RESUMEN
Diazepam administration has been shown to influence the release of histamine in various brain areas involved in motor behavior. Therefore, the present study explored the plausible regulatory role of the central histaminergic system in diazepam-induced deficits in motor performance in mice using the rota-rod and beam walking tests. In this study, several doses of diazepam (0.5, 1, 2, and 3â mg/kg, i.p.) were assessed in mice for changes in motor performance on the rota-rod and beam walking test. In addition, the brain histamine levels were determined after diazepam administration, and the diazepam-induced motor deficits were assessed in mice, pretreated centrally (intracerebroventricular) with histaminergic agents such as histamine (0.1, 10â µg), histamine precursor (L-histidine: 0.1, 2.5â µg), histamine neuronal releaser/H 3 receptor antagonist (thioperamide: 0.5, 10â µg), H 1 and H 2 receptor agonist [2-(3-trifluoromethylphenyl) histamine (FMPH: 0.1, 6.5â µg; amthamine: 0.1, 5â µg)/antagonist (H 1 : cetirizine 0.1â µg) and (H 2 : ranitidine: 50â µg)]. Results indicate that mice treated with diazepam at doses 1, 2â mg/kg, i.p. significantly increased the brain histamine levels. Moreover, in mice pretreated with histaminergic transmission-enhancing agents, the diazepam (2â mg/kg, i.p.)-induced motor incoordination was significantly reversed. Contrastingly, diazepam (1â mg/kg, i.p.) in its subeffective dose produced significant motor deficits in mice preintracerebroventricular injected with histamine H 1 and H 2 receptor antagonists on both the employed tests. Therefore, it is postulated that endogenous histamine operates via H 1 and H 2 receptor activation to alleviate the motor-impairing effects of diazepam.
Asunto(s)
Diazepam , Histamina , Animales , Diazepam/farmacología , Ratones , Histamina/farmacología , Histamina/metabolismo , Masculino , Relación Dosis-Respuesta a Droga , Actividad Motora/efectos de los fármacos , Caminata , Agonistas de los Receptores Histamínicos/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Histidina/farmacologíaRESUMEN
Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE.
Asunto(s)
Potenciación a Largo Plazo , Efectos Tardíos de la Exposición Prenatal , Receptores Histamínicos H3 , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Femenino , Masculino , Ratas , Embarazo , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/efectos de los fármacos , Agonistas de los Receptores Histamínicos/farmacología , Ratas Sprague-Dawley , Etanol/farmacología , Agonismo Inverso de Drogas , Potenciales Postsinápticos Excitadores/efectos de los fármacosRESUMEN
Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R activity together with significant in vivo H3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3 , Receptores Histamínicos H3 , Ratas , Humanos , Animales , Histamina , Agonismo Inverso de Drogas , Receptores Histamínicos H3/metabolismo , Simulación del Acoplamiento Molecular , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Esteroides , Microsomas Hepáticos/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacología , Antagonistas de los Receptores HistamínicosRESUMEN
The histamine H3 receptor (H3R) regulates as a presynaptic G protein-coupled receptor the release of histamine and other neurotransmitters in the brain, and is consequently a potential therapeutic target for neuronal disorders. The human H3R encodes for seven splice variants that vary in the length of intracellular loop 3 and/or the C-terminal tail but are all able to induce heterotrimeric Gi protein signaling. The last two decades H3R drug discovery and lead optimization has been exclusively focused on the 445 amino acids-long reference isoform H3R-445. In this study, we pharmacologically characterized for the first time all seven H3R isoforms by determining their binding affinities for reference histamine H3 receptor agonists and inverse agonists. The H3R-453, H3R-415, and H3R-413 isoforms display similar binding affinities for all ligands as the H3R-445. However, increased agonist binding affinities were observed for the three shorter isoforms H3R-329, H3R-365, and H3R-373, whereas inverse agonists such as the approved anti-narcolepsy drug pitolisant (Wakix®) displayed significantly decreased binding affinities for the latter two isoforms. This opposite change in binding affinity of agonist versus inverse agonists on H3R-365 and H3R-373 is associated with their higher constitutive activity in a cAMP biosensor assay as compared to the other five isoforms. The observed differences in pharmacology between longer and shorter H3R isoforms should be considered in future drug discovery programs.
