Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders

Abstract

Cysteinyl leukotrienes are a group of the inflammatory lipid molecules well known as mediators of inflammatory signaling in the allergic diseases. Although they are traditionally known for their role in allergic asthma, allergic rhinitis, and others, recent advances in the field of biomedical research 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 (atherosclerotic), and in cancer. Among the CNS diseases, they, along with their synthesis precursor enzyme 5-lipoxygenase and their receptors, have been shown to be associated with brain injury, Multiple sclerosis, Alzheimer's disease, Parkinson's disease, brain ischemia, epilepsy, and others. However, a lot more remains elusive as the research in these areas is emerging and only a little has been discovered. Herein, through this review, we first provided a general up-to-date information on the synthesis pathway and the receptors for the molecules. Next, we summarized the current findings on their role in the brain disorders, with an insight given to the future perspectives.

Keywords: Alzheimer's disease; Cerebral ischemia; Cysteinyl leukotrienes type 1 receptor; G-protein-coupled receptor 17; Multiple sclerosis.

Figure 1

Biosynthesis pathway of the Cys‐LT and their receptors. cPLA2‐derived arachidonic acid is converted to LTA4 by the action of 5‐LOX and FLAP (this step can be blocked by 5‐LOX/FLAP inhibitor zileuton). LTA4 is then rapidly converted to LTB4 by LTA4‐H or to LTC4 by LTC4‐S; LTC4 is further converted to LTD4 and LTE4. LTC4, LTD4, and LTE4 can bind to CysLT ₁R, CysLT ₂R, and GPR17 (CysLT ₁R antagonists can block the activity of CysLT ₁R or GPR17, but not CysLT ₂R). Among the Cys‐LT, only LTE4 shows preferential binding toward GPR99, PPAR γ, and P2Y₁₂.

Figure 2

Transcellular biosynthesis of Cys‐LT in the brain. Neutrophils, which infiltrate the inflamed brain area, transfer LTA4 to the surrounding neurons, glial cells, and brain endothelial cells. This LTA4 then can further be utilized by these brain resident cells to produce Cys‐LT.

Figure 3

Contribution of 5‐LOX/Cys‐LT/CysLTRs in CNS and other diseases. They are traditionally known for mediation of asthma and the CysLT ₁R antagonists or 5‐LOX inhibitors are used for clinical management of the disease; montelukast is also approved by the Food and Drug Administration of the USA for the management of other allergic diseases. However, the importance of these inflammatory molecules is emerging in other fields and has been shown to be associated with cancer, atherosclerosis, and several brain diseases as displayed in the Figure. (Figure illustrations were created using MOTIFOLIO Biomedical PowerPoint Toolkits for Presentations and Microsoft Office PowerPoint).