Histamine H3R Inverse-Agonism as a treatment for Prader-Willi

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HISTAMINE H3R INVERSE-AGONISM AS A TREATMENT FOR PRADER WILLI

RATIONAL

HISTAMINE H3R INVERSE-AGONIST (EX. PITOLISANT) FOR PWS – RATIONAL

- H3R is a histamine auto receptor. It responds to high levels of histamine, and its action is down regulating brain histamine levels, and down-regulating dopamine, GABA, acetylcholine, noradrenaline, serotonin and more. It also has constitutive activity, so an inverse-agonist can exist for this receptor [20, 21] Therefore: inverse-agonist for H3R will increase brain levels of Histamine, dopamine, GABA …

- The hypothesis: PWS have a messed-up histamine 3 receptor, which is over-active (its constitutive activity is high), so it is down-regulating the brain histamine, dopamine, GABA, serotonin REASONS THAT CREATED THE HYPOTHESIS - It was found that insufficient histamine, delays the feeling of satiety. OEA, induced from the gut, needs brain histamine to induce satiety (links below). It was shown that H3R-antagonist counters the effect of low-histamine [1, 2, 3]. Therefore: the absence of satiety in PWS can be caused by reduced histamine levels [ex1, ex2]

- It is also found the increased histamine levels in the hypothalamus (either by injection or by H3R antagonism) leads to increased water intake, it is known that PWS drink little water, which fits the low-histamine due to improper H3R function theory [4, 5, 10] Therefore: increasing brain histamine levels allows better water intake [ex3, ex4, ex5]

- Histamine balances the sleep-wake cycle, it is known that PWS has irregular REM sleep, sleep disorders and daytime sleepiness [7, 8]. It is tested that Pitolisant balances REM sleep in mice [6, 9] Therefore: when the PWS person sleeps, he sleeps better, when he’s awake, he’s awake better [ex6, ex7]

- Histamine H3R interacts with the Oxytocin system (as seen in sucking example above), research shows internasal oxytocin improve social skills with PWS [Tauber at al] Therefore: histamine H3 inverse-agonist might improve social skills with PWS [ex8, ex9]

- PWS people have low level of Serotonin levels [12, 13] Therefore: the low serotonin levels can be caused by over constitutive activity of the Histamine H3R

- PWS people recover from disease slowly [ex10], Therefore: reducing the baseline activity of the Histamine autoregulatory system will cause faster increase in Histamine levels at sickness, and will activate the immune-system faster [11]

- In PWS, the piece of DNA that is missing codes for regulatory RNA SNORD116 (and for other things). According to hypothesis (I didn’t find reference) – The histamine 3 receptor seems to be co-localized with SNORD116 (also-known-as HBII-85).


RELEVANT RESEARCH

HISTAMINE H3R RECEPTOR

[20] H3 receptor overview

[21] H3 receptor constitutive activity

HISTAMINE IS NEEDED FOR FEELING OF SATIETY:

[1] of histaminergic and noradrenergic receptors in the oxytocin-induced food intake in neonatal meat-type chicks.
“ … Several studies have shown that central histaminergic and adrenergic systems synapse on oxytocin neurons ... These results suggest that the effect of oxytocin on food intake is probably mediated by histaminergic (via H1 and H3 receptors) and noradrenergic (via β2 receptors) systems in broiler chickens … "

[2] factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake.
“ … we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. … “ “ … Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA … “

[3] enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue cultures: “ … The results indicate that NH hormone release is influenced directly by the histaminergic system, and the histaminergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary …”

HYPOTHALAMIC HISTAMINE INCREASES WATER INTAKE

Research show that higher hypothalamic histamine elicits water intake :

H3 agonism increased water intake in rats

[4]and water intake Histamine injection to the hypothalamus increase water intake in rats

[5] https://www.sciencedirect.com/science/article/pii/0006899373901200

[10] Histamine 3 receptor : H3 agonists is related to sucking of liquids

OXYTOCIN SECRATION AND H3R RELATION

H3-antagonist is assumed to increase (regulate) the Oxytocin levels in brain (link to list of articles): https://www.ncbi.nlm.nih.gov/pubmed/?term=oxytocin%20histamine%20(h3)%20receptor&fbclid=IwAR3skC2XdzMQdTOwrHd2NCCXeYYhHPjI2cAG6gfGWCblSs5ujJd8RF5HSlM


PWS AND SLEEP DISORDERS

PWS people suffer from sleep disorders and irregular REM sleep :
[7] and PWS
[8] vol 40 : sleep disturbances in Prader willi
(from [8]) “ … We recently suggested pitolisant (a new drug that increases brain histamine with a low frequency of irritability) to two patients who stopped modafinil because of side effects, with one case of good effectiveness without side effects and one case lost to follow-up …” “ … Treatment with modafinil is not associated with the development of either dependence or tolerance.28 Use of modafinil is currently established for narcolepsy and idiopathic hypersomnia in adults. A similar, open-label pilot study showed good efficacy for modafinil (reduced scores on the Epworth sleepiness scale) without side effects in nine children and adolescents with PWS plus a complaint of excessive sleepiness and no sleep disordered breathing.29 The risk of increasing irritability and aggressiveness in one third of PWS patients when using modafinil suggests that it would be interesting to try pitolisant, the new anti-H3 stimulant, in patients with PWS. The benefits of pitolisant on sleepiness are similar to those of modafinil,30 but the former seems to induce less irritability, both in trials and in our clinical experience with more than 200 patients … “

PWS MICE EXPERIMENTS

Sleep Medicine, vol 40 : Pre-clinical trial : Pitolisant as new intervention for sleep problems for PWS:
[9] https://www.sciencedirect.com/science/article/pii/S138994571730494X
“ … In this new study, mutants treated with Pitolisant presented a reduction of non-REM sleep during the active phase (i.e. dark phase, the 12 hours immediately following the injection). This latter effect on sleep was present also in wild-type PWScrm+/p+ mice, in which REM sleep was almost suppressed during active phase and wakefulness was significantly increased. On the other hand, the wake promoting effect of Pitolisant disappeared during inactive phase … Moreover, the baseline increase in REM sleep characteristic of PWScrm+/p- mice, already described in our previous paper, was abolished after Pitolisant administration … “

Elevated levels of brain glutamate are believed to cause anxiety and ADHD behaviors. it is reported that Pitolisant improves REM sleep, reduces Brain glutamate levels in PWS mice [6]

HISTAMINE NEEDED FOR IMMUNE-SYSTEM ACTIVATION

[10] Role in regulation of the immune response

HISTAMINE H3R AND SEROTONIN

[12] levels of brain serotonin by PWS type
“ … Greater serotonin turnover (greater plasma monoamine oxidase B and cerebrospinal fluid 5-hydroxyindolacetic acid) has been previously demonstrated in patients with PWS, compared with healthy controls.6, 7 In addition, treatment with selective serotonin reuptake inhibitors have been found to be effective in tackling affective and behavioural problems in individuals with PWS. … “ [13] higher levels of serotonin breakdown is found in PWS