Ferré Sergi, Quiroz César, Guitart Xavier, Rea William, Seyedian Arta, Moreno Estefanía, Casadó-Anguera Verònica, Díaz-Ríos Manuel, Casadó Vicent, Clemens Stefan, Allen Richard P, Earley Christopher J, García-Borreguero Diego
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, United States.
Center for Biomedical Research in Neurodegenerative Diseases Network and Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, Barcelona, Spain.
Front Neurosci. 2018 Jan 8;11:722. doi: 10.3389/fnins.2017.00722. eCollection 2017.
The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the αδ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS.
不宁腿综合征（RLS）的症状包括睡眠期间周期性腿部运动（PLMS）、感觉异常和觉醒过度。多巴胺能系统的改变，即突触前多巴胺能亢进状态，似乎与PLMS有关，而谷氨酸能神经传递的改变，即突触前谷氨酸能亢进状态，似乎与觉醒过度以及PLMS有关。脑铁缺乏（BID）被公认为RLS的主要初始病理生理机制。啮齿动物的BID提供了一个RLS的发病模型，该模型概括了RLS多巴胺能系统的生化改变，尽管没有类似PLMS的运动异常。另一方面，啮齿动物的BID再现了RLS的昼夜睡眠结构，表明该模型可为RLS中的谷氨酸能亢进状态提供线索。我们最近发现，啮齿动物的BID与腺苷能传递的变化有关，腺苷A受体（A1R）的下调是最敏感的生化发现。据推测，A1R下调导致纹状体谷氨酸能终末超敏和纹状体多巴胺释放增加。通过光遗传学-微透析方法在患有BID 的啮齿动物中证实了纹状体谷氨酸能终末的超敏反应，表明它可能是导致RLS中PLMS的主要致病因素。事实上，用于RLS初始症状治疗的多巴胺能激动剂普拉克索和罗匹尼罗以及αδ配体加巴喷丁，完全抵消了光遗传学诱导的正常和BID诱导的超敏皮质纹状体谷氨酸能终末的谷氨酸释放。本文的一个主要观点是，在RLS中，腺苷能系统的单一改变，即A1R下调，破坏了由纹状体中腺苷和多巴胺受体异聚体独特控制的腺苷-多巴胺-谷氨酸平衡，以及A1R介导的对皮质和其他非纹状体脑区谷氨酸能神经传递的抑制控制，这共同决定了PLMS和觉醒过度。由于A1R激动剂会带来严重的心血管影响，据推测，核苷平衡转运体抑制剂，如双嘧达莫，通过增加内源性腺苷介导的A1R的持续性激活，可能代表一种治疗RLS的新的替代策略。事实上，初步临床数据表明双嘧达莫可以显著改善RLS的症状。
