energy substrates are metabolized and shuttled amongst astrocytes and neurons - neuroenergetic coupling. Both activity-dependent increase of CBF and O and glucose utilization by active neural cells are inextricably linked, establishing a functional metabolic axis in the brain, the neurovascular-neuroenergetic coupling axis. This axis incorporates and links previously independent processes that need to be coordinated in the normal brain. We here review evidence supporting the role of neuronal-derived nitric oxide (NO) as the master regulator of this axis. Nitric oxide is produced in tight association with glutamatergic activation and, diffusing several cell diameters, may interact with different molecular targets within each cell type. Hemeproteins such as soluble guanylate cyclase, cytochrome c oxidase and hemoglobin, with which NO reacts at relatively fast rates, are but a few of the key in determinants of the regulatory role of NO in the neurovascular-neuroenergetic coupling axis. Accordingly, critical literature supporting this concept is discussed. Moreover, in view of the controversy regarding the regulation of catabolism of different neural cells, we further discuss key aspects of the pathways through which NO specifically up-regulates glycolysis in astrocytes, supporting lactate shuttling to neurons for oxidative breakdown. From a biomedical viewpoint, derailment of neurovascular-neuroenergetic axis is precociously linked to aberrant brain aging, cognitive impairment and neurodegeneration. Thus, we summarize current knowledge of how both neurovascular and neuroenergetic coupling are compromised in aging, traumatic brain injury, epilepsy and age-associated neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, suggesting that a shift in cellular redox balance may contribute to divert NO bioactivity from regulation to dysfunction.
大脑对能量有着严格的需求，要求根据神经元活动水平不断变化的特定时空模式来精细调节营养供应和利用。这是通过调节局部脑血流 (CBF) 来实现的，调节方式是根据活动水平进行调节——神经血管耦合；还可以通过改变能量底物在星形胶质细胞和神经元之间的代谢和穿梭方式来实现——神经能量耦合。活动依赖性的 CBF 增加以及活跃的神经细胞对 O2 和葡萄糖的利用是紧密相连的，这在大脑中建立了一个功能性代谢轴，即神经血管-神经能量耦合轴。这个轴将以前需要在正常大脑中协调的独立过程结合起来。在这里，我们回顾了支持神经元衍生的一氧化氮 (NO) 作为这个轴的主要调节因子的证据。一氧化氮是在谷氨酸能激活紧密相关的情况下产生的，并且可以扩散几个细胞直径，可能与每个细胞类型中的不同分子靶标相互作用。与 NO 以相对较快的速度反应的血红素蛋白，如可溶性鸟苷酸环化酶、细胞色素 c 氧化酶和血红蛋白，只是决定 NO 在神经血管-神经能量耦合轴中的调节作用的关键因素之一。因此，讨论了支持这一概念的关键文献。此外，鉴于对不同神经细胞分解代谢调节的争议，我们进一步讨论了 NO 特异性上调星形胶质细胞糖酵解的途径的关键方面，支持乳酸穿梭到神经元进行氧化分解。从生物医学的角度来看，神经血管-神经能量轴的脱轨与异常的大脑衰老、认知障碍和神经退行性变过早相关。因此，我们总结了目前关于神经血管和神经能量耦合在衰老、创伤性脑损伤、癫痫和与年龄相关的神经退行性疾病（如阿尔茨海默病和帕金森病）中受损的知识，表明细胞氧化还原平衡的转变可能导致 NO 生物活性从调节转向功能障碍。
