Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, (UIPS), Utrecht University, Utrecht, The Netherlands.
Department of Biopsychology, Faculty of Psychology, Ruhr-Universität, Bochum.
Rheumatology (Oxford). 2019 Nov 1;58(Suppl 5):v35-v50. doi: 10.1093/rheumatology/kez413.
Today, inflammatory rheumatic disorders are effectively treated, but many patients still suffer from residual fatigue. This work presents pathophysiological mechanisms of fatigue. First, cytokines can interfere with neurotransmitter release at the preterminal ending. Second, a long-term increase in serum concentrations of proinflammatory cytokines increase the uptake and breakdown of monoamines (serotonin, noradrenaline and dopamine). Third, chronic inflammation can also decrease monoaminergic neurotransmission via oxidative stress (oxidation of tetrahydrobiopterin [BH4]). Fourth, proinflammatory cytokines increase the level of enzyme indoleamine-2, 3-dioxygenase activity and shunt tryptophan away from the serotonin pathway. Fifth, oxidative stress stimulates astrocytes to inhibit excitatory amino acid transporters. Sixth, astrocytes produce kynurenic acid that acts as an antagonist on the α7-nicotinic acetylcholine receptor to inhibit dopamine release. Jointly, these actions result in increased glutamatergic and decreased monoaminergic neurotransmission. The above-described pathophysiological mechanisms negatively affect brain functioning in areas that are involved in fatigue.
如今，炎症性风湿性疾病的治疗已取得显著成效，但许多患者仍饱受剩余疲劳的困扰。本研究介绍了疲劳的病理生理机制。首先，细胞因子可干扰神经递质在末端前体的释放。其次，促炎细胞因子在血清中的长期浓度升高会增加单胺（血清素、去甲肾上腺素和多巴胺）的摄取和分解。第三，慢性炎症还可通过氧化应激（四氢生物蝶呤 [BH4]氧化）降低单胺能神经传递。第四，促炎细胞因子增加色氨酸 2,3-双加氧酶活性，使色氨酸从血清素途径分流。第五，氧化应激刺激星形胶质细胞抑制兴奋性氨基酸转运体。第六，星形胶质细胞产生的犬尿氨酸可作为α7-烟碱型乙酰胆碱受体的拮抗剂，抑制多巴胺释放。上述这些作用导致谷氨酸能神经传递增加和单胺能神经传递减少。上述描述的病理生理机制会对参与疲劳的大脑区域的功能产生负面影响。
