All About Histamine H3 Receptors (HRH3/HR3): Genetics, Mechanisms, And Antagonists

Basics Of Histamine And Histamine Receptors

Histamine plays a huge role in the body: circadian rhythms, catalepsy, energy homeostasis, thermoregulation, neuroendocrine and cardiovascular control, drinking and feeding, learning and memory, locomotion, sexual behavior, analgesia and emotion. R

Naturally, histamine is synthesized from the amino acid L-Histidine by the enzyme Histidine Decarboxylase (HDC), which follows a circadian rhythm, being more active while awake. R R 

After histamine is released, two enzymes participate in its degradation, Diamine Oxidase (DAO) and Histamine N-Methyltransferase (HNMT), with HMNT being the major enzyme responsible of the catabolism of histamine in the brain. R R

 
 https://molcellped.springeropen.com/articles/10.1186/s40348-015-0027-1

https://molcellped.springeropen.com/articles/10.1186/s40348-015-0027-1

 

There are 4 Histamine Receptors (H1R-H4R) which all play different roles in the body:

  • H1R - found in peripheral tissues, gut, smooth muscle, adrenal medulla, bronchia, blood vessels, and lymphocytes , neocortex, claustrum, hippocampal formation, posterior hypothalamus, and thalamus R
  • H2R - also found in peripheral tissues and the CNS, specifically gastric parietal cells, smooth muscle, and immune cells and in the CNS in hippocampus, amygdala, raphe nuclei, BG, and cerebral cortex R
  • H3R - exclusively expressed by CNS/PNS neuronal cells - found in the cerebral cortex, thalamus, BG, cerebellum, amygdala, hippocampus, hypothalamus, corpus callosum, raphe nuclei, locus coeruleus, and spinal cord R
  • H4R - mainly expressed in peripheral cells (mast cells, eosinophils, and T cells) and tissues such as the lung and gut, and it plays role in immune responses and inflammation R

Among the 4 histamine receptors, H3R almost exclusively expresses in the nervous system and has dual functions as an auto- and hetero-receptor.

This allows H3Rs to modulate the histaminergic as well as other other neurotransmitter systems. 

Although, H1 agonists and H3 inverse agonists have similar effects. R R

How The H3 Receptor Works In The Brain

 
 https://link.springer.com/chapter/10.1007/978-3-319-40308-3_11

https://link.springer.com/chapter/10.1007/978-3-319-40308-3_11

 

In the brain the highest levels of histamine occur in the hypothalamus and the lowest values are found in the cerebellum. R

Most histaminergic neurons are located in the Hypothalamus Tuberomammillary Nucleus (TMN), and their axons innervate almost all brain regions including the Basal Ganglia (BG - part of the brain which integrates motor and sensorial information originated in the cerebral cortex and the thalamus).

This placement of H3Rs in the BG is an evolutionarily (strategic) move, as it allows H3Rs to modulate both incoming and outgoing synaptic information.

Overall in the brain, the activity of histamine is regulated by: R R R

  • Excitatory Glutamatergic inputs -cortex and the hypothalamus (via NMDA and AMPA receptors)
  • Inhibitory GABAergic afferents -  hypothalamus (via activation of GABAA receptors)
  • Orexins - released by neighboring neuronal cells (excite the histaminergic neurons)

Histamine-containing nerve fibers release histamine along several points and the H3R as an autoreceptor helps inhibit this process (see more in agonists). R R

In the human and rat brain, H3R binding levels follow the rank order: R

  1. SNr
  2. nucleus accumbens
  3. striatum
  4. GP
  5. SNc
  6. STN

Whereas mRNA signal intensity follows the rank order: R

  1. striatum
  2. nucleus accumbens
  3. STN
  4. SN
  5. GP

In the Striatum (caudate-putamen), H3Rs work on GABAergic Medium-Sized Spiny Neurons (MSNs).

 
 https://www.ncbi.nlm.nih.gov/pubmed/24636456

https://www.ncbi.nlm.nih.gov/pubmed/24636456

 

MSNs are divided into two systems:

  1. Producing Enkephalins, expresses Dopamine D2-like Receptors (D2Rs) and Adenosine A2A Receptors (A2ARs) R
  2. Synthesizes Dynorphins, expresses Dopamine D1-like Receptors (D1Rs) and Adenosine A1 Receptors (A1Rs) R

H3Rs also play a role in the Globus Pallidus (GP), Entopeduncular nucleusSubthalamic nucleus (STN), and Substantia nigra [compacta (SNc) and reticulata (SNr)] - more described in Mechanism Of Action section.

