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  • In addition to the blockade of airway smooth

    2020-07-24

    In addition to the blockade of airway smooth muscle contractions, CysLT1 receptor antagonists also exerted a potent anti-inflammatory effect at this level. The oral administration of MEN91507, Pranlukast, Montelukast, and Zafirlukast also produced a long-lasting inhibition of leukotriene D4-induced microvascular leakage. Again, no significant differences were observed in the duration of the anti-inflammatory effect of these antagonists. Differences in the potencies of various antagonists in blocking different effects induced by the same agonist (e.g., leukotriene D4-induced bronchoconstriction vs. plasma leakage) are not uncommon and could be due to a differential distribution of the drug in the target tissues. The affinity of MEN91507, Montelukast, Zafirlukast, and Pranlukast, for CysLT1 receptors in guinea-pig lung membranes is comparable, therefore the higher potency of MEN91507 in inhibiting leukotriene D4-induced bronchoconstriction following the i.v. administration could be indicative of a greater metabolic stability, lower excretion rate, or differential tissue distribution as compared to the other CysLT1 receptor antagonists. In human tissue (dU937 cells), the affinity of Zafirlukast (Ki=0.73 nM) and Pranlukast (Ki=0.64 nM) was comparable to that of MEN91507 (Ki=0.65 nM) and Montelukast (Ki=0.60 nM). However, oral doses of 10, 40, and 450 mg/die are respectively needed for Montelukast, Zafirlukast, and Pranlukast to exert a therapeutic effect in asthmatic patients Markham and Faulds, 1998, Roquet et al., 1997, Tomari et al., 2001. Therefore, although Montelukast was the most potent CysLT1 receptor antagonist after oral administration in both humans and guinea-pigs, the oral effective doses of Pranlukast and Zafirlukast greatly diverge in humans, whereas they are similar in guinea-pigs. Even when considering Montelukast only, its oral bioavalability seems higher in humans than in guinea-pigs (see above), since an oral dose of 10 mg produced a clinical effect that was comparable to an intravenous dose of 7 mg (Dockhorn et al., 2000). All these results indicate the presence of important species-related differences in the pharmacokinetic, metabolic, and absorptive properties amongst different chemical classes of CysLT1 receptor antagonists. In conclusion, MEN91507 behave as a potent and selective CysLT1antagonist in guinea-pigs and human in vitro assays. In vivo, MEN91507 shares with the other CysLT1 antagonists anti-bronchospastic and anti-inflammatory effects; since these effects are long-lasting and are also observed following the oral administration, MEN91507 would merit to be tested in humans. If the favourable pharmacological profile of MEN91507 observed in guinea-pigs also applies for humans, this compound can be proposed for the clinical development in therapy of asthma.
    Introduction The leukotrienes are a group of major pro-inflammatory lipid mediators derived from the lipoxygenase pathway of the arachidonic Kinase Inhibitor Library mg metabolism and were so named, because of the salient feature that they can be produced by leukocytes and they have a common conjugated triene in their structure. The leukotrienes consist of cysteinyl leukotrienes (cysLTs) and leukotriene B4 (LTB4). The various subtypes known for CysLTs are leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) (also shown in Fig. 1). CysLTs and LTB4 mediates their biological activity through G protein-coupled receptors (GPCR) i.e. cysLT receptors (cysLT-1 and cysLT-2) and BLT receptors (BLT1 and BLT2) respectively (Ghosh et al., 2016). The cysLTs are characterized by the presence of a cysteine ring whereas LTB4 is a non-cysteine containing dihydroxy-leukotriene (Capra, 2004). The biological properties of leukotrienes suggest that cysLTs in particular, play an important role in the pathogenesis of allergic and severe asthma (Capra et al., 2007). During the inflammatory activation, these leukotrienes are synthesized and become functional. CysLTs induce smooth muscle contraction, vascular leakage, eosinophil recruitment, mucus production and chemotaxis, whereas LTB4 induces leukocyte chemoattraction, particularly of granulocytes and T cells, rapid invasion and recruitment of these cells to the plasma membrane of endothelial cells and production of reactive oxygen species. Studies have shown weak expression of cysLT receptors in healthy brain but a significant increase is observed during pathological conditions (Fang et al., 2006, Fang et al., 2007). CysLT-1 and cysLT-2 receptor contain 336 and 345 amino acid residues respectively. The cyslt-1 receptor was found to be localized on X chromosome (Xq13–Xq21) while and cysLT-2 receptor was found on chromosome 13q14 (Singh et al., 2010). CysLT-1 receptor shows a higher affinity towards LTD4 but lower affinity towards LTC4 and LTE4 while cysLT-2 receptor shows an equal affinity for both LTC4 and LTD4 but lower affinity for LTE4 (Gelosa et al., 2017). Interestingly, studies have reported that astrocytic proliferation is mainly mediated through the activation of cysLT-1 receptors (Huang et al., 2008, Huang et al., 2012) while microglial activation was mediated through the activation of CysLT-2 receptors (Chu et al., 2006, Shi et al., 2015). Three cysLT-1 antagonists are already in the market viz. pranlukast, zafirlukast, montelukast. The specific LTB4 modulators, BLT antagonists, on the other hand, are still in the preliminary stages of clinical development (Montuschi et al., 2007). Although leukotrienes are traditionally known for their role in allergic asthma, allergic rhinitis; the recent literature has highlighted the role of these inflammatory mediators in a broader range of diseases such as in the inflammation associated with the central nervous system (CNS) disorders, vascular inflammation (atherosclerosis), and in cancer (Gelosa et al., 2017, Ghosh et al., 2016). Among the CNS diseases, cysteinyl leukotrienes along with their synthesis precursor enzyme 5-lipoxygenase (5-LOX) and their receptors have been shown to be associated with brain injury, multiple sclerosis, Alzheimer’s disease (AD), Parkinson’s disease, brain ischemia, epilepsy, Huntington’s disease and depression (Ghosh et al., 2016). However, a lot more remains to be elucidated as the research in these areas have emerging interest and only a little has been known so far. Herein, through this review, we have provided current and emerging information on the role of cysLTs and their receptors in the progression and development of neuromodulatory complications associated with the pathophysiology of AD, with an insight on the future perspectives.