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In vitro effects of histamine receptor 1 antagonists on proliferation and histamine release in canine neoplastic mast cells.

ABSTRACT: Canine mastocytomas (MCTs) are characterized by rapid proliferation of neoplastic mast cells (MCs) and clinical signs caused by MC-derived mediators. In dogs suffering from MCT, histamine receptor 1 (HR1) antagonists are frequently used to control mediator-related clinical symptoms. Previous studies have shown that the HR1 antagonists loratadine and terfenadine exert some growth-inhibitory effects on neoplastic MCs. We examined whether other HR1 antagonists used in clinical practice (desloratadine, rupatadine, cyproheptadine, dimetindene, diphenhydramine) affect proliferation and survival of neoplastic MCs. Furthermore, we analysed whether these HR1 antagonists counteract IgE-dependent histamine release from a MC line harbouring a functional IgE-receptor. HR1 antagonists were applied on two canine MC lines, C2 and NI-1, and on primary MCs obtained from three MCT samples. The HR1 antagonists desloratadine, rupatadine and cyproheptadine were found to be more potent in decreasing proliferation of C2 and NI-1 cells when compared with dimetindene and diphenhydramine. Similar effects were seen in primary neoplastic MCs, except for diphenhydramine, which exerted more potent growth-inhibitory effects than the other HR1 antagonists. Drug-induced growth-inhibition in C2 and NI-1 cells was accompanied by apoptosis. Loratadine, desloratadine and rupatadine also suppressed IgE-dependent histamine release in NI-1 cells. However, drug concentrations required to elicit substantial effects on growth or histamine release were relatively high (>10 µM). Therefore, it remains unknown whether these drugs or similar, more potent, HR1-targeting drugs can suppress growth or activation of canine neoplastic MCs in vivo.

SUBMITTER: Gamperl S

PROVIDER: S-EPMC7840218 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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In vitro effects of histamine receptor 1 antagonists on proliferation and histamine release in canine neoplastic mast cells.

Gamperl Susanne S Stefanzl Gabriele G Willmann Michael M Valent Peter P Hadzijusufovic Emir E

Veterinary medicine and science 20200913 1

Canine mastocytomas (MCTs) are characterized by rapid proliferation of neoplastic mast cells (MCs) and clinical signs caused by MC-derived mediators. In dogs suffering from MCT, histamine receptor 1 (HR1) antagonists are frequently used to control mediator-related clinical symptoms. Previous studies have shown that the HR1 antagonists loratadine and terfenadine exert some growth-inhibitory effects on neoplastic MCs. We examined whether other HR1 antagonists used in clinical practice (desloratadi ...[more]

PMID: 32924324

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Project description:Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit-/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.

Dataset Information

In vitro effects of histamine receptor 1 antagonists on proliferation and histamine release in canine neoplastic mast cells.

Publications

In vitro effects of histamine receptor 1 antagonists on proliferation and histamine release in canine neoplastic mast cells.

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