Why Antagonize The H3 Receptor?

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884744/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884744/

 

Many of the benefits from the H3R come from inhibiting H3R's effects, either by antagonism or inverse agonists.

For example, antagonizing H3R may be neuroprotective in the brain by increasing levels of inhibitory neurons, such as GABA and DopamineR R

For more detail, antagonizing H3R may abrogate the effects describe in the "Simple" Mechanism Of Action Section.

Modulation of H3R has shown may potential benefits in narcolepsy, attention deficit hyperactivity disorder (ADHD), schizophrenia, Alzheimer’s disease, and excessive daytime sleepiness in obstructive sleep apnea or Parkinson’s disease. R

Clinical Trials Of H3R Antagonism

 
 https://link.springer.com/chapter/10.1007/978-3-319-40308-3_11

https://link.springer.com/chapter/10.1007/978-3-319-40308-3_11

 

Benefits Of Blocking The H3 Receptor

1. Combats Obesity, Improves Weight Loss and Fights Diabetes

H3R antagonism may benefit Weight Loss, as H3Rs play a role in energy homeostasis (by regulating hypothalamic histamine synthesis and release). R R

H3R antagonists (such as Thioperamide) demonstrate that H3Rs negatively regulate food intake.

For example, when rodents were given the H3R antagonist NNC 38-1049, histamine in the hypothalamus had increased and led a to reduction in food intake. R

Another example is with A-331440, which has shown to significantly decrease weight comparably to the serotonergic anorectic drug dexfenfluramine. R

A-331440 (at 15 mg/kg) has also shown to reduce weight in mice comparable to mice fed a low-fat diet. R

H3R antagonists may help with diabetes and obesity by modulating energy homeostasis (via leptin, insulin, ghrelin, serotoninneuropeptide Y, melanocortin, dopamine, and cholecystokinin). R R R

High doses of A-331440 were able to reduce body fat and normalize insulin tolerance. R

Other examples of H3R antagonists in obesity and diabetes:

  • Compound 39 (at a dose of 30 mg/kg) demonstrated both antidiabetic (63 mg/L, glucose level reduction) and anti-obesity effect (3.85% food inhibition, 0.64% body weight loss) in streptozotocin (STZ) diet-induced obesity (DIO) type 2 diabetic mice (STZ-DIO). R
  • Compound 40 demonstrated antihyperglycemic effect in 2 days when compared with vehicle-treated mice, whereas it dose-dependently blocked the increase of glycated hemoglobin (HbA1c) following a 12-day treatment in STZ- DIO mice model. R
  • NNC38-1049 (BID 20mg/kg) in old and dietary obese rats resulted in sustained reduction of food intake throughout a 2-week period without any changes in energy expenditure. R

H3R antagonism may be good for diabetes as it helps with glucose utilization and insulin resistance (by improving glucagon secretion and glucose-induced insulin secretion). R R

2. Improves Wakefulness And May Benefit Narcolepsy

 
 https://www.nature.com/articles/nrneurol.2015.99

https://www.nature.com/articles/nrneurol.2015.99

 

Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as Excessive Daytime Sleepiness (EDS) as well as other sleep or cognitive disorders. R

For example, the H3R antagonist APD916 can significantly increase total wake time during the first 2 h after administration. R

CEP-32215 as a wake-promoting histamine H3R antagonist has been proposed for potential utility in the treatment of a variety of sleep disorders. R

BF2.649 completed two phase 3 studies showing efficacy in a dose range of 5–20 mg/day on EDS in patients with obstructive sleep apnea with CPAP treatment and without it. R R

