Role of Histamine H3 Receptor Antagonist Pitolisant in Early Neural Differentiation of Mouse Embryonic Stem Cells.

The histamine H3 receptor, prominently expressed in neurons with a minor presence in glial cells, acts as both an autoreceptor and an alloreceptor, controlling the release of histamine and other neurotransmitters. The receptor impacts various essential physiological processes. Our team's initial investigations had demonstrated that the histamine H3 receptor antagonists could facilitate nerve regeneration by promoting the histamine H1 receptors on primary neural stem cells (NSCs) in the traumatic brain injury mouse, which suggested the potential of histamine H3 receptor as a promising target for treating neurological disorders and promoting nerve regeneration. Pitolisant (PITO) is the only histamine H3 receptor antagonist approved by the Food and Drug Administration (FDA) for treating narcolepsy. However, there is no report on Pitolisant in neural development or regeneration, and it is urgent to be further studied in strong biological activity models in vitro. The embryonic stem (ES) cells were differentiated into neural cells in vitro, which replicated the neurodevelopmental processes that occur in vivo. It also provided an alternative model for studying neurodevelopmental processes and testing drugs for neurological conditions. Therefore, we aimed to elucidate the regulatory role of Pitolisant in the early differentiation of ES cells into neural cells. Our results demonstrated that Pitolisant could promote the differentiation of ES cells toward NSCs and stimulated the formation of growth cones. Furthermore, Pitolisant was capable of inducing the polarization of NSCs through the cAMP-LKB1-SAD/MARK2 pathway, but had no significant effect on later neuronal maturation. Pitolisant altered mitochondrial morphology and upregulated the levels of mitochondrion-related proteins TOM20, Drp1, and p-Drp1, and reversed the inhibitory effect of Mdivi-1 on mitochondrial fission during the early neural differentiation of ES cells. In addition, Pitolisant induced the increase in cytosolic Ca2+. Our study provided an experimental foundation for the potential application of histamine H3 receptor-targeted modulators in the field of neuroregeneration.

Nanodelivery of histamine H3 receptor inverse agonist BF-2649 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury.

Military personnel are often victims of spinal cord injury resulting in lifetime disability and decrease in quality of life. However, no suitable therapeutic measures are still available to restore functional disability or arresting the pathophysiological progression of disease in victims for leading a better quality of life. Thus, further research in spinal cord injury using novel strategies or combination of available neuroprotective drugs is urgently needed for superior neuroprotection. In this regard, our laboratory is engaged in developing TiO2 nanowired delivery of drugs, antibodies and enzymes in combination to attenuate spinal cord injury induced pathophysiology and functional disability in experimental rodent model. Previous observations show that histamine antagonists or antioxidant compounds when given alone in spinal cord injury are able to induce neuroprotection for short periods after trauma. In this investigation we used a combination of histaminergic drugs with antioxidant compound H-290/51 using their nanowired delivery for neuroprotection in spinal cord injury of longer duration. Our observations show that a combination of H3 receptor inverse agonist BF-2549 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury. These observations suggests that histamine receptors are involved in the pathophysiology of spinal cord injury and induce superior neuroprotection in combination with an inhibitor of lipid peroxidation H-290/51, not reported earlier. The possible mechanisms and significance of our findings in relation to future clinical approaches in spinal cord injury is discussed.

The benefits of betahistine or vestibular rehabilitation (Tetrax biofeedback) on the quality of life and fall risk in patients with Ménière's disease.

OBJECTIVE: This study aimed to evaluate the benefits of betahistine or vestibular rehabilitation (Tetrax biofeedback) on the quality of life and fall risk in patients with Ménière's disease. METHODS: Sixty-six patients with Ménière's disease were randomly divided into three groups: betahistine, Tetrax and control groups. Patients' Dizziness Handicap Index and Tetrax fall index scores were obtained before and after treatment. RESULTS: Patients in the betahistine and Tetrax groups showed significant improvements in Dizziness Handicap Index and fall index scores after treatment versus before treatment (p < 0.05). The improvements in the Tetrax group were significantly greater than those in the betahistine group (p < 0.05). CONCLUSIONS: Betahistine and vestibular rehabilitation (Tetrax biofeedback) improve the quality of life and reduce the risk of falling in patients with Ménière's disease. Vestibular rehabilitation (Tetrax biofeedback) is an effective management method for Ménière's disease.

Using betahistine in the treatment of patients with Menière's disease: a meta-analysis with the current randomized-controlled evidence.

