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  • br Role of cysLT signaling


    Role of cysLT signaling on various neurological complications which are associated with Alzheimer’s disease Alzheimer’s disease, first described in 1906 by Alois Alzheimer, is a neurodegenerative disease and a very common cause of dementia progressively leading to death. Even though years of research have discovered a great deal about AD still it cannot be cured or prevented (Kalra and Khan, 2015, Sala Frigerio and De Strooper, 2016). The AD is multi-facet disease and thus no single major cause of AD is discovered. It is mainly characterized by the accumulation of extracellular senile plaques, intracellular neurofibrillary tangles, and loss of neurons. Some other causes are also known like cholinergic dysfunction, oxidative stress, cerebral ischemia, neuroinflammation (Eikelenboom et al., 2010, Hussain et al., 2018, Kozlov et al., 2017, Pluta et al., 2013). Earlier studies have associated cysLTs and their receptors in several CNS diseases like, multiple sclerosis, Parkinson’s disease, Huntington’s disease, epilepsy and in the AD (Gelosa et al., 2017, Ghosh et al., 2016). These inflammatory lipid mediators have shown effects on various aggravating factors of Alzheimer’s disease. In this article, we have reviewed the effects of cysLT signaling on Alzheimer’s disease and its associated complications (also refer to Table 1).
    Therapeutic indications of cysLT inhibitors and their receptors antagonist in Alzheimer’s disease Leukotriene modifiers were clinically developed way back in the 1980’s and now basically two classes of these drugs can be found: (1) Inhibitors of leukotrienes biosynthesis i.e. 5-Lipoxygenase-activating protein (FLAP) inhibitors (MK-886) and 5-LOX inhibitors (zileuton, minocycline, caffeic acid, BWB70C, REV 5901 and AA-861) and (2) leukotriene receptor antagonists i.e. non-selective cysLT receptor antagonist (Bay u9773), cysLT-1 receptor antagonist (montelukast, zafirlukast and pranlukast) and cysLT-2 receptor antagonist (HAMI 3379). Various studies have demonstrated distinctive effects these leukotriene modifiers on different aspects of abnormalities found in the AD (for each class also refer to Table 2 and Fig. 2).
    Concluding remarks Pro-inflammatory lipid mediators, leukotrienes, have shown a significant role in mediating inflammatory conditions both peripherally and centrally. In the past decade, several studies have established their role in neurodegenerative diseases thereby indicating the pleiotropic action of cysLTs in our system. Several decades of research on AD have implied that it is a condition where the neurons get entangled with various neuromodulatory complications like Aβ accumulation, glial Fmoc-D-Lys(Boc)-OH synthesis proliferation, neuroinflammation, NPCs reduction, mitochondrial dysfunction, oxidative stress and several others. Either inhibition of cysLTs production or cysLT receptors activation has shown profound actions against different neuromodulatory complications in various in vitro and in vivo studies. It is the current need to clinically determine the therapeutic safety and efficacy of csyLT receptor antagonist against the AD. Fortunately, some of the cysLT-1 receptor antagonists are already being marketed but they have never been studied against AD clinically. Although only one clinical study titled “Safety, and Efficacy of a New Buccal Film of Montelukast in Patients With Mild to Moderate Alzheimer\'s Disease (BUENA)” was found that is about to be started in September 2018 ( NCT03402503; Registered on: January 10, 2018). We also suggest that more studies are needed to determine the immunomodulatory role of cysLTs and their inhibitors in CNS.
    Conflict of interest
    Introduction P2Y receptors are membrane bound and G-protein-coupled receptors (GPCRs) for extracellular nucleotides (Burnstock and Kennedy, 1985). Eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) have been identified (Ralevic and Burnstock, 1998; von Kügelgen and Wetter, 2000; Abbracchio et al., 2006; von Kügelgen and Harden, 2011; von Kügelgen and Hoffmann, 2016; Kennedy, 2017; Pérez-Sen et al., 2017; von Kügelgen, 2017). All P2Y receptors belong to the δ-subgroup of class A GPCRs (Fredriksson et al., 2003; Lagerström and Schiöth, 2008). Two subfamilies of P2Y receptors have been defined by similarities in amino acid sequences and signal transduction pathways (Abbracchio et al., 2006; von Kügelgen, 2006). The first subfamily consists of the P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors. These receptors couple via Gq-proteins. The P2Y11 receptor couples in addition to Gs-proteins (Fig. 1; references in Table 1). The receptors of the second subfamily (P2Y12, P2Y13, and P2Y14 receptors) mediate cellular responses via activation of Gi-proteins (Fig. 1; references in Table 1). Some GPCRs with a published “p2y” nomenclature do not function as P2Y receptors for extracellular nucleotides. E.g., the “p2y5” receptor protein acts as a receptor for lysophosphatidic acid (Pasternack et al., 2008). P2Y receptors play important roles in physiology and pathophysiology (Ralevic and Burnstock, 1998, 2003; Müller, 2002; Leipziger, 2003; Burnstock, 2007; Burnstock et al., 2011; Burnstock and Boeynaems, 2014; Franke and Illes, 2014; Idzko et al., 2014; Oliveira et al., 2016; Burnstock, 2017; Le Duc et al., 2017; Nishimura et al., 2017). The ADP-induced platelet aggregation is mediated by activation of P2Y1 and P2Y12 receptors (Cattaneo, 2011; Liverani et al., 2014b). The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel inhibit platelet P2Y12 receptors and reduce thereby platelet aggregation. These drugs are used for the prevention and therapy of cardiovascular events (Cattaneo, 2011). The P2Y2 receptor agonist diquafosol is used for the treatment of the dry eye syndrome (Jacobson and Civan, 2016).