PF-03654746 completed a phase 2 study on EDS associated with narcolepsy with proved efficacy in two-drug groups vs placebo. R

By regulating glutamate, GABA, and Dopamine in the striatum of the brain, H3R inverse agonists can improve sleep rhythms, exploratory behavior, and mood in rodents. R 

H3R inverse agonists have also shown benefits in treatment for Narcolepsy. R

For example, BF2.649 displayed efficacy in a 22-patient narcolepsy phase 3 trial in which a 40-mg daily dose reduced sleepiness versus placebo, with efficiency in the Epworth Sleepiness Scale comparable to Provigil (Modafinil), the wakefulness-promoting histaminergic drug. R

GSK-189254 can also increase wakefulness and decrease slow-wave and paradoxical sleep comparable to modafinil (64 mg/kg, p.o.), while it reduced narcoleptic episodes. R

The H3R antagonist Pitolisant may produce less adverse reactions compared to Provigil. R

Pitolisant can also reverse the sedative effects of the antipsychotic drug Olanzapine. R

Interestingly, Orexin/Ataxin-3 narcoleptic mice are more sensitive to the H3R antagonists (such as JNJ-10181457). R R

3. May Improve Pain From Neuropathy And Arthritis

H3R antagonists may improve Neuropathy- and Arthritis-based pain. R R

For example, the H3R antagonist A-960656 is able to: R

  • Reduce osteoarthritis and neuropathic pain
  • Fully block mechanical allodynia, comparably to drug Gabapentin (but at much smaller amounts)

For example, A-960656 can suppress neuropathic sensitivity by blocking autoinhibitory H3R on histaminergic nerve terminals releases histamine and increases descending noradrenegic pain inhibition. R

Two H3R antagonists GSK-207040 and GSK-334429 have shown to significantly reverse capsaicin-induced pain. R

In ostoarhtirits, AZD5213 (H3R antagonist) has been studied in preclinical trials. R

Clinical trials with AZD5213 in combination with pregabalin have also been evaluated for diabetic neuropathic pain, but with no disclosed results. R

4. May Help Parkinson's Disease Treatment

Histamine levels are significantly increased in the SNc, GP, and striatum of Parkinson’s Disease (PD) patients. R

H3R antagonists enhance Dopamine release in prefrontal cortex and the striatum. R R R

In PD patients, 40mg of Pitolisant, once a day for 1 week, was able to reduce daytime sleepiness without interfering L-Dopa treatment. R R

H3R antagonism may help with circadian rhythms in those with PD. R

5. Combats Addiction And Addictive Traits

H3R antagonists may help with addiction, especially from certain stimulants and depressants. R

For example, ABT-239 (H3R antagonist with oral bioavailability of 37% and brain-to-plasma ratio of more than 20x) has shown to attenuate methamphetamine-induced hyperactivity in mice, enhance Acetylcholine (ACh) release (in frontal cortex and hippocampus) and enhance Dopamine release (in frontal cortex, but not striatum). R

ABT-239 can also attenuate ketamine-induced deficits on motor movement. R

Ciprofaxan (H3R antagonist) can reverse down-regulation of Brain-Derived Neurotrophic Factor (BDNF) and N-Methyl-D-Aspartate (NMDA) levels after methamphetamine-induced hyperactivity. R

ABT-288 can also attenuate methamphetamine-induced hyperactivity (without any observation of any potential abuse). R

H3R antagonists may help with alcoholism, alcohol abuse, and alcohol cravings. R 

For example, multiple H3R antagonists (e.g. DL77, JNJ-39220675) can reduce alcohol intake in rodents (with no effect observed on histidine decarboxylase). R R R

They may even protect the brain during drinking.

For example, ABT-239 has shown to improve ethanol-induced deficits on hippocampal Long-Term Potentiation (LTP). R R

H3R antagonism may also help protect the brain from MDMA and morphine abuse. R

6. May Improve Alzheimer's Disease And Dementia

Speaking of protecting the brain, H3R antagonism may improve cognition and learning. 