Background: Betahistine is used worldwide to treat patients with Menière's disease. However, despite it being used for decades, diverging opinions on the effect of betahistine on Menière's symptomatology still exist.Aims: The objective of this systematic review was to provide an overview and rate the certainty of the current evidence base regarding the use of betahistine to treat patients with Menière's disease.Materials and methods: A systematic literature search was conducted in October 2019. The search strategy was subdivided into searches for existing guidelines, systematic reviews and individual randomized controlled trials (RCT) investigating the usage of betahistine as compared to placebo, in patients with Ménière's disease. The primary outcome was the frequency of vertigo attack(s) and occurrence of serious adverse events.Results: We identified three relevant guidelines and three systematic reviews: however, neither included any relevant trials matching our inclusion criteria. An individual search for RCTs identified one trial. The results from this particular trial showed no difference in effects on symptoms following treatment with betahistine.Conclusions and Significance: There is a need for further well-conducted placebo RCTs. Currently, there is still a lack of substantial evidence supporting betahistine as a significant and adequate treatment for patients diagnosed with Menière's disease. Trial registration number: The protocol is registered in PROSPERO. Registration number: CRD42018110127 Accepted 11.10.2018.

Histamine-induced plasticity and gene expression in corticostriatal pathway under hyperammonemia.

AIMS: Histamine H3 receptor (H3R) antagonists/inverse agonists increase vigilance. We studied brain histaminergic pathways under hyperammonemia and the transcriptome of receptors and their signaling cascades to provide a rationale for wake-promoting therapies. METHODS: We analyzed histamine-induced long-lasting depression of corticostriatal synaptic transmission (LLDhist). As the expression of dopamine 1 receptors (D1R) is upregulated in LGS-KO striatum where D1R-H3R dimers may exist, we investigated actions of H3R and D1R agonists and antagonists. We analyzed transcription of selected genes in cortex and dorsal striatum in a mouse model of inborn hyperammonemia (liver-specific glutamine synthetase knockout: LGS-KO) and compared it with human hepatic encephalopathy. RESULTS: LGS-KO mice showed significant reduction of the direct depression (DD) but not the long-lasting depression (LLD) by histamine. Neither pharmacological activation nor inhibition of D1R significantly affected DDhist and LLDhist in WT striatum, while in LGS-KO mice D1R activation suppressed LLDhist. Histaminergic signaling was found unchanged at the transcriptional level except for the H2R. A study of cAMP-regulated genes indicated a significant reduction in the molecular signature of wakefulness in the diseased cortex. CONCLUSIONS: Our findings provide a rationale for the development of aminergic wake-promoting therapeutics in hyperammonemic disorders.

H1-antihistamines may no longer be necessary for patients with refractory chronic spontaneous urticaria after initiation of omalizumab

No disponible

Microinjection of histamine and its H3 receptor agonist and antagonist into the agranular insular cortex influence sensory and affective components of neuropathic pain in rats.

Many areas of the brain along with neurotransmitters involve in processing of nociceptive, emotional and cognitive dimensions of neuropathic pain. Brian neuronal histamine through H1, H2, H3 and H4 receptors mediates many physiological functions such as cognition, emotion and pain. In the present study we investigated the effects of intra-agranular insular cortex microinjection of histamine and its H3 receptor agonist and antagonist on sensory and affective aspects of neuropathic pain. Spared nerve injury model of neuropathic pain was used. Two guide cannulas were surgically implanted in the right and left sides of agranular insular cortex. Sensory component (mechanical hyperalgesia) was recorded by application of von Frey filaments onto the plantar surface of the hind paw. Area under curve of mechanical hyperalgesia was calculated. Affective aspect (place escape avoidance paradigm) was recorded using an inverse white/black chamber. Histamine (0.5, 1 and 2 µg/site) and thioperamide (a histamine H3 receptor antagonist, 4 µg/site) decreased, whereas immepip (a histamine H3 receptor agonist, 2 µg/site) increased the percentages of paw withdrawal frequency and time spent in white side of white/black box. Prior administration of thioperamide (4 µg/site) increased the suppressive effects induced by histamine and inhibited immepip (2 µg/site)-induced hyperalgesia and aversion. Based on the present results, it is concluded that histamine and its H3 receptor at the agranular insular cortex level may involve in modulation of sensory and affective components of neuropathic pain.

Patient Perceptions of Effectiveness in Treatments for Menière's Disease: a National Survey in Italy.

