H2-receptor Research Articles

Abdominal Epilepsy, A Diagnosis to Consider in Children with Recurrent Vomiting: A Case Report

gastrointestinal complaints and central nervous system involvement, mainly confusion, fatigue, headache, dizziness, syncope, and lethargy resulting during the abdominal seizure activity. Chronic vomitting or other gastrointestinal symptoms often lead to fluid and nutritional deficiencies which resulted in malnutrition. To date, there was no study has been reported on abdominal epilepsy in Indonesia. Case Presentation: We presented a case of two-year-old girl with chief complaint of recurrent profuse vomiting every month for the past year. Patient complained of headaches and abdominal pain and tended to sleep all day during relapse. Physical examination showed sunken eyes and decreased skin turgor. EEG showed abnormal results, diffuse irritative, epileptiform with normal basic rhythm. Esophageal polyps were also found on endoscopy. Patient was given anti-epileptic drugs and histamine H2 receptor antagonists and responded well to those therapies. Conclusion: Abdominal epilepsy is a rare case which may resulted in vomiting and abdominal pain in children. EEG examination is an important test for diagnosing abdominal epilepsy. Treatment with anti-epileptic drugs is known to respond well in this case.

Study of Chlorpheniramine-induced Genotoxicity in Human Peripheral Blood Lymphocytes

Background: Chlorpheniramine is an H1 receptor inverse agonist, which belongs to the first-generation class. It is generally regarded as a strong antihistamine with a wide variety of indications in allergic and non-allergic diseases. The extensive consumption of chlorpheniramine might culminate in less evident adverse effects, such as genotoxicity. Objectives: In this study, we attempted to assess the possible potential of chlorpheniramine in inducing genotoxicity. Methods: Human lymphocytes were separated into groups as follows: control group (Phosphate Buffered saline), Chlorpheniramine group (0.1, 0.5, 0.75, 1.5 mM), and Positive control group (cisplatin 0.4 µg/mL). After 24 hours of incubation, we conducted an alkaline comet assay to evaluate the DNA damage. Also, oxidative stress damage was evaluated by the levels of lipid peroxidation and glutathione oxidation. Results: Significant increases were observed in DNA percentage in tail and tail moment at high concentration (1.5mM, P<0.05). Likewise, at the same concentration, the MDA levels increased significantly in addition to the significant depletion in the level of glutathione. Conclusion: High concentration of chlorpheniramine significantly induced genotoxicity in human lymphocytes. In addition, we showed that oxidative stress was one of the mechanisms elaborated in chlorpheniramine genotoxicity at high concentrations.

Histamine and its H1 receptors in the ventral pallidum mediate formalin-induced pain-related behaviors through this region and spinal cord opioid receptors.

Many structures of the central nervous system recruit different neurotransmitters in pain processing. This study focused on the contribution of histamine and its H1 receptors in the ventral pallidum (VP) in mediating pain-triggered behaviors. Intra-VP microinjection of histamine and 2-pyridylethylamine (2-PEA, a histamine H1 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 H1 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 H1 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.

The histamine H3 receptor modulates dopamine D2 receptor–dependent signaling pathways and mouse behaviors

The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)-expressing and D2 receptor (D2R)-expressing populations. A crossantagonistic interaction between H3R and D1R has been demonstrated in mice, both at the behavioral level and at the biochemical level. Although interactive behavioral effects have been described upon coactivation of H3R and D2R, the molecular mechanisms underlying this interaction are poorly understood. Here, we show that activation of H3R with the selective agonist R-(-)-α-methylhistamine dihydrobromide mitigates D2R agonist-induced locomotor activity and stereotypic behavior. Using biochemical approaches and the proximity ligation assay, we demonstrated the existence of an H3R-D2R complex in the mouse striatum. In addition, we examined consequences of simultaneous H3R-D2R agonism on the phosphorylation levels of several signaling molecules using immunohistochemistry. H3R agonist treatment modulated Akt (serine/threonine PKB)-glycogen synthase kinase 3 beta signaling in response to D2R activation via a β-arrestin 2-dependent mechanism in D2R-SPNs but not in D1R-SPNs. Phosphorylation of mitogen- and stress-activated protein kinase 1 and rpS6 (ribosomal protein S6) was largely unchanged under these conditions. As Akt-glycogen synthase kinase 3 beta signaling has been implicated in several neuropsychiatric disorders, this work may help clarify the role of H3R in modulating D2R function, leading to a better understanding of pathophysiology involving the interaction between histamine and dopamine systems.