In Alzheimer's Disease (AD), decreased histamine levels in the caudate nucleus have been reported in patients (−25 % of the control values). R

H3R antagonism may have benefit in AD and clinical trials are currently under way.

For example, GSK-239512 has completed a phase 1 clinical trial with modest efficacy in mild–moderate AD patients (no results posted yet). R

Also SAR-110894 has completed a phase 2 of clinical study for mild–moderate AD in conjunction with the drug donepezil (no results posted yet). R

In animal models of AD, the H3R antagonist ABT-239 has shown to reduce GSK-3β hippocampal expression in Amyloid-beta overexpressing mice and reduce tau-phosphorylation. R

7. Improves Cognition And Memory

 
 https://www.ncbi.nlm.nih.gov/pubmed/25484194

https://www.ncbi.nlm.nih.gov/pubmed/25484194

 

H3R antagonists have stimulant and nootropic effects and may improve cognition and memory. 

For example, in a 7-trial passive avoidance model the administration of 11j (H3R antagonist) showed to significantly increase time spent awake, increase in Acetylcholine (ACh) levels in frontal cortex, and induce pro-cognitive effects. R

Other H3R antagonists also prevents low ACh levels by reducing the expression of Acetylcholinesterase (AChE). R

For example, the dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 can reverse amnesia induced by scopolamine or dizocilpine. R

GSK-207040 and GSK-334429 have also shown to significantly reverse scopolamine-induced memory impairment. R

JNJ-5207852 was found to prevent memory deficit induced by pentylenetetrazole kindling in weanling mice. R

JNJ-10181457 is able to improve memory (by increased extracellular Noradrenaline and ACh levels in the frontal cortex). R

JNJ-10181457 has also shown to  reverse the scopolamine-induced working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised. R

ABT-239 has shown to improve social memory in adult and aged rats. R

BF2.649 has shown to enhance dopamine and ACh levels (prefrontal cortex in rats), thus enhancing wakefulness, vigilance, and memory recognition. R 

In Phase 3 clinical trials, BF2.649 has also been found to promote wakefulness in patients with Excessive Daytime Sleepiness (EDS) associated with narcolepsy (phase 3), PD (phase 3), Obstructive Sleep Apnea syndrome (phase 3), and epilepsy (phase 3).

BF2.649 has also completed a phase 2 clinical study addressing Cognitive Impairment Associated with Schizophrenia (CIAS) and showed in doses up to 20 mg/day had pro-cognitive effects. R

ABT-288 has shown memory-enhancing effects in numerous preclinical experiments. R

H3R antagonism may also benefit blood flow in the brain.

For example, MK-3134 has completed phase 1 study measuring Cerebral Blood Flow (CBF) using fMRI (although outcome has yet to be disclosed). R

8. Enhances Attention

H3R antagonism significantly improves attention and may help with Attention Deficit Disorders (ADD).

For example, A-688057 (an H3R antagonist with high brain penetration) can improve attention and cognition in animal models. R

In rats, ciproxifan has shown to enhance attention and vigilance. R

Compared to Nicotine, Ciproxifan may be better at reducing impulsivity and improving attention in animal models. R 

Cipralisant has been used for Attention Deficit Hyperactivity Disorders (ADHD) in clinical trials. R

In a phase 2 clinical trial, PF-03654746 has shown to be safe and effective (1 and 2 mg/day) in adults with ADHD. R

9. May Help Schizophrenia Treatment

H3R antagonists may help with cognition in Schizophrenia

For example, ciproxifan has been shown to improve attention and cognitive performance in animal models of schizophrenia. R

ABT- 239 can improve methamphetamine-induced hyperactivity in mice with schizophrenia. R

PF-03654746 has completed a phase 1 study addressing Cognitive Impairment Associated with Schizophrenia (CIAS, but no results have been posted). R

CEP-26401 may have therapeutic potential in treating schizophrenia or as adjunctive therapy to approved antipsychotics. R

A phase 2 study has shown GSK-239512 to be safe in patients with schizophrenia, but ineffective for CIAS. R

10. May Relieve Anxiety, Fear, And Depression

H3R antagonism may benefit anxiety and depression.