OBJECTIVES: The aim of the present study was to investigate current treatment practices and self-reported effectiveness in Ménière's disease. MATERIALS AND METHODS: Members of two Italian Ménière's disease support (n=170) with ≥6-month history of Ménière's disease were administered an online survey about recent treatments. Vertigo episode count, work absenteeism, and limitations in family life, social life, work, or travel as included in the Social Life and Work Impact of Dizziness Questionnaire before and after recent treatments were queried. RESULTS: Twenty-four different treatments were reported for Ménière's disease, with dietary modifications (55%), diuretics (47%), and betahistine (41%) being the most common. The majority (71%) received multiple simultaneous treatments. Prior to the most recent treatments, 78%-89% of respondents indicated limitations in family or social life, work, or traveling. After their most recent treatment, respondents reported improvements in mean vertigo episode counts (5.7±7.6 vs. 2.6±4.6, p<0.001), days off work per month (10.1±9.2 vs. 4.2±6.7, p<0.001), and proportions indicating limitations in any functional measure assessed (p<0.05). These findings were consistent regardless of treatment approach (p<0.05 for all). Intratympanic gentamicin provided the greatest reductions in vertigo count, functional limitations, and work absenteeism (p<0.01 for all), as well as the fewest respondents reporting post-treatment functional limitations (16%-37%). CONCLUSION: Despite many treatment approaches targeting different proposed pathophysiology for Ménière's disease in this cross-sectional survey, all treatments are reported as effective by patients. These findings support a prominent placebo effect in Ménière's disease and highlight challenges in studying treatment outcomes; there is a critical need to better understand Ménière's disease.

The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders.

Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).

Sleep Medicine: Insomnia and Sleep.

Insomnia disorder is an economic burden and public health concern affecting up to one-third of the population of the United States. It is mostly seen in older age groups, and often considered a normal aging phenomenon. The diagnosis and treatment of insomnia rely mainly on a thorough sleep history to address the precipitating factors as well as maladaptive behaviors resulting in poor sleep. It is important for clinicians to recognize and manage the symptoms of insomnia to prevent the morbidity associated with it. This review aims to highlight the pathophysiology, associated comorbidities, clinical evaluation and effective management strategies for insomnia disorder.

Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice.

We previously reported that hypothalamic tumor necrosis factor-alpha (TNF-α) mRNA expression via histamine H4 receptors contributes to the development of cisplatin-induced anorexia; however, its precise mechanisms remain unclear. It has been reported that chemotherapeutic agents induce the suppression of orexin neuron activity, and the administration of orexin inhibits chemotherapeutic agent-induced gastric discomfort. Other studies demonstrated that the central administration of TNF-α impairs the orexinergic system, and that orexin excites the histaminergic system. We investigated the involvement of orexinergic and histaminergic systems in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia. Cisplatin decreased the expression of prepro-orexin mRNA, which encodes precursors of orexin, in the hypothalamus of mice. The period of expression decreased in parallel with the onset of anorexia, and treatment with an H4 receptor antagonist (JNJ7777120, 10 mg/kg) inhibited the decrease in expression. The effect of the H4 receptor antagonist on cisplatin-induced anorexia in mice was antagonized by an orexin OX2 receptor antagonist (JNJ10397049, 5 mg/kg) rather than an orexin OX1 receptor antagonist (SB408124, 30 mg/kg). Although an OX2 receptor agonist (YNT-185, 20 mg/kg) or a histamine H3 receptor inverse agonist (ciproxifan, 1 mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX2 receptor agonist was antagonized by an H3 receptor silent antagonist (VUF5681, 5 mg/kg). The combination of JNJ7777120 (10 mg/kg) and ciproxifan (0.5 mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia.

Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade.

Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.e. EL-4 lymphoma, MC-38 colorectal carcinoma, and 4T1 mammary carcinoma. In vivo treatment with HDC delayed EL-4 and 4T1 tumor growth and reduced the ROS formation by intratumoral MDSCs. HDC treatment of EL-4 bearing mice also reduced the accumulation of intratumoral MDSCs and reduced MDSC-induced suppression of T cells ex vivo. Experiments using GR1-depleted and Nox2 knock out mice supported that the anti-tumor efficacy of HDC required presence of NOX2+ GR1+ cells in vivo. In addition, treatment with HDC enhanced the anti-tumor efficacy of programmed cell death receptor 1 (PD-1) and PD-1 ligand checkpoint blockade in EL-4- and MC-38-bearing mice. Immunomodulatory effects of a HDC-containing regimen on MDSCs were further analyzed in a phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996) where patients with acute myeloid leukemia received HDC in conjunction with low-dose IL-2 (HDC/IL-2) for relapse prevention. Peripheral CD14+HLA-DR-/low MDSCs (M-MDSCs) were reduced during cycles of HDC/IL-2 therapy and a pronounced reduction of M-MDSCs during HDC/IL-2 treatment heralded favorable clinical outcome. We propose that anti-tumor properties of HDC may comprise the targeting of MDSCs.

Report from a Consensus Conference on the treatment of Ménière's disease with betahistine: rationale, methodology and results.

