High Histamine H3 and Low iron in RLS brain (2020 rat study)


Senior Member

Pitolisant, a H3 receptor blocker is already used for Narcolepsy

FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy | Phoenix Rising ME/CFS Forums

Striatal histamine mechanism in the pathogenesis of restless legs syndrome
Yuan-Yang Lai, Kung-Chiao Hsieh, Yu-Hsuan Cheng, Keng-Tee Chew, Darian Nguyen, Lalini Ramanathan, Jerome M Siegel

Sleep, Volume 43, Issue 2, February 2020, zsz223, https://doi.org/10.1093/sleep/zsz223


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.


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.


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.

A striatal histamine mechanism may be involved in ID anemia-induced RLS.

Histamine H3R antagonists may be useful for the treatment of RLS.


Senior Member
Antagonism to HRH3 may have therapeutic value in parkinson as well:

Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology. Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy

Aruna Sharma 1


Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives.

PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology.

However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases.

These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology.

In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations.

Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1mg/kg, i.p.) or CLBPT (1mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25μL) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology.

These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.