For example, in preclinical cognition studies, ABT-239 has shown to improve confidence levels (via passive avoidance test). R R

ST-1283 has demonstrated both anxiolytic-like and antidepressant-like effects (at a dose of 7.5 mg/kg) in mice. R

11. Reduces Seizures, Improves Epilepsy, And Fights Excitotoxicity

Elevated histamine levels have shown to suppress seizure activities. R

H3R antagonism may be beneficial for controlling seizures in epilepsy. R R R

For example, the H3R antagonist 2-18 can protect mice against electroshock-induced convulsions. R

Another H3R antagonist DL77 has also shown to found to significantly and dose-dependently reduce electroshock-induced seizure duration and improving cognition/memory retrieval in animal models. R

Excitotoxicity is considered to be a key mechanism underlying neurodegenerative processes including epileptic seizures. R

ABT-239 was found to reduce Kainic Acid-induced seizures and excitotoxicity  R

H3R antagonism can also alleviate NMDA-induced neurotoxicity by activating the cAMP/PKA pathway, which subsequently facilitates GABA release (see H3R agonism benefits below for caveats about this). R

Some mechanisms by which H3R antagonism may help neuroprotection, seizures, convulsion, excitotoxicity, etc are: R

  • reversal of auto-inhibitory HA synthesis and release
  • ↑ HDC activity
  • ↑ GABA
  • ↑ HA release / ↑ Brain HA release

12. May Help Nasal Allergies

H3R antagonists may help with nasal-related allergies. R

In clinical trials in patients with allergic rhinitis, JNJ-39220675 has shown to have decongestant properties. R

In other studies with allergic rhinitis patients , PF-03654746 caused a reduction in allergen-induced nasal symptoms when used in combination with the H1R antagonist fexofenadineR R

Intranasal GSK-1004723 has completed phase 2 of various clinical trials in patients with allergic rhinitis (submission results pending). R

13. May Benefit Huntington's Disease Treatment

H3R antagonists may have some benefits in Huntington's Disease (HD). R

For example, in mouse models of HD, GSK189254 has shown to improve several behavioral measures including strengthening of activity rhythms, cognitive performance, and mood. R

14. May Improve Tourette's Syndrome Treatment

H3R antagonists may benefit Tourette's Syndrome (TS). R

For example, AZD-5213 has completed phase 2 stage of two clinical studies addressing its effectiveness in adolescent TS (with undisclosed results). R

Mouse-models and other research has demonstrated that reducing histamine concentration via H3R causes tics, but adding histamine in the striatum (H3R antagonism) decreases these symptoms. R R R

This may be explained by the expression of HRH3 is elevated in the basal ganglia in Hdc knockout mouse models of TS. R

15. May Improve Immune System In Multiple Sclerosis

Inverse agonists of the H3R such as GSK247246 may help improve remyelination in Multiple Sclerosis (MS) by promoting Oligodendrocyte Precursor Cell (OPC) differentiation. R

For example, in a phase 2 clinical trail the H3R antagonist GSK- 239512 given to patients with multiple sclerosis was able to help improve remyelination. R

16. May Fight Brain Cancer

H3R antagonism may be beneficial in fighting Brain Cancer.  R

For example, the overexpression of H3R is associated with glioma progression, whereas the inhibition of H3R leads to suppressed invasion and epithelial to mesenchymal transition of glioblastoma (by inactivating the PI3K/Akt and MEK/ERK pathways). R

17. May Play A Role In Autism Treatment

Expression of gene H3R has shown to be increased in Autism Spectrum Disorder (ASD). R

Inhibiting H3R's expression may have a benefit in ASD. R

Caveats Of Blocking The H3 Receptor

Imidazole-based H3R antagonists been found to potently bind to the cardiac hERG channel in vitro and to induce phospholipidosis – a potentially toxic condition. R R

Strong binding to hERG K+ channel can lead to QT prolongation. R

In a clinical trial, drug interactions between multiple doses of JNJ-31001074 and a single dose of an Oral Contraceptive (ethinyl estradiol / levonorgestrel) have been seen in female healthy volunteers. R