Asunto(s)
Histamina , Receptores Histamínicos H3 , Humanos , Histamina/farmacología , Receptores Histamínicos H3/metabolismo , Agonismo Inverso de Drogas , Receptores Histamínicos , Isoformas de Proteínas , Agonistas de los Receptores Histamínicos/farmacologíaRESUMEN
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.
Asunto(s)
Histamina , Piperidinas , Receptores Histamínicos H3 , Ratones , Animales , Histamina/farmacología , Células Madre Embrionarias de Ratones/metabolismo , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/uso terapéutico , Receptores Histamínicos H3/metabolismoRESUMEN
Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H4 receptor (H4R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H4R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe3447.39, which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of H4R and subtype selectivity of histamine receptors, and show that the H4R structures may be valuable in rational drug design of drugs targeting the H4R.
Asunto(s)
Histamina , Receptores Acoplados a Proteínas G , Humanos , Histamina/metabolismo , Receptores Histamínicos H4 , Microscopía por Crioelectrón , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Agonistas de los Receptores Histamínicos/farmacologíaRESUMEN
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.
Asunto(s)
Nanocables , Receptores Histamínicos H3 , Traumatismos de la Médula Espinal , Humanos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Agonismo Inverso de Drogas , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/uso terapéutico , Neuroprotección , Calidad de Vida , Receptores Histamínicos H3/uso terapéutico , Receptores Histamínicos H4RESUMEN
Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H1-receptor (H1R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers (τ-tautomer, π-tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H1R-Gq complex. In atomistic molecular dynamics simulations, the τ-tautomer formed stable interactions with the receptor, while the π-tautomer induced a rotation of the histamine ring by 180° and formed only weaker hydrogen bonding interactions. This suggests that the τ-tautomer is more relevant for stabilization of the active ternary histamine-H1R-Gq complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H1R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H1R-Gq complex and rather induces an inactive conformation in the absence of the Gq protein. Our data thus indicate that the charge state of histamine critically affects its interactions with the H1R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H1R activation states.
Asunto(s)
Histamina , Receptores Histamínicos H1 , Histamina/metabolismo , Receptores Histamínicos H1/química , Receptores Histamínicos H1/metabolismo , Agonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H2 , Proteínas de Unión al GTP/metabolismoRESUMEN
Many structures of the central nervous system recruit different neurotransmitters in pain processing. This study focused on the contribution of histamine and its H 1 receptors in the ventral pallidum (VP) in mediating pain-triggered behaviors. Intra-VP microinjection of histamine and 2-pyridylethylamine (2-PEA, a histamine H 1 receptor agonist) at the same doses of 0.5 and 1 µg/200 nl reduced both the first and second phases of licking/biting duration as well as flinching number induced by intra-plantar (ipl) injection of formalin (2.5%, 50 µl). Premicroinjection of mepyramine (a histamine H 1 antagonist, 2 µg/200 nl) into the VP antagonized the suppressive effects of 1 µg/200 nl histamine and 2-PEA on licking/biting and flinching behaviors. The possible mechanisms of the above-mentioned pain-reducing effects were followed by intra-VP and intrathecal administration of naloxone (an opioid receptor antagonist). Naloxone (2 µg/200 nl) preadministration into the VP inhibited attenuating effects of histamine and 2-PEA on both the licking/biting and flinching behaviors, whereas intrathecal injection of naloxone only inhibited their suppressing effects on flinching behavior. None of the treatments used in this study altered the animal's motor activity. The obtained results may reveal the role of histamine and its activated H 1 receptor in the VP in suppressing the pain behaviors caused by formalin. Opioid receptors in the VP and spinal cord may contribute to these functions.
