Striatal histamine mechanism in the pathogenesis of restless legs syndrome

Abstract Study Objectives Restless legs syndrome (RLS) has been hypothesized to be generated by abnormal striatal dopamine transmission. Dopaminergic drugs are effective for the treatment of RLS. However, long-term use of dopaminergic drugs causes adverse effects. We used iron-deficient (ID) and iron-replacement (IR) rats to address the neuropathology of RLS and to determine if a histamine H3 receptor (H3R) antagonist might be a useful treatment. Histamine H3R antagonists have been shown to decrease motor activity. Methods Control and ID rats were surgically implanted with electrodes for polysomnographic recording. After 3 days of baseline polysomnographic recordings, rats were systemically injected with the H3R agonist, α-methylhistamine, and antagonist, thioperamide. Recordings were continued after drug injection. Striatal H3R levels from control, ID, and IR rats were determined by western blots. Blood from control, ID, and IR rats was collected for the measurement of hematocrit levels. Results α-Methylhistamine and thioperamide increased and decreased motor activity, respectively, in control rats. In ID rats, α-methylhistamine had no effect on motor activity, whereas thioperamide decreased periodic leg movement (PLM) in sleep. Sleep–wake states were not significantly altered under any conditions. Striatal H3R levels were highest in ID rats, moderate to low in IR rats, and lowest in control rats. Striatal H3R levels were also found to positively and negatively correlate with PLM in sleep and hematocrit levels, respectively. Conclusions A striatal histamine mechanism may be involved in ID anemia-induced RLS. Histamine H3R antagonists may be useful for the treatment of RLS.

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Ascertainment of Iron Depletion and Deficiency in Blood Donors Through Screening Questions for Pica and Restless Legs Syndrome.

Blood ◽

10.1182/blood.v120.21.2283.2283 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2283-2283

Author(s):

Barbara J. Bryant ◽

Yu Ying Yau ◽

Sarah M. Arceo ◽

Julie A. Hopkins ◽

Susan F. Leitman

Keyword(s):

Iron Deficiency ◽

Restless Legs Syndrome ◽

Blood Donors ◽

Oral Iron ◽

Iron Therapy ◽

Iron Depletion ◽

Restless Legs ◽

Iron Deficient ◽

Screening Questions ◽

Iron Replacement

Abstract Abstract 2283 Background: Pica and restless legs syndrome (RLS) are associated with iron depletion and deficiency. Pica refers to the compulsive craving for and persistent consumption of non-nutritive substances. Pagophagia, the pathological consumption of ice, is a specific pica strongly associated with iron deficiency. RLS is a neurological movement disorder characterized by uncomfortable sensations in the lower extremities, with a compelling urge to move the extremities to relieve the discomfort. Primary RLS is a central nervous system disorder; however, secondary RLS may be caused or exacerbated by iron deficiency. The purpose of this study was to prospectively assess the prevalence of pica and RLS in blood donors presenting to a hospital-based donor center, to correlate the findings with donor hemoglobin and iron levels, and to study the effects of oral iron replacement on the resolution of symptoms. Methods: During a 39-month period, 1236 blood donors deferred for fingerstick hemoglobin <12.5 g/dL and 400 non-deferred “control” donors underwent health screening and laboratory testing (CBC, ferritin, iron, transferrin). Iron deficiency was defined as a ferritin level below the institutional reference range of 9 mcg/L in females and 18 mcg/L in males. Iron depletion was defined as a ferritin of 9 – 19 mcg/L in females and 18 – 29 mcg/L in males. Pica and RLS were assessed by direct questioning. Deferred donors and iron-deficient control donors were given ferrous sulfate 325 mg daily for 60 days. Reassessments were performed and additional iron tablets dispensed at subsequent visits. Results: Pica was reported in 11% of donors with iron depletion/deficiency, compared with 4% of iron-replete donors (p<0.0001). The prevalence of pica rose to 21% in females with ferritin <9 mcg/L. Pagophagia (ice pica) was most common and was often of extraordinary intensity, with characteristics of an addiction. Donors with pagophagia given iron reported a marked reduction in the desire to eat ice by day 5–8 of therapy, with disappearance of symptoms by day 10–14. RLS was reported in 16% of subjects with iron depletion/deficiency compared with 11% of iron-replete donors (p=0.012). Iron replacement generally resulted in improvement of RLS symptoms, however, at least 4–6 weeks of iron therapy was necessary. The positive predictive values of pica and RLS in iron deficient/depleted blood donors were 73% and 58%, respectively. Conclusion: The presence of pica is highly predictive of iron depletion/deficiency in blood donors; however, RLS lacks a strong correlation in this population. Screening questions for pica, in particular pagophagia, may be useful in the ascertainment of iron depletion and deficiency in blood donors and may identify those who would benefit from oral iron therapy. Disclosures: No relevant conflicts of interest to declare.

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Pharmacologic treatment of restless legs syndrome

Current Neuropharmacology ◽

10.2174/1570159x19666201230150127 ◽

2020 ◽

Vol 19 ◽

Author(s):

Qing Lv ◽

Xinlin Wang ◽

Tetsuya Asakawa ◽

Xiao Ping Wang

Keyword(s):

Restless Legs Syndrome ◽

Association Studies ◽

Cell Loss ◽

Genome Wide Association Studies ◽

Neural Pathways ◽

Dopaminergic Drugs ◽

Restless Legs ◽

Genome Wide ◽

Mechanistic Basis

: Restless legs syndrome (RLS)/Willis-Ekbom disease is a neurologic disorder characterized by a strong desire to move when at rest (usually in the evening) and paraesthesia in their lower legs. The most widely used therapies for first-line treatment of RLS are dopaminergic drugs; however, their long-term use can lead to augmentation. α2δ Ligands, opioids, iron, glutamatergic drugs, adenosine, and sleep aids have been investigated as alternatives. The pathogenesis of RLS is not well understood. Despite the efficacy of dopaminergic drugs in the treatment of this disorder, unlike in Parkinson’s disease dopaminergic cell loss in the substantia nigra has not been observed in RLS. The etiology of RLS is likely complex, involving multiple neural pathways. RLS-related genes identified in genome-wide association studies can provide insight into the mechanistic basis and pathophysiology of RLS. Here we review the current treatments and knowledge of the mechanisms underlying RLS.

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