Modulation of metabolic activity of phagocytes by antihistamines

Abstract

The purpose of the study was to investigate the effects of H1-antihistamines of the 1st generation (antazoline, bromadryl, brompheniramine, dithiaden, cyclizine, chlorcyclizine, chlorpheniramine, clemastine) and the 2nd generation (acrivastine, ketotifen, and loratadine) on the respiratory burst of phagocytes. Reactive oxygen species generation in neutrophils isolated from rat blood was measured using luminol-enhanced chemiluminescence. Changes in nitrite formation and iNOS protein expression by RAW 264.7 macrophages were analysed using Griess reaction and Western blotting. The antioxidative properties of drugs in cell-free systems were detected spectrophotometrically, luminometrically, fluorimetrically, and amperometrically. The majority of the H1-antihistamines tested (bromadryl, brompheniramine, chlorcyclizine, chlorpheniramine, clemastine, dithiaden, and ketotifen) exhibited a significant inhibitory effect on the chemiluminescence activity of phagocytes. H1-antihistamines did not show significant scavenging properties against superoxide anion and hydroxyl radical, thus this could not contribute to the inhibition of chemiluminescence. H1-antihistamines had a different ability to modulate nitric oxide production by LPS-stimulated macrophages. Bromadryl, clemastine, and dithiaden were the most effective since they inhibited iNOS expression, which was followed by a significant reduction in nitrite levels. H1-antihistamines had no scavenging activity against nitric oxide. It can be concluded that the effects observed in the H1-antihistamines tested are not mediated exclusively via H1-receptor pathway or by direct antioxidative properties. Based on our results, antihistamines not interfering with the microbicidal mechanisms of leukocytes (antazoline, acrivastine and cyclizine) could be used preferentially in infections. Other antihistamines should be used, under pathological conditions accompanied by the overproduction of reactive oxygen species.

Cyclizine‐induced proinflammatory responses through Akt‐NFκB pathway in macrophages

“…32 In the present study, cyclizine did not inhibit NO generation or iNOS expression in RAW264.7 cells. 32 Conversely, NO generation and iNOS expression were significantly induced by cyclizine at concentrations of 200, 300, and 500 μM. Therefore, cyclizine in macrophages may stimulate proinflammation through the overexpression of proinflammatory cytokines and mediators.…”

Evaluation of New Scaffolds of Myeloperoxidase Inhibitors by Rational Design Combined with High-Throughput Virtual Screening

“…In parallel it has been demonstrated that 2-thioxanthine derivatives are suicide substrates of MPO, e.g., 2-isobutyl thioxanthine (IC 50 = 0.87 μM). − Other compounds that affected MPO activity were H1-antihistaminic drugs and naphthalene derivatives, e.g., 6-methoxy1-ethyl-3,4-dihydro-naphthalene (IC 50 = 3 μM) . In any case, these studies have shown that there is additional need for alternative scaffolds to conceive more efficient inhibitors with activity in the nanomolar range …”

Levocetirizine Pretreatment Mitigates Lipopolysaccharide-Induced Lung Inflammation in Rats

“…Histamine was shown to stimulate release of hydrogen peroxide by primary bronchial epithelial cells via H 1 receptor-dependent signaling [ 28 ]. Several H 1 -antihistamines diminished the production of ROS in neutrophils isolated from rat blood [ 29 ]. Moreover, it may be possible that levocetirizine inactivates ROS through direct scavenging activity or via activation of SOD, the only antioxidant enzyme that can scavenge superoxide [ 30 ].…”