Asunto(s)
Prosencéfalo Basal , Histamina , Animales , Histamina/farmacología , Receptores Opioides/metabolismo , Formaldehído/efectos adversos , Prosencéfalo Basal/metabolismo , Dolor/tratamiento farmacológico , Agonistas de los Receptores Histamínicos/farmacología , Naloxona/farmacología , Médula EspinalRESUMEN
The human histamine H3 receptor (hH3R) is predominantly expressed in the CNS, where it regulates the synthesis and release of histamine and other neurotransmitters. Due to its neuromodulatory role, the hH3R has been associated with various CNS disorders, including Alzheimer's and Parkinson's disease. Markedly, the hH3R gene undergoes extensive splicing, resulting in 20 isoforms, of which 7TM isoforms exhibit variations in the intracellular loop 3 (IL3) and/or C-terminal tail. Particularly, hH3R isoforms that display variations in IL3 (e.g., hH3R-365) are shown to differentially signal via Gαi-dependent pathways upon binding of biased agonists (e.g., immepip, proxifan, imetit). Nevertheless, the mechanisms underlying biased agonism at hH3R isoforms remain unknown. Using a structure-function relationship study with a broad range of H3R agonists, we thereby explored determinants underlying isoform bias at hH3R isoforms that exhibit variations in IL3 (i.e., hH3R-445, -415, -365, and -329) in a Gαi-dependent pathway (cAMP inhibition). Hence, we systematically characterized hH3R isoforms on isoform bias by comparing various ligand properties (i.e., structural and molecular) to the degree of isoform bias. Importantly, our study provides novel insights into the structural and molecular basis of receptor isoform bias, highlighting the importance to study GPCRs with multiple isoforms to better tailor drugs.
Asunto(s)
Histamina , Receptores Histamínicos H3 , Humanos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos , Isoformas de Proteínas/metabolismo , Ligandos , Agonistas de los Receptores Histamínicos/farmacologíaRESUMEN
Pitolisant is a histamine 3-receptor antagonist/inverse agonist effective and safe for the treatment of excessive daytime sleepiness and cataplexy in narcolepsy. We report a 19-year-old woman affected by narcolepsy type 1 who presented panic attacks and dissociative symptoms induced by pitolisant. The patient medical history was unremarkable except that for familiarity for anxiety disorder and chronic insomnia. Moreover, a detailed psychometric evaluation revealed a profile of low resilience, a severe grade of depression, an anxiety trait and a propension to dissociative symptoms. Our report suggests that caution should be used in patients with predisposing factors to psychiatric disorders, especially during the first period of treatment with pitolisant. In consideration of the high prevalence of psychiatric comorbidities in narcolepsy, it seems worth to carefully investigate psychiatric background of narcoleptic patients.
Asunto(s)
Cataplejía , Narcolepsia , Trastorno de Pánico , Femenino , Humanos , Adulto Joven , Adulto , Agonismo Inverso de Drogas , Narcolepsia/inducido químicamente , Narcolepsia/diagnóstico , Narcolepsia/tratamiento farmacológico , Agonistas de los Receptores Histamínicos/farmacologíaRESUMEN
Histamine H3 receptor (H3 R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 (1) has been reported previously as a high-affinity non-imidazole H3 R (partial) agonist. Our structure-activity relationship analysis using derivatives of 1 identified both basic moieties as key interaction motifs and the distance of these from the central core as a determinant for H3 R affinity. However, in spite of the reported H3 R (partial) agonism, in our hands, 1 acts as an inverse agonist for Gαi signaling in a CRE-luciferase reporter gene assay and using an H3 R conformational sensor. Inverse agonism was also observed for all of the synthesized derivatives of 1. Docking studies and molecular dynamics simulations suggest ionic interactions/hydrogen bonds to H3 R residues D1143.32 and E2065.46 as essential interaction points.