Investigation of a Quantitative Bioanalytical HPLC Method for the Assessment of Famotidine in Pre-clinical Samples: Application for Pharmacokinetic Studies

Famotidine (FAM), a histamine H2 receptor antagonist, is effective against peptic ulcers and Zollinger Ellison syndrome. In the current investigation, a HPLC approach was developed to detect the Famotidine (FAM) in pre-clinical samples (rat plasma). To get rid of any chromatographic solvent effects, methanolic extraction method was used to prepare biological samples. A C18 column was used for chromatographic separation, with a pH-adjusted to 8 as mobile phase of water, methanol, and acetonitrile (70: 20: 10, v/v/v) at a flow rate of 1 mL/min and UV detection at 264 nm. The retention times of FAM was found to be 5.7 min. The technique was linear in the range of 50 to 1400 ng/mL in plasma concentration with R2 of 0.9985. The newly proposed method’s respective limits for quantification and detection were found to be 151.45 ± 6.47 ng/mL and 49.97 ± 2.14 ng/mL. The average recovery rates were discovered to range from 98.06 to 103.56%. After numerous freeze-thaw cycles of the treated plasma samples, analyte was stable and showed no sign of significant deterioration. After a single oral dose of 10 mg/kg of FAM, the approach was effectively used to assess the pharmacokinetic characteristics in Wistar albino rats. Consequently, the straightforward technique would enable quick with affordable detection of the FAM from biological samples.

Multitargeting Histamine H3 Receptor Ligands among Acetyl- and Propionyl-Phenoxyalkyl Derivatives

Alzheimer's disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H3 receptors (H3Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H3R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H3Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H3Rs (Ki: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC50 = 3.60 µM, BuChE IC50 = 0.55 µM; 17: AChE IC50 = 1.06 µM, BuChE IC50 = 2.86 µM), and lack of cell toxicity up to 50 µM.

Ergotamine Stimulates Human 5-HT4-Serotonin Receptors and Human H2-Histamine Receptors in the Heart

Ergotamine (2'-methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus Claviceps purpurea. Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT1-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT4-serotonin receptors or H2-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H2-TG (mouse which exhibits cardiac-specific overexpression of the human H2-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT4-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT4-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT4-TG and H2-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H2-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT4-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT4-serotonin receptors as well at human H2-histamine receptors. Ergotamine acts as an agonist on H2-histamine receptors in the human atrium.

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

Efficacy of betahistine in counteracting second-generation antipsychotics-induced weight gain: A meta-analysis with trial sequential analysis

IntroductionDespite being effective in schizophrenia, second-generation antipsychotics are potent histamine-H1 receptor antagonists associated with weight gain. Histaminergic agonists can potentially counteract the weight gain effects of antipsychotics. Betahistine is a centrally acting histamine-H1 agonist and, therefore, may reduce antipsychotic-induced weight gain, but it has never been examined in a meta-analysis.ObjectivesThis meta-analysis aims to examine the efficacy of betahistine in counteracting the weight gain effects of antipsychotics.MethodsWe searched PubMed, Scopus, Web of Science, and Cochrane Controlled Register of Trials (CENTRAL) for all relevant trials. We used Hedges’ g with its confidence interval as our effect size to correct for the small sample size. The primary outcomes of this study were changes in weight and body mass index (BMI). Changes in insulin resistance and lipid parameters were secondary outcomes.Results165 studies were included in the title/abstract screening, and 5 studies with 217 patients were finally included. Betahistine led to statistically significant changes in weight (Hedges’ g -1.13, 95% CI [-1.66, -0.60], p < 0001), BMI (Hedges’ g -1.64, 95% CI [-2.39, -0.89], p < 0.0001), and waist circumference (Hedges’ g -0.98, 95% CI [-1.47, -0.49], p < 0001). Nevertheless, betahistine did not lead to any significant changes in fasting glucose (Hedges’ g 0.02, 95% CI [-0.41, 0.44], p = 0.94) or insulin levels (Hedges’ g -0.07, 95% CI [-1.78, 1.64], p = 0.94).ConclusionsBetahistine is an effective add-on treatment for second-generation antipsychotics to counteract weight gain experienced with these medications. Further trials are recommended to examine its effect on blood lipids and side effects.Disclosure of InterestNone Declared