Ménière's disease is a disorder of the inner ear that causes vertigo, tinnitus, fullness and hearing loss. Although several treatments are available, the success rate is reported to be around 70%, similar to placebo. Betahistine, a weak H1 receptor agonist and an effective H3 receptor antagonist, is frequently prescribed for Ménière's disease, especially to reduce recurrent vertigo attacks. The effects of this drug on hearing and other audiological symptoms remains unclear. Given the inconclusive reports in the literature, we proposed a consensus conference on the use of betahistine in Ménière's disease. The aim was to define best practice criteria for therapy for Ménière's disease, improve clinical suitability and reduce heterogeneity of the therapeutic approach. The consensus conference on betahistine for Ménière's disease involved a group of Italian experts in vestibular disorders who were asked a series of questions prepared by opinion leaders. The Delphi method, an iterative investigation method, was used to increase consensus. Via a tele-voting system, each participant anonymously evaluated all statements using a Likert 5-point scale. Betahistine was considered useful for the treatment of dizziness and vertigo during the intercritical phase of the disease (87% agreeing answers). However, during the acute phase of the disease betahistine was considered less effective and useful only when associated with other drugs (71% agreement). Similarly, the efficacy of the drug was considered low when used to reduce progressive hearing loss, tinnitus, and ear fullness. The experts advocated the use of betahistine during the intercritical phase of Ménière's disease to reduce the number and severity of vertigo attacks. Its use seems to be at low risk of major side effects.

Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study.

RATIONALE: Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics. METHOD: We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales. RESULTS: In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients. CONCLUSIONS: These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

European Position Statement on Diagnosis, and Treatment of Meniere's Disease.

Meniere Disease keeps challenges in its diagnosis and treatment since was defined by Prosper Meniere at the beginning of 19th Century. Several classifications and definition were made until now and speculations still exist on its etiology. As the etiology remains speculative the treatment models remain in discussion also. The European Academy of Otology and Neurotology Vertigo Guidelines Study Group intended to work on the diagnosis and treatment of Meniere's disease and created the European Positional Statement Document also by resuming the consensus studies on it. The new techniques on diagnosis are emphasized as well as the treatment models for each stage of the disease are clarified by disregarding the dilemmas on its treatment. The conservative, noninvasive and invasive therapeutic models are highlighted.

The histamine H3 receptor inverse agonist pitolisant reduces body weight in obese mice.

The pharmacological profile of pitolisant, a histamine H3 receptor antagonist/inverse agonist, indicates that this compound might reduce body weight and metabolic disturbances. Therefore, we studied the influence of pitolisant on body weight, water and sucrose intake as well as metabolic disturbances in the high-fat and high-sugar diet-induced obesity model in mice. To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat blend for 14 weeks, water and 30% sucrose solution available ad libitum. Glucose tolerance test was performed at the beginning of week 15. Insulin tolerance was tested the day after. At the end of study, plasma levels of triglycerides and cholesterol were determined. Pitolisant at dose of 10 mg/kg bw (ip) was administrated during 14 days, starting from the beginning of week 13. Metformin at dose of 100 mg/kg bw (ip) was used as reference drug. Mice fed with high-fat diet and sucrose solution showed more weight gain throughout the 12-week period of inducing obesity. Animals fed with high-fat diet and treated with pitolisant (for the next 14 days) showed significantly less weight gain than mice from the control group consuming a high-fat feed. In the group treated with pitolisant, glucose levels were significantly lower than glucose levels of control obese mice after glucose load. The plasma triglyceride levels in pitolisant-treated mice were significantly lower compared with those in control obese group. In conclusion, pitolisant has a favorable influence of body weight and improves glucose tolerance and the lipid profile in obese mice.

QSAR Modeling of Histamine H3R Antagonists/inverse Agonists as Future Drugs for Neurodegenerative Diseases.

BACKGROUND: Histamine H3 receptor (H3R) is associated with several neuropsychological diseases, and thus it is an important target involved in several CNS disorders, such as narcolepsy, attention deficit hyperactivity disorder and schizophrenia. Since QSAR modeling is a feasible approach to explain the role of the molecular substituents in the biological activity, it can help in improving the design of better H3R ligands for these conditions. METHODS: This article reviews papers previously published in literature to show the current status of the contribution from QSAR modeling to reach H3R antagonists/inverse agonists. RESULTS: Classical and 3D-QSAR models were retrieved, showing that the steric and hydrophobic properties of the H3R ligands are most important to reach good affinity. CONCLUSION: Although QSAR methods are valuable to design better H3R antagonists/inverse agonists, pharmacokinetics should also be considered in future models to ensure good CNS penetration.

Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (AßP) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering AßP (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 µl, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3 weeks of AßP administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and AßP deposits were examined in the brain. A significant reduction in AßP deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier.