Histamine H3 Receptor Expression Research Articles

Therapeutic potential of LINS01 histamine H3 receptor antagonists as antineoplastic agents for triple negative breast cancer

The aims of this work were to evaluate the expression of histamine H3 receptor (H3R) in triple negative breast cancer (TNBC) samples and to investigate the antitumoral efficacy and safety of the LINS01 series of H3R antagonists, through in silico, in vitro, and in vivo approaches. Antitumor activity of LINS01009, LINS01010, LINS01022, LINS01023 was assayed in vitro in 4T1 and MDA-MB-231 TNBC cells (0.01–100 μM), and in vivo in 4T1 tumors orthotopically established in BALB/c mice (1 or 20 mg/kg). Additionally, H3R expression was assessed in 50 human TNBC samples. We have described a higher H3R mRNA expression in basal-like/TNBC tumors vs. matched normal tissue using TCGA Pan-Cancer Atlas data, and a higher H3R expression in human tumor samples vs. peritumoral tissue evidenced by immunohistochemistry associated with poorer survival. Furthermore, while all the essayed compounds showed antitumoral properties, LINS01022 and LINS01023 exhibited the most potent antiproliferative effects by: i) inducing cell apoptosis and suppressing cell migration in 4T1 and MDA-MB-231 TNBC cells, and ii) inhibiting cell growth in paclitaxel-resistant 4T1 cells (potentiating the paclitaxel antiproliferative effect). Moreover, 20 mg/kg LINS01022 reduced tumor size in 4T1 tumor-bearing mice, exhibiting a safe toxicological profile and potential for druggability estimated by ADME calculations. We conclude that the H3R is involved in the regulation of TNBC progression, offering promising therapeutic potential for the novel LINS01 series of H3R antagonists.

Social Stress Upregulates Histamine H3 Receptor mRNA in Murine Urinary Bladder Smooth Muscle

In mice, social stress causes mast cell degranulation and alters voiding behavior. Histamine, a mast cell‐derived biogenic amine, is hallmarked as a modulator that can drive neurogenic bladder overactivity. Additionally, histamine causes a rapidly desensitizing contraction of the urinary bladder smooth muscle (UBSM) in normal mice that is H1 receptor‐dependent. However, histamine receptor expression in UBSM after social stress is unclear. We sought to determine if the expression of histamine receptors change in urinary bladder smooth muscle cells after social stress. We hypothesized that histamine H1 receptor expression would be upregulated in UBSM cells collected from stressed mice as compared to non‐stressed. Prior to cell isolation and collection, 4‐week‐old C57BL/6 male mice were randomly housed with CD1 adult male aggressor mice for 5 minutes, after which both mice were placed in barrier housing for 1 hour. Social stress was repeated with different aggressor mice for 14 days. Afterward, bladders were enzymatically dissociated, and urinary bladder smooth muscle cells were isolated for single cell qRT‐PCR. Non‐stressed UBSM cells expressed only Hrh1and Hrh2 mRNA. However, UBSM cells from stressed mice also expressed Hrh3 mRNA. These data suggest that social stress alters histamine receptor expression in UBSM, specifically by upregulating histamine H3 receptor expression. Since H3 receptors are involved in inflammatory peptide release in other organ systems, the functional role of H3 receptors in stress‐induced bladder dysfunction warrants further investigation.

Influence of betahistine on the expression of histamine H3 receptor in the medial vestibular nucleus following unilateral labyrinthectomy in guinea pigs

To observe the influence of betahistine on the expression of histamine H3 receptor in the medial vestibular nucleus (MVN) following unilateral labyrinthectomy (UL). Fifty-six healthy guinea pigs were randomly divided into three groups:the sham-operated group (group I), the UL group[group II, and UL+betahistine (BET) group (group III)], BET was intraperitoneally injection at 2.17 mg×kg(-1)×d(-1) for 7 days. The expression of histamine H3 receptor was analyzed by immunohistochemistry at 1 day, 3 days and 7 days after UL. H3 receptors were presented in the MVN and the expression of histamine H3 receptor were increased significantly in the ipsilateral MVN at 1 and 3 days after UL(P < 0.05), the change turned into the normal value at 7 days(P > 0.05). In the UL+BET group, the intensity of histamine H3 receptor was lower than that in the UL at 1 day and 3 days(4.25 ± 0.71, 3.50 ± 0.92 vs 5.75 ± 0.71, 5.50 ± 0.93, P < 0.05). However, the changes turned into the normal values at 3 and 7 days (P > 0.05). The early stage of the vestibular compensation process may be associated with the change of H3 receptor expression in MVN. In the UL+BET group the histamine H3 receptor recovered quickly.

Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms

The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. Here we show that H3R expression is upregulated after I/R in two mouse models. H3R antagonists and H3R knockout attenuate I/R injury, which is reversed by an H3R-selective agonist. Interestingly, H1R and H2R antagonists, a histidine decarboxylase (HDC) inhibitor and HDC knockout all fail to compromise the protection by H3R blockade. H3R blockade inhibits mTOR phosphorylation and reinforces autophagy. The neuroprotection by H3R antagonism is reversed by 3-methyladenine and siRNA for Atg7, and is diminished in Atg5−/− mouse embryonic fibroblasts. Furthermore, the peptide Tat-H3RCT414-436, which blocks CLIC4 binding with H3Rs, or siRNA for CLIC4, further increases I/R-induced autophagy and protects against I/R injury. Therefore, H3R promotes I/R injury while its antagonism protects against ischaemic injury via histamine-independent mechanisms that involve suppressing H3R/CLIC4 binding-activated autophagy, suggesting that H3R inhibition is a therapeutic target for cerebral ischaemia.

House-dust mite allergen and ozone exposure decreases histamine H3 receptors in the brainstem respiratory nuclei

Allergic airway diseases in children are a common and a growing health problem. Changes in the central nervous system (CNS) have been implicated in contributing to some of the symptoms. We hypothesized that airway allergic diseases are associated with altered histamine H3 receptor expression in the nucleus tractus solitarius (NTS) and caudal spinal trigeminal nucleus, where lung/airway and nasal sensory afferents terminate, respectively. Immunohistochemistry for histamine H3 receptors was performed on brainstem sections containing the NTS and the caudal spinal trigeminal nucleus from 6- and 12-month-old rhesus monkeys who had been exposed for 5 months to house dust mite allergen (HDMA) + O 3 or to filtered air (FA). While histamine H3 receptors were found exclusively in astrocytes in the caudal spinal trigeminal nucleus, they were localized to both neuronal terminals and processes in the NTS. HDMA + O 3 exposure significantly decreased histamine H3 receptor immunoreactivity in the NTS at 6 months and in the caudal spinal trigeminal nucleus at 12 months of age. In conclusion, exposing young primates to HDMA + O 3 changed histamine H3 receptor expression in CNS pathways involving lung and nasal afferent nerves in an age-related manner. Histamine H3 receptors may be a therapeutic target for allergic asthma and rhinitis in children.

Histamine H3 Receptor-Mediated Signaling Protects Mice from Cerebral Malaria

BackgroundHistamine is a biogenic amine that has been shown to contribute to several pathological conditions, such as allergic conditions, experimental encephalomyelitis, and malaria. In humans, as well as in murine models of malaria, increased plasma levels of histamine are associated with severity of infection. We reported recently that histamine plays a critical role in the pathogenesis of experimental cerebral malaria (CM) in mice infected with Plasmodium berghei ANKA. Histamine exerts its biological effects through four different receptors designated H1R, H2R, H3R, and H4R.Principal FindingsIn the present work, we explored the role of histamine signaling via the histamine H3 receptor (H3R) in the pathogenesis of murine CM. We observed that the lack of H3R expression (H3R−/− mice) accelerates the onset of CM and this was correlated with enhanced brain pathology and earlier and more pronounced loss of blood brain barrier integrity than in wild type mice. Additionally tele-methylhistamine, the major histamine metabolite in the brain, that was initially present at a higher level in the brain of H3R−/− mice was depleted more quickly post-infection in H3R−/− mice as compared to wild-type counterparts.ConclusionsOur data suggest that histamine regulation through the H3R in the brain suppresses the development of CM. Thus modulating histamine signaling in the central nervous system, in combination with standard therapies, may represent a novel strategy to reduce the risk of progression to cerebral malaria.

Opposite Functions of Histamine H1 and H2 Receptors and H3 Receptor in Substantia Nigra Pars Reticulata

The substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus. Inhibitory outputs from SNr are encoded in spike frequency and pattern of the inhibitory SNr projection neurons. SNr output intensity and pattern are often abnormal in movement disorders of basal ganglia origin. In Parkinson's disease, histamine innervation and histamine H3 receptor expression in SNr may be increased. However, the functional consequences of these alterations are not known. In this study, whole cell patch-clamp recordings were used to elucidate the function of different histamine receptors in SNr. Histamine increased SNr inhibitory projection neuron firing frequency and thus inhibitory output. This effect was mediated by activation of histamine H1 and H2 receptors that induced inward currents and depolarization. In contrast, histamine H3 receptor activation hyperpolarized and inhibited SNr inhibitory projection neurons, thus decreasing the intensity of basal ganglia output. By the hyperpolarization, H3 receptor activation also increased the irregularity of the interspike intervals or changed the pattern of SNr inhibitory neuron firing. H3 receptor-mediated effects were normally dominated by those mediated by H1 and H2 receptors. Furthermore, endogenously released histamine provided a tonic, H1 and H2 receptor-mediated excitation that helped keep SNr inhibitory projection neurons sufficiently depolarized and spiking regularly. These results suggest that H1 and H2 receptors and H3 receptor exert opposite effects on SNr inhibitory projection neurons. Functional balance of these different histamine receptors may contribute to the proper intensity and pattern of basal ganglia output and, as a consequence, exert important effects on motor control.