Asunto(s)
Histamina , Receptores Histamínicos H3 , Agonismo Inverso de Drogas , Ligandos , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/química , Relación Estructura-Actividad , Receptores HistamínicosRESUMEN
Histamine is well known for mediating peripheral inflammation; however, this amine is also found in high concentrations in the brain where its roles are much less known. In vivo chemical dynamics are difficult to measure, thus fundamental aspects of histamine's neurochemistry remain undefined. In this work, we undertake the first in-depth characterization of real time in vivo histamine dynamics using fast electrochemical tools. We find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptors and metabolism. We find two breakthrough aspects of histamine modulation. First, differences in H3 receptor regulation between sexes show that histamine release in female mice is much more tightly regulated than in male mice under H3 or inflammatory drug challenge. We hypothesize that this finding may contribute to hormone-mediated neuroprotection mechanisms in female mice. Second, a high dose of a commonly available antihistamine, the H1 receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This finding highlights the sheer significance of pharmaceuticals on neuromodulation. Our study opens the path to better understanding and treating histamine related disorders of the brain (such as neuroinflammation), emphasizing that sex and modulation (of serotonin) are critical factors to consider when studying/designing new histamine targeting therapeutics.
Asunto(s)
Histamina , Receptores Histamínicos H3 , Femenino , Animales , Masculino , Ratones , Histamina/metabolismo , Serotonina/metabolismo , Receptores Histamínicos H3/metabolismo , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/metabolismo , Encéfalo/metabolismoRESUMEN
Histamine is a major neurotransmitter and alleviates neuronal damage after ischemic injury via H2 receptors. Herein, we investigated the effects of H2 receptor agonists on the blood-brain barrier (BBB) disruption after traumatic brain injury (TBI). Male ddY mice were used to generate the TBI model, in which a fluid percussion injury (FPI) was induced by a hydraulic impact. The BBB disruption was evaluated using Evans blue extravasation. H2 receptor agonists, amthamine and dimaprit, were administered into the lateral cerebroventricle (i.c.v.) or tail vein (i.v.) from 3 hours to 3 days after FPI. The i.c.v. or i.v. administration of amthamine and dimaprit reduced FPI-induced Evans blue extravasation and promoted mRNA expression of vascular protective factors, including angiopoietin-1 and sonic hedgehog. The co-administration of ranitidine, a H2 receptor antagonist, inhibited these effects. Expression of the H2 receptor was observed in astrocytes and brain microvascular endothelial cells (BMECs) in the injured cortex. Treatment with amthamine and dimaprit promoted mRNA expression of vascular protective factors in astrocytes and BMECs. These results suggest that H2 receptor agonists alleviate TBI-induced BBB disruption by increasing the expression of vascular protective factors in astrocytes and BMECs.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Agonistas de los Receptores Histamínicos , Angiopoyetina 1/metabolismo , Angiopoyetina 1/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Dimaprit/metabolismo , Dimaprit/farmacología , Células Endoteliales/metabolismo , Azul de Evans/metabolismo , Azul de Evans/farmacología , Proteínas Hedgehog , Histamina/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Agonistas de los Receptores Histamínicos/farmacología , Masculino , Ratones , Factores Protectores , ARN Mensajero/metabolismo , Ranitidina/metabolismo , Ranitidina/farmacología , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , TiazolesRESUMEN
Studies have shown that brain histamine has a role in seizure pathophysiology. Histamine acts by four distinct receptor subtypes (H1R-H4R). Previous reports signified the anticonvulsant activity of histamine H3R antagonists. We evaluated the effect of intra-amygdala injection of pitolisant the H3R inverse agonist on seizures induced by the electrical kindling model of epilepsy. Eighteen adult male rats with an approximate weight of 300 g were used. A tri-polar electrode twisted with the guide cannula, and two monopolar electrodes were implanted into the basolateral amygdala or the surface of the skull using stereotaxic surgery. One week after surgery, the threshold was determined in the animals. Twenty-four hours afterward, the animals received six stimuli daily with the threshold intensity until the generation of three consecutive stages five seizures. Then, saline, and 24 h later, pitolisant at three doses (1, 10, and 100 µg) were injected into the amygdala in distinct rats. Thirty minutes after injection of the drug or its solvent, seizure parameters including after-discharge duration (ADD), seizure stage (SS), and stage five duration (S5D) were recorded. Data analysis indicated that pitolisant reduced S5D at all doses, significantly. Pitolisant at the dose of 100 µg also decreased ADD and SS, significantly. However, pitolisant at the doses of 1 and 10 µg did not change ADD and SS. The dose-response curves showed that the anticonvulsant activity of pitolisant changed in a dose-dependent manner. In conclusion, the results confirmed the powerful anticonvulsant effects of pitolisant in the electrical kindling model of epilepsy.