As expected, H3R antagonists may interfere with sleep - for example, JNJ-5207852 increases time spent awake but decreases REM sleep and slow-wave sleep. R

Their ability to cause insomnia has influenced cessation many clinical trials - for example, APD916 has an excessive half-life (T1/2) of 50 h. R

As an auto-receptor for histamine, H3R antagonism may not be best for those with Histamine Intolerance. R

H3R Antagonists/Inverse Agonists

 
 

Supplements:

Neurotransmitters/Hormones:

  • Glutamate R

Drugs/Chemicals:

Piperidine, (Methyl)Pyrrolidine Derivatives and Imidazole-based H3R Antagonists:

  • A-317920 R
  • A-331440 R
  • A-349,821 R R
  • A-688057 R 
  • A-960656 - highly selective (>330-fold) for histamine H3Rs versus off-target sites screened in a commercial panel of >80 receptors, enzymes, and ion channels...low molecular weight (295 g mol−1), high solubility, moderate lipophilicity, and good CNS penetration (brain/plasma ratio of 1.3) proved to be of low potential for phospholipidosis, genotoxicity, and CYP450 inhibition in in vitro toxicological tests.  R
  • ABT-239 R
  • APD916 (discontinuated) R
  • Bavisant R
  • BP1.3432 R
  • BP1.4160 - satisfactory oral absorption, as well as brain penetration and exhibited no significant interaction with the hERG channel (Ki = 5.8 μM) and CYP450 3A4, 2D6, and 2C9 (IC50 > 30 μM) R
  • Burimamide - also weak H2 antagonist R
  • CEP-26401 R
  • CEP-32215 R
  • Cipralisant (strong, but poor BBB penetration) - aka GT-2331 and perceptin R
  • Ciproxifan (strong, but poor BBB penetration) R
  • Clobenpropit (strong, but poor BBB penetration) R
  • Dimaprit R
  • DL77 R
  • Ergoline (CXCR3 antagonist) R
  • E159 R R
  • Failproxifan (no tolerance formation, like with Ciproxifan) R
  • GSK-189254 (discontinuated) R
  • GSK-207040 R
  • GSK-239512 R
  • GSK-334429 R
  • Impentamine  R
  • Iodophenpropit R
  • Irdabisant R
  • JNJ-10181457 R
  • JNJ-39220675 R
  • JNJ-5207852 - long half life (t1/2 > 13 h) with a long brain residency time after single bolus administration (10 mg/kg p.o.) which allowed a full receptor occupancy that was still observed after 24 h of administration R
  • MK-0249 - (discontinuated - many clinical trials have failed to produce major benefits) R R R
  • NNC38-1049 R
  • OUP-186 R
  • PF-03654746 (discontinuated) R
  • PF-03654764 R
  • Pitolisant (uses CYP4A4) R
  • Proxyfan (complex functional selectivity; partial agonist effects on cAMP inhibition and MAPK activity, antagonist on histamine release, and inverse agonist on arachidonic acid release) R
  • SAR110068 R
  • SCH-79687 R
  • ST-1025 R
  • ST-1036 R
  • ST-1283 R
  • Thioperamide (strong, but poor BBB penetration) - also H4 antagonist R
  • UCL-1972 R
  • UW-MD-72 R
  • WakixR/Betahistine (BF2.649) - also weak H1 agonist R
  • VUF-5681 R
  • 2-18 R

Other:

  • Cholera and Pertussis toxin R

H3R Antagonists May Go Well With...

