cholesterol absorption inhibitor 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 cholesterol absorption inhibitor 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 cells 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 (ClinicalTrials.gov: 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
Basophils are central to IgE-mediated inflammation, are found at increased levels in tissues of allergic subjects, and are further increased after allergen challenge., , Cross-linking high-affinity IgE receptors with allergens leads to generation of leukotriene (LT) C, which is converted to LTD and then to LTE.,