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

The histamine H3 receptor binding affinities of cyclohexylamine derivatives has been analysed with the topological and molecular features from Dragon software. Analysis of the structural features in conjunction with the biological endpoints in combinatorial protocol in multiple linear regression (CP-MLR) led to the identification of 26 descriptors for modelling the activity. The study clearly suggested the role of atomic properties such as mass, electronegativity or charge content, polarizability, atomic van der Waals volume, average valence connectivity index chi-5 and absence of number of acceptor atoms for H-bonds (N, O, F) type functionality to optimise the histamine H3 receptor binding affinity of titled compounds. The models developed and the participating descriptors advocate that the substituent groups of the cylohexylamine moiety hold scope for further modification in the optimization of the H3 receptor binding affinity. Analysis of these descriptors in partial least squares (PLS) highlighted their relative significance in modulating the biological response. The selected descriptors are enriched with information corresponding to the activity when compared to the remaining ones. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.

Structures and Anti-Allergic Activities of Natural Products from Marine Organisms.

In recent years, allergic diseases have occurred frequently, affecting more than 20% of the global population. The current first-line treatment of anti-allergic drugs mainly includes topical corticosteroids, as well as adjuvant treatment of antihistamine drugs, which have adverse side effects and drug resistance after long-term use. Therefore, it is essential to find alternative anti-allergic agents from natural products. High pressure, low temperature, and low/lack of light lead to highly functionalized and diverse functional natural products in the marine environment. This review summarizes the information on anti-allergic secondary metabolites with a variety of chemical structures such as polyphenols, alkaloids, terpenoids, steroids, and peptides, obtained mainly from fungi, bacteria, macroalgae, sponges, mollusks, and fish. Molecular docking simulation is applied by MOE to further reveal the potential mechanism for some representative marine anti-allergic natural products to target the H1 receptor. This review may not only provide insight into information about the structures and anti-allergic activities of natural products from marine organisms but also provides a valuable reference for marine natural products with immunomodulatory activities.

Development of acute peptic ulcers complicated by gastrointestinal bleeding in patients with novel coronavirus infection

The study enrolled patients with acute gastrointestinal ulcers and gastrointestinal bleeding, EGD confirmed, against the background of the novel coronavirus infection (61 patients). There were 39 men (63.9 %), women — 22 (36.1 %), the mean age of the patients was 57 years. It was found that preventive schemes of acid blockers administration have not been sufficiently effective and is unsafe for the patients with COVID-19. Based on this, as a prevention of the acute gastrointestinal ulcers in patients with the novel coronavirus infection without GI bleeding, we recommend the administration of the H2 receptor antagonists. The risk of gastrointestinal bleeding increases in patients with COVID-19, so there is a need for further investigation of the efficacy and safety of the preventive therapy in this category of patients.

Histamine promotes angiogenesis through a histamine H1 receptor-PKC-VEGF-mediated pathway in human endothelial cells

Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R–PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways.

Histamine H2 receptor deficit in glutamatergic neurons contributes to the pathogenesis of schizophrenia

Schizophrenia is a serious mental disorder, and existing antipsychotic drugs show limited efficacy and cause unwanted side effects. The development of glutamatergic drugs for schizophrenia is currently challenging. Most functions of histamine in the brain are mediated by the histamine H1 receptor; however, the role of the H2receptor (H2R) is not quite clear, especially in schizophrenia. Here, we found that expression of H2R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H2R gene (Hrh2) in glutamatergic neurons (CaMKIIα-Cre; Hrh2 fl/fl) induced schizophrenia-like phenotypes including sensorimotor gating deficits, increased susceptibility to hyperactivity, social withdrawal, anhedonia, and impaired working memory, as well as decreased firing of glutamatergic neurons in the medial prefrontal cortex (mPFC) in invivo electrophysiological tests. Selective knockdown of H2R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H2R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H2R overexpression in glutamatergic neurons or H2R agonism in the mPFC counteracted schizophrenia-like phenotypes in an MK-801-induced mouse model of schizophrenia. Taken together, our results suggest that deficit of H2R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H2R agonists can be regarded as potentially efficacious medications for schizophrenia therapy. The findings also provide evidence for enriching the conventional glutamate hypothesis for the pathogenesis of schizophrenia and improve the understanding of the functional role of H2R in the brain, especially in glutamatergic neurons.