H3R antagonists/inverse agonists may go well with:

Benefits Of Increasing The H3 Receptor

1. May Help With Weight Gain

The H3R plays a role in important role in mediating Amylin's satiating effect on eating. R

For example, the H3R agonists imetit and R-α-methylhistamine (RAMH) block the release of endogenous histamine via presynaptic histamine H3 receptors, thus reducing amylin's inhibitory effect on feeding. R

2. Protects The Gut

In conscious rats, the selective H3R antagonists immethridine and methimepip significantly reduced (66% and 48% inhibition, respectively) the gastric lesions induced by HCl (possibly via modulation of histamine and ghrelin). R R

3. Improves Multiple Sclerosis And Autoimmunity

H3R agonists may have benefits in reducing immune activity in Multiple Sclerosis. R

For example, in animal models of Experimental Autoimmune Encephalomyelitis (EAE) the H3R agonist immethridine decreased the percentage of Th1 and Th17 in the spleen and down-regulated surface molecules (such as CD40, CD86 or MHCII on DCs). R

The regulation of the Blood-Brain Barrier (BBB) by H3R agonists may be beneficial for autoimmunity in the brain. R

H3R KO mice exhibit a significant increase in BBB permeability, and their T cells selectively express more MIP-2, IP-10, and CXCR3 (CXCR3 marks T cells that are competent to migrate across the BBB). R

4. May Have Neuroprotective Effects In TBI and Hypoxia

 
 http://onlinelibrary.wiley.com/doi/10.1111/jnc.13559/abstract

http://onlinelibrary.wiley.com/doi/10.1111/jnc.13559/abstract

 

Stimulation of H3 receptors triggers activation of the Akt/GSK-3β pathway and protects against NMDA-induced neurotoxicity. R

During a Traumatic Brain Injury (TBI), Mast Cells secrete histamine. R

Histamine released from degranulated mast cells induces a transient increase in presynaptic auto-inhibitory HRH3 immunoreactivity and mRNA expression as a mechanism to counteract histamine neurotoxicity. R

H3R agonists may also benefits brain cells during Oxygen and Glucose Deprivation Conditions (OGD) and Hypoxia. R

5. May Fight Bile Duct Cancer

The histamine agonist RAMH can inhibit Cholangiocarcinoma (bile duct cancer) growth (decreases tumor growth and expression of VEGF and its receptors; increases PKCα expression). R

6. May Help Sleep And Migraines

H3R agonist prodrugs have shown to both inhibit neurogenic inflammation in dura, to induce sleep, and to reduce pain. R

H3R agonists may potentially have migraine prophylactic properties. R

H3R Agonists

  • Histamine R
  • Imetit R
  • Immepip R
  • Immethridine R
  • Memantine - mRNA increased in the cerebral cortex, hippocampus, hypothalamus, and striatum from chronic use R
  • Methimepip R
  • Not necessarily an agonist... Prenatal Alcohol Exposure - increases H3R-Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus R
  • Quinpirole R
  • R-α-methyl-histamine (RAMH) R

Mechanism Of Action

 
 https://www.ncbi.nlm.nih.gov/pubmed/27563055

https://www.ncbi.nlm.nih.gov/pubmed/27563055

 

Simple:

  • Increases Akt R
  • Increases Arachidonic Acid R
  • Increases β-arrestin R
  • Increases DAG R
  • Increases EGFR R
  • Increases ERK1/2 R
  • Increases GDNF R
  • Increases GH R
  • Increases GIRKs R
  • Increases IP3 R
  • Increases MAPK R
  • Increases PKC R 
  • Increases PLA2 R
  • Increases PLAC/PLC R R
  • Increases PLD R
  • Increases PI3K R
  • Increases VGLUT1 R
  • Reduces AC R
  • Reduces ACh R
  • Reduces Adenylyl Cyclase R
  • Reduces A2AR R
  • Reduces cAMP R
  • Reduces CaMKII R
  • Reduces D-Aspartate (in GP) R
  • Reduces Dopamine (synthesis, not DA release...in Striatum, SNr, NAC) R 
  • Reduces GABA (in Striatum, GP, and SNr) R
  • Reduces Glucagon (secretion in pancreas) R
  • Reduces Glutamate (in Striatum) R
  • Reduces GSK-3β R
  • Reduces Histamine (synthesis and release in Striatum) R
  • Reduces IFN-γ R
  • Reduces IL-6 R
  • Reduces IL-12 R
  • Reduces IL-17A R
  • Reduces Na+/H+ exchanger R
  • Reduces Noradrenaline R
  • Reduces N- and P-/Q- types of voltage-gated Ca2+ channels R
  • Reduces 5HT (in SNr) R
  • Reduces TGF-β R
  • Reduces TNF-α R
  • Reduces VEGF R
 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514756/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514756/