Asunto(s)
Epilepsia , Excitación Neurológica , Receptores Histamínicos H3 , Animales , Anticonvulsivantes/toxicidad , Epilepsia/tratamiento farmacológico , Histamina/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos , Masculino , Piperidinas , Ratas , ConvulsionesRESUMEN
Histamine is a neurotransmitter that modulates neuronal activity and regulates various brain functions. Histamine H3 receptor (H3R) antagonists/inverse agonists enhance its release in most brain regions, including the cerebral cortex, which improves learning and memory and exerts an antiepileptic effect. However, the mechanism underlying the effect of H3R antagonists/inverse agonists on cortical neuronal activity in vivo remains unclear. Here, we show the mechanism by which pitolisant, an H3R antagonist/inverse agonist, influenced perirhinal cortex (PRh) activity in individual neuron and neuronal population levels. We monitored neuronal activity in the PRh of freely moving mice using in vivo Ca2+ imaging through a miniaturized one-photon microscope. Pitolisant increased the activity of some PRh neurons while decreasing the activity of others without affecting the mean neuronal activity across neurons. Moreover, it increases neuron pairs with synchronous activity in excitatory-responsive neuronal populations. Furthermore, machine learning analysis revealed that pitolisant altered the neuronal population activity. The changes in the population activity were dependent on the neurons that were excited and inhibited by pitolisant treatment. These findings indicate that pitolisant influences the activity of a subset of PRh neurons by increasing the synchronous activity and modifying the population activity.
Asunto(s)
Agonistas de los Receptores Histamínicos , Corteza Perirrinal , Animales , Histamina , Agonistas de los Receptores Histamínicos/farmacología , Humanos , Ratones , Neuronas , PiperidinasRESUMEN
The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78). Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability in a dose-dependent manner (p < 0.05). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands. Importantly, we screened a drug repurposing library of 433 FDA-approved compounds (1 µM) in combination with histamine (10 µM) in Hut78 cells. Histamine produced a favorable antitumor effect with 18 of these compounds, including the histone deacetylase inhibitor panobinostat. Apoptosis, proliferation, and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that the H4R is expressed in TCL, and it is involved in histamine-mediated responses.
Asunto(s)
Antineoplásicos/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Linfoma de Células T/tratamiento farmacológico , Receptores Histamínicos H4/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HEK293 , Histamina/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Linfoma de Células T/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Several of the drugs currently available for the treatment of premature ejaculation (PE) (e.g., local anesthetics or antidepressants) are associated with numerous safety concerns and exhibit weak efficacy. To date, no therapeutics for PE have been approved in the United States, highlighting the need to develop novel agents with sufficient efficacy and fewer side effects. In this study, we focused on the histamine H3 receptor (H3R) as a potential target for the treatment of PE and evaluated the effects of imetit (an H3R/H4R agonist), ciproxifan (an H3R antagonist), and JNJ-7777120 (an H4R antagonist) in vivo. Our in vivo electrophysiological experiments revealed that imetit reduced mechanical stimuli-evoked neuronal firing in anesthetized rats. This effect was inhibited by ciproxifan but not by JNJ-7777120. Subsequently, we evaluated the effect of imetit using a copulatory behavior test to assess ejaculation latency (EL) in rats. Imetit prolonged EL, although this effect was inhibited by ciproxifan. These findings indicate that H3R stimulation suppresses mechanical stimuli-evoked neuronal firing in the spinal-penile neurotransmission system, thereby resulting in prolonged EL. To our knowledge, this is the first report to describe the relationship between H3R and PE. Thus, H3R agonists may represent a novel treatment option for PE.
