Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients\u2019 sera in a mouse model of restless legs syndrome

Kazuhiro Muramatsu,Yuichi Inoue,Noriyuki Shimizu,Hiroyoshi Séi,Sachiko Chikahisa

doi:10.1038/s41598-019-52735-z

Kazuhiro Muramatsu, Yuichi Inoue + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-52735-z

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Abstract

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Hemodialysis patients also exhibit higher rates of RLS compared with the healthy population. However, little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. Here we evaluated sleep and leg muscle activity of Btbd9 mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. At baseline, the amount of rapid eye movement (REM) sleep was decreased and leg muscle activity during non-REM (NREM) sleep was increased in MT mice compared to wild-type (WT) mice. Wake-promoting effects of rotigotine were attenuated by injection of serum from RLS patients in both WT and MT mice. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity. Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS.

Highlights

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS
No mRNA expression of Btbd[9] was detected by reverse transcription polymerase chain reaction (RT-PCR) assay based on total RNA extracted from mice prefrontal cortex
The amounts of wakefulness and NREM sleep of MT and WT mice were similar, whereas the amount of rapid eye movement (REM) sleep was decreased for MT mice relative to WT mice

Summary

Introduction

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. We evaluated sleep and leg muscle activity of Btbd[9] mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS. We injected wild-type (WT) and Btbd[9] mutant (MT) mice with serum from RLS patients with and without renal involvement who had and had not undergone hemodialysis to examine whether substances in RLS patient serum affect response of RLS symptoms to rotigotine

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