 

Advanced:

  • Six isoforms have been reported with varying distribution (H3A-F). R R
  • Some of these drugs may inhibit CYP450 and have poor BBB penetration, so conessine may be the best. R
    • Both the H3Aand H3D isoforms contain the full-length third intracellular loop but have different C-termini.
    • All the other isoforms have deletions in that loop (H3B and H3E: 32 amino acids; H3C and H3F: 48 amino acids).
    • Isoforms H3A-C have the same C-terminus, while isoforms H3E-F have an alternative C-terminus
  • H3R, a G-protein coupled receptor (GPCR, coupled to Gi/o proteins), is able to signal on its own i.e., without activation by an agonist, and thus displays constitutive activity. R
    • H3R activation inhibits synthesis of histamine through adenylate cyclase/protein kinase A and calcium/calmodulin-dependent protein kinase type II (CaMKII) pathways. R
    • H3R can activate phospholipase A2 (PLA2) mediated release of arachidonic acid (AA) and phosphoinositol-3-kinase activity resulting in activation of the Akt/glycogen synthase kinase (GSK)-3β axis. R 
    • H3Rs activate Gαi/o proteins, and their inhibitory effect on neurotransmitter release is thus likely to involve the reduction in depolarization-induced Ca2+ entry, via the action of Gβγ complexes at the pore-forming α1-subunit of N- and P-/Q-type voltage-gated Ca2+ channels. R
    • H3R can modulate neurotransmitter release is the inhibition of the cAMP/PKA pathway via the action of the Gαi/o sub- units on adenylyl cyclases. R
      • The lowering of intracellular levels of cAMP through the activation of H3 autoreceptors (by an agonist or via a constitutive property) results in the modulation of histamine synthesis in histaminergic nerve terminals through the AC/PKA pathway. R
    • H3Rs activate G protein-gated inwardly rectifying K+ channels (GIRKs) which inhibit corticostriatal transmission. R
  • Vesicular glutamate transporter 1 (VGLUT1) colocalizes with H3Rs in the striatum. R
  • Histamine strongly attenuates GABAergic transmission by acting at H3Rs for synapses onto D2-MSNs and at both H3 and H2 receptors for synapses onto D1-MSNs. R
  • In the striatum, H3Rs act on acetylcholine release in rat entorhinal cortex, frontoparietal cortex, hippocampus, nucleus accumbens, and basolateral amygdala, but this effect appears to involve transsynaptic actions rather than a direct effect at receptors located on cholinergic nerve terminals. R
  • In the GP, H3R activation inhibited the stimulatory effect of A2ARs. R
  • In the substantia nigra pars reticulata, H3R agonists RAMH and immepip reduced the electrically evoked release of 5-HT by 51 % and 61 %, respectively, with the effect being prevented by the antagonist thioperamide. R
  • Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. R
  • In the ear, H3R is expressed in the organ of Corti and lateral wall of the cochlea. R
  • H3R evokes ERK1/2 activation via a MMP-dependant EGFR transactivation pathway in HEK293 cells and cortical neurons. R

Genetics

HRH3

rs3787429

  • T alleles
    • Exhibited protective effect against Chronic Heart Failure R
  • C alleles
    • Higher risk of Chronic Heart Failure R
    • Has greater reduction in Brief Psychiatric Rating Scale (BPRS) at 4 weeks vs TT with risperidone therapeutic in Chinese population R

rs3787430

  • C alleles
    • Greater reduction in BPRS at 4 weeks and 8 weeks vs TT with risperidone therapeutic in Chinese population R

More Research

  • HRH3 knockout larvae adapt faster to sudden darkness, suggesting a role for this receptor in regulating responses to changes in the environment. R
  • Administration of pitolisant can reverse olanzapine-induced high triglyceride levels. R