Müller N, Schwarz M J
Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, München, Germany.
Mol Psychiatry. 2007 Nov;12(11):988-1000. doi: 10.1038/sj.mp.4002006. Epub 2007 Apr 24.
Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-gamma, or tumor necrosis factor-alpha activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes - counteracting this metabolism due to the lack of an enzyme of this metabolism - have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
除了众所周知的血清素能神经传递缺陷作为重度抑郁症（MD）的病理生理关联外，最近的证据还表明谷氨酸受体激活增加也起着关键作用。然而，这些神经递质改变的原因及其相互作用尚不清楚。在本综述中，我们提出了一个假说，将当前的神经传递概念以及下丘脑 - 垂体 - 肾上腺（HPA）轴失调与MD中的免疫改变和脑形态学改变的研究结果整合在一起。在MD中反复描述了包括促炎细胞因子产生增加在内的免疫激活。促炎细胞因子如白细胞介素 - 2、干扰素 - γ或肿瘤坏死因子 - α可激活色氨酸和血清素降解酶吲哚胺2,3 - 双加氧酶（IDO）。炎症性躯体疾病期间的抑郁状态也与促炎细胞因子增加以及通过IDO激活导致的色氨酸消耗增加有关。通过IDO激活增加血清素及其前体色氨酸的消耗，很可能解释了MD中血清素能神经传递可用性的降低。此外，促炎细胞因子对IDO及其后续酶犬尿氨酸单加氧酶的激活增加，导致喹啉酸的产生增加，喹啉酸是谷氨酸能N - 甲基 - D - 天冬氨酸受体的强效激动剂。在中枢神经系统的炎症状态下，IDO主要在小胶质细胞中被激活，小胶质细胞优先将色氨酸代谢为NMDA受体激动剂喹啉酸，而由于缺乏这种代谢酶而抵消这种代谢的星形胶质细胞在MD中已被观察到减少。因此，与星形胶质细胞/小胶质细胞失衡相关的1型/2型免疫反应失衡导致血清素能缺乏和谷氨酸能过量产生。星形胶质细胞还强烈参与谷氨酸的再摄取和代谢转化。星形胶质细胞数量减少可能导致小胶质细胞中IDO活性的反调节减弱以及谷氨酸能神经传递改变。进一步寻找抗抑郁药应考虑到抗炎药物，例如环氧化酶 - 2抑制剂，可能通过作用于血清素能缺乏、谷氨酸能功能亢进并拮抗喹啉酸的神经毒性作用而发挥抗抑郁作用。