Plasticity of histamine H3 receptor expression and binding in the vestibular nuclei after labyrinthectomy in rat

BackgroundIn rat, deafferentation of one labyrinth (unilateral labyrinthectomy) results in a characteristic syndrome of ocular and motor postural disorders (e.g., barrel rotation, circling behavior, and spontaneous nystagmus). Behavioral recovery (e.g., diminished symptoms), encompassing 1 week after unilateral labyrinthectomy, has been termed vestibular compensation. Evidence suggesting that the histamine H3 receptor plays a key role in vestibular compensation comes from studies indicating that betahistine, a histamine-like drug that acts as both a partial histamine H1 receptor agonist and an H3 receptor antagonist, can accelerate the process of vestibular compensation.ResultsExpression levels for histamine H3 receptor (total) as well as three isoforms which display variable lengths of the third intracellular loop of the receptor were analyzed using in situ hybridization on brain sections containing the rat medial vestibular nucleus after unilateral labyrinthectomy. We compared these expression levels to H3 receptor binding densities.Total H3 receptor mRNA levels (detected by oligo probe H3X) as well as mRNA levels of the three receptor isoforms studied (detected by oligo probes H3A, H3B, and H3C) showed a pattern of increase, which was bilaterally significant at 24 h post-lesion for both H3X and H3C, followed by significant bilateral decreases in medial vestibular nuclei occurring 48 h (H3X and H3B) and 1 week post-lesion (H3A, H3B, and H3C). Expression levels of H3B was an exception to the forementioned pattern with significant decreases already detected at 24 h post-lesion. Coinciding with the decreasing trends in H3 receptor mRNA levels was an observed increase in H3 receptor binding densities occurring in the ipsilateral medial vestibular nuclei 48 h post-lesion.ConclusionProgressive recovery of the resting discharge of the deafferentated medial vestibular nuclei neurons results in functional restoration of the static postural and occulomotor deficits, usually occurring within a time frame of 48 hours in rats. Our data suggests that the H3 receptor may be an essential part of pre-synaptic mechanisms required for reestablishing resting activities 48 h after unilateral labyrinthectomy.

Expression of the H3 receptor in the developing CNS and brown fat suggests novel roles for histamine

Histamine and histamine receptors have been implicated in signaling mechanisms in developmental processes in the brain and peripheral organs. Pharmacological studies have also implied that the histamine H3 receptor, in addition to acting as a presynaptic auto- and heteroreceptor in the central nervous system, is active in peripheral tissues. We show that detectable histamine H3-receptor expression during development and in adult rat is restricted to specific areas of the brain and to adipocytes and the capillary network in brown adipose tissue. Histamine H3-receptor mRNA expression was not detected in other internal organs studied, or in spinal or sympathetic chain ganglia. These results support a histaminergic involvement in brain development through activation of the histamine H3 receptor and indicate a possible novel involvement of the histamine H3 receptor as a mediator of the effects of histamine in thermogenesis in brown adipose tissue.

Increased brain histamine H3 receptor expression during hibernation in golden-mantled ground squirrels

BackgroundHibernation is a state of extremely reduced physiological functions and a deep depression of CNS activity. We have previously shown that the histamine levels increase in the brain during hibernation, as does the ratio between histamine and its first metabolite, suggesting increased histamine turnover during this state. The inhibitory histamine H3 receptor has both auto- and heteroreceptor function, rendering it the most likely histamine receptor to be involved in regulating the activity of histamine as well as other neurotransmitters during hibernation. In view of accumulating evidence that there is a global depression of transcription and translation during hibernation, of all but a few proteins that are important for this physiological condition, we reasoned that an increase in histamine H3 receptor expression would clearly indicate an important hibernation-related function for the receptor.ResultsIn this study we show, using in situ hybridization, that histamine H3 receptor mRNA increases in the cortex, caudate nucleus and putamen during hibernation, an increase that is accompanied by elevated receptor binding in the cerebral cortex, globus pallidus and substantia nigra. These results indicate that there is a hibernation-related increase in H3 receptor expression in cortical neurons and in striatopallidal and striatonigral GABAergic neurons. GTP-γ-S binding autoradiography shows that the H3 receptors in the globus pallidus and substantia nigra can be stimulated by histamine throughout the hibernation cycle, suggesting that they are functionally active during hibernation.ConclusionsThese results show that the histamine H3 receptor gene is one of the few with a transcript that increases during hibernation, indicating an important role for the receptor in regulating this state. Moreover, the receptor is functionally active in the basal ganglia, suggesting a function for it in regulating e.g. dopaminergic transmission during hibernation.