Asunto(s)
Agonistas de los Receptores Histamínicos/farmacología , Histamina/metabolismo , Eyaculación Prematura/tratamiento farmacológico , Eyaculación Prematura/metabolismo , Receptores Histamínicos H3/metabolismo , Animales , Imidazoles/farmacología , Masculino , Piperidinas/farmacología , Ratas , Ratas Wistar , Tiourea/análogos & derivados , Tiourea/farmacologíaRESUMEN
Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.
Asunto(s)
Afecto , Antipruriginosos/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Mecanorreceptores/fisiología , Mentol/farmacología , Fibras Nerviosas Amielínicas/fisiología , Nervio Peroneo/fisiología , Percepción del Tacto/fisiología , Adulto , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Antipruriginosos/administración & dosificación , Femenino , Histamina/farmacología , Agonistas de los Receptores Histamínicos/administración & dosificación , Humanos , Pierna/inervación , Masculino , Mecanorreceptores/efectos de los fármacos , Mentol/administración & dosificación , Fibras Nerviosas Amielínicas/efectos de los fármacos , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Nervio Peroneo/efectos de los fármacos , Nervio Radial/efectos de los fármacos , Nervio Radial/fisiología , Percepción del Tacto/efectos de los fármacos , Adulto JovenRESUMEN
Histamine has been implicated in urinary bladder dysfunction as an inflammatory mediator driving sensory nerve hypersensitivity. However, the direct influence of histamine on smooth muscle has not been thoroughly investigated. We hypothesized that histamine directly contracts urinary bladder smooth muscle (UBSM) independent of effects on nerves. Single cell quantitative RT-PCR determined that only histamine H1 and H2 receptors were expressed on UBSM cells. In isolated tissue bath experiments, histamine (200 µM) caused a highly variable and rapidly desensitizing contraction that was completely abolished by the H1 receptor antagonist fexofenadine (5 µM) and the Gq/11 inhibitor YM254890 (1 µM). Neither the muscarinic receptor antagonist atropine (1 µM), the Na+ channel blocker tetrodotoxin (1 µM), nor the transient receptor potential vanilloid type 1 antagonist capsazepine (10 µM) altered responses to histamine, suggesting that nerve activation was not involved. UBSM desensitization to histamine was not due to receptor internalization, as neither the cholesterol-depleting agent methyl-ß-cyclodextrin (10 mM), the dynamin-mediated endocytosis inhibitor dynasore (100 µM), nor the clathrin-mediated endocytosis inhibitor pitstop2 (15 µM) augmented or prolonged histamine contractions. Buffer from desensitized tissues still contracted histamine-naïve tissues, revealing that histamine was not metabolized. Prolonged exposure to histamine also had no effect on contractions due to electrical field stimulation, suggesting that both efferent nerve and UBSM excitability were unchanged. Together, these data suggest that histamine, although able to transiently contract UBSM, does not have a lasting effect on UBSM excitability or responses to efferent nerve input. Thus, any acute effects of histamine directly on UBSM contractility are unlikely to alter urinary bladder function.NEW & NOTEWORTHY Histamine is commonly associated with inflammatory bladder pathologies. We sought to investigate the role of histamine on urinary bladder contractility. Histamine contracts the bladder, but this response is highly variable and desensitizes completely in minutes. This desensitization is not due to internalization of the receptor or metabolism of histamine. Because nerve-evoked contractions are also not increased in the presence of histamine, our findings suggest that histamine is not directly acting to change contractility.