Sphingosine 1-Phosphate Receptors in Cerebral Ischemia
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ORIGINAL PAPER
Sphingosine 1‑Phosphate Receptors in Cerebral Ischemia Bhakta Prasad Gaire1 · Ji Woong Choi1 Received: 19 July 2020 / Accepted: 2 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S 1P1–5. Through these receptors, S1P can mediate diverse biological activities in both healthy and diseased conditions. S1P is produced by S1P-producing enzymes, sphingosine kinases (SphK1 and SphK2), and is abundantly present in different organs, including the brain. The medically important roles of receptor-mediated S1P signaling are well characterized in multiple sclerosis because FTY720 (Gilenya™, Novartis), a non-selective S1P receptor modulator, is currently used as a treatment for this disease. In cerebral ischemia, its role is also notable because of FTY720’s efficacy in both rodent models and human patients with cerebral ischemia. In particular, some of the S1P receptors, including S1P1, S1P2, and S 1P3, have been identified as pathogenic players in cerebral ischemia. Other than these receptors, S1P itself and S1P-producing enzymes have been shown to play certain roles in cerebral ischemia. This review aims to compile the current updates and overviews about the roles of S1P signaling, along with a focus on S1P receptors in cerebral ischemia, based on recent studies that used in vivo rodent models of cerebral ischemia. Keywords Sphingosine 1-phosphate · S1P receptors · Cerebral ischemia
Introduction Cerebral ischemia/stroke is a pathophysiological condition. It is primarily caused by an insufficient blood supply to the brain and is characterized by either rupture (hemorrhagic stroke) or blockage (ischemic stroke) of the blood vasculature in the brain. Ischemic stroke is one of the leading causes of death and disability worldwide and accounts for more than 80% of strokes (Sturmer et al. 2002; White et al. 2000). Tissue plasminogen activator (tPA) was approved by the FDA for ischemic stroke and remains as its only indicated medication (Fagan et al. 1998; Kwiatkowski et al. 1999). However, with its narrow therapeutic window and potentially adverse effects, the therapeutic use of tPA is limited (Hacke et al. 2008). This raises the urgent need to discover potential therapeutic agents to treat cerebral ischemia. During the past decades, many pharmacological agents have been studied to treat cerebral ischemia in animal models for * Ji Woong Choi [email protected] 1
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Inchon 21936, Republic of Korea
their beneficial effects. However, there has been no clearly successful development of a new drug to treat cerebral ischemia. Receptor-mediated sphingosine 1-phosphate (S1P) signaling has emerged as an important target for drug development to treat cerebral ischemia because of FTY720 (fingolimod, Gilenya™, Nov
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