Molecular pharmacology of antihistamines in inhibition of oxidative burst of professional phagocytes

Abstract

Antihistamines of the H 1 and H 3 /H 4 groups interfere with oxidative burst of human professional phagocytes in vitro. In the concentration of 10 μM, H 1 antihistamines of the 1 st and 2 nd generation inhibited oxidative burst of human neutrophils in the rank order of potency: dithiaden > loratadine > brompheniramine > chlorpheniramine > pheniramine. Of the H 1 antihistamines, the most effective was dithiaden in suppressing oxidative burst of whole human blood and dosedependently the chemiluminescence of isolated neutrophils at extra-and intracellular level. Inhibition of free oxygen radical generation in isolated neutrophils by dithiaden resulted from the inhibition of protein kinase C activation. The potentiation of recombinant caspase-3 by dithiaden is supportive of the antiinflammatory effect of dithiaden and suggestive of increasing the apoptosis of professional phagocytes. Of the H 3 /H 4 antihistamines, the most effective was JNJ7777120 in decreasing chemiluminescence in whole blood and also at extra-and intracellular sites of isolated neutrophils. JNJ 10191584 and thioperamide were less effective and the latter significantly potentiated free oxygen radical generation intracellularly. The results demonstrated that, compared with the H 3 /H 4 antihistamines investigated, H 1 antihistamines were much more potent in inhibiting free oxygen radical generation in human professional phagocytes. This finding should be taken into account therapeutically.

On the Pharmacology of Oxidative Burst of Human Neutrophils

“…This was confirmed in isolated neutrophils by measuring the intracellular chemiluminescence (Drábikova et al 2009) decreasing it in the rank order of potency curcumin > resveratrol > N-feruloylserotonin > quercetin. The intracellular inhibition of luminol-enhanced CL with antioxidants is dose-dependent and differs for the substances investigated (Nosáľ et al 2015, Jančinová et al 2012a. On the other hand, all the compounds tested decreased extracellular isoluminol-enhanced CL corresponding to their scavenging activities for oxidants, most probably as a result of the physico-chemical structure of their molecules, as demonstrated for H1 antihistamines (Králová et al 2009).…”

“…The results showed that the compounds tested inhibited oxidative burst in stimulated whole human blood as measured by luminol-enhanced chemiluminescence (CL). The inhibition of stimulated chemiluminescence was found to be dose dependent for H1 antihistamines (Nosáľ et al 2015), carvedilol (Nosáľ et al 2005) and many polyphenolic compounds (Jančinová et al 2012a). Since the generation of reactive oxygen species was induced with PMA bypassing membrane receptors and stimulated protein kinase C, the inhibitory effect with three therapeutically used drugs (bromphenyramine, carvedilol and dithiaden) and five polyphenols (arbutin, curcumin, N-feruloylserotonin, quercetin and resveratrol) appeared intracellularly.…”

“…The effect of N-feruloylserotonin was not significant. The caspase-3 activity increased with dithiaden was dose-dependent (Nosáľ et al 2015). Caspase-3 belongs to the effector group of caspases which are responsible for the executive phase of apoptosis (Fan et al 2005).…”

Pharmacological intervention with oxidative burst in human neutrophils

“…These are represented by the H1-antihistamines (Drábiková et al, 2006 a,b; Jančinová et al, 2006 a , b ; Nosáľ et al, 2005) and carvedilol (Nosáľ et al, 2009 ). The pyridol derivative stobadine (Drábiková et al, 2007 ) and a number of natural compounds like glucomannans (Drábiková et al, 2009 ), arbutin (Jančinová et al, 2007 ), curcumin (Jančinová et al, 2009 ) and N-feruoyl serotonin (Nosáľ et al, 2015 ) demonstrated antioxidant activity on stimulated neutrophils in vitro . Many pharmacologically active drugs, like glucomannans, significantly decreased oxidative burst of blood phagocytes in the model of rat adjuvant polyarthritis (Drábiková et al, 2009 ; Jančinová et al, 2007 ).…”

“…Professional phagocytic cells play a central role in defending the host against microorganisms by producing reactive oxygen species (ROS) via the NADPH oxidase enzyme complex (Raad et al, 2009 ). A number of therapeutically used drugs and natural compounds with antioxidative properties have been demonstrated to interfere with oxidative burst of human whole blood and isolated neutrophils (Nosáľ et al, 2015 , 2014 , 2011 , Jančinová et al, 2015 , 2009 ), When appropriately stimulated by a variety of stimuli, they undergo dramatic physiological and biochemical changes. These are resulting in phagocytosis, chemotaxis and degranulation with the activation of ROS production in a metabolic pathway known as respiratory burst (O’Dowd et al, 2004 ).…”