Effects of histamine on the contractility of the rat distal cauda epididymis

The motor activity of the epididymis duct is an essential process for male fertility and it is regulated by hormonal, neuronal and epithelial mechanisms. However, although there is evidence for the presence of histamine in the epididymis, its effects on epididymal motor activity are unknown. This study sought to evaluate the contractile effects of histamine on the rat distal cauda epididymis duct. Segments of the distal cauda epididymis duct from male Wistar rats were isolated and used in isolated organ bath experiments to evaluate the contractile effects of histamine in the absence or presence of antagonists of histamine receptors, α1-adrenoceptors and muscarinic acetylcholine receptors. The effects of histamine on noradrenaline induced contractions were also investigated. Histamine was able to induce phasic contractions on rat distal cauda epididymis duct which were prevented by promethazine 10–1000 nM (H1 receptor antagonist), ranitidine 1–100 μM (H2 receptor antagonist), atropine 100 nM (muscarinic antagonist), and prazosin 100 nM (α1-adrenoceptor antagonist). In addition, histamine was also able to modify noradrenaline-induced contractions possibly via activation of H1 and H2 receptors. In conclusion, this study demonstrates that histamine can induce phasic contractions of rat distal cauda epididymis via H2 receptors and autonomic neurotransmitters. Histamine may also exert modulatory actions on contractions of rat distal cauda epididymis duct induced by adrenergic receptor agonists. Further studies are necessary to unveil the localization of histamine receptors within the epididymal duct and the consequences of manipulation of the histaminergic system on epididymal function and male fertility.

Ranitidine as an adjuvant regulates macrophage polarization and activates CTLs through the PI3K-Akt2 signaling pathway

Adjuvants are an indispensable component of vaccines, but there are few adjuvants for human vaccines. H2 receptor blockers, inhibiting gastric acid secretion, have immune enhancement effects. Ranitidine (RAN) is a water-soluble H2 receptor blocker, and whether it has an immune-enhancing effect is still unknown. In this study, flow cytometry, western blotting, and immunofluorescence methods were used to analyze whether RAN could activate macrophage polarization to the M1 phenotype in vivo and in vitro. Here, we found that the M1 inflammatory cytokine levels and surface markers in RAW264.7 cells were upregulated by NF-κB activation, possibly through the PI3K-Akt2 signaling pathway, after RAN treatment. Endocytic function was also enhanced by feedback regulation of Akt2/GSK3β/Dynmin1 signaling. Furthermore, to evaluate the adjuvant function of RAN, we used OVA plus RAN as a vaccine to inhibit the growth of B16-OVA tumors in mice. We also found that in the RAN adjuvant group, macrophage polarization to M1, Th1 cell differentiation, and cytotoxic T lymphocyte (CTL) activation were significantly upregulated. The tumor growth of mice was inhibited, and the survival rate of mice was significantly improved. This study provides new evidence for the mechanism by which RAN activates the immune response and is expected to provide a new strategy for the research and development of tumor vaccine adjuvants.

Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease

Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Simultaneous determination of 10 first-generation histamine h1 receptor blockers in feeds by ultra-high-performance liquid chromatography triple quadrupole ion trap hybrid mass spectrometer.

A method for simultaneous determination of 10 first-generation histamine H1 receptor blockers in feeds by ultra-high-performance liquid chromatography triple quadrupole mass spectrometry combined with solid phase extraction. Instrument conditions, extraction solvents, and purification methods have been optimized. Under the optimum conditions, these analytes were separated effectively at 6min. These feeds have been extracted by acid acetonitrile and purified by mixed cation exchange solid-phase extraction. The performance of this method meets the requirements of veterinary residue detection in feeds in China. It is appropriate for the confirmatory monitoring and quantitative analysis of 105 feed samples, five kinds of histamine H1 receptor blockers have been detected in 10 samples.

Bepotastine Sensitizes Ovarian Cancer to PARP Inhibitors through Suppressing NF-κB-Triggered SASP in Cancer-Associated Fibroblasts.

Therapy-induced senescence (TIS) is common in tumor cells treated with PARP inhibitors (PARPis) and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPis and contribute to consequential treatment failure remain unclear. We previously revealed that PARPis triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPis showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent cancer-associated fibroblasts (CAFs) displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPis in both homologous recombination-deficient (HRD) and -proficient ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPis in three-dimensional organotypic cultures and HRD-positive patient-derived xenograft models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.