Zeynab Kolahdooz1, Sanaz Nasoohi2, Masoumeh Asle-Rousta3, Abolhassan Ahmadiani1, Leila Dargahi4. 1. 1Neuroscience Research Center,Shahid Beheshti University of Medical Sciences,Teheran. 2. 2Department of Pharmacology and Toxicology, Faculty of Pharmacy,Shahid Beheshti University of Medical Sciences,Teheran. 3. 4Department of Biology, Faculty of Basic and Medical Sciences,Zanjan Branch,Islamic Azad University,Zanjan,Iran. 4. 3NeuroBiology Research Center,Shahid Beheshti University of Medical Sciences,Teheran.
Abstract
BACKGROUND: Recent evidence suggests that an extreme shift may occur in sphingosine metabolism in neuroinflammatory contexts. Sphingosine 1-phosphate (S1P)-metabolizing enzymes (SMEs) regulate the level of S1P. We recently found that FTY720, a S1P analogue, and SEW2871, a selective S1P receptor 1 (S1P1) agonist, provide protection against neural damage and memory deficit in amyloid beta (Aβ)-injected animals. This study aimed to evaluate the effects of these two analogues on the expression of SMEs as well as their anti-inflammatory roles. METHODS: Rats were treated with intracerebral lipopolysaccharide (LPS) or Aβ. Memory impairment was assessed by Morris water maze and the effects of drugs on SMEs as well as inflammatory markers, TNF- α and COX-II, were determined by immunoblotting. RESULTS: Aβ and LPS differentially altered the expression profile of SMEs. In Aβ-injected animals, FTY720 and SEW2871 treatments exerted anti-inflammatory effects and restored the expression profile of SMEs, in parallel to our previous findings. In LPS animals however, in spite of anti-inflammatory effects of the two analogues, only FTY720 restored the levels of SMEs and prevented memory deficit. CONCLUSION: The observed ameliorating effects of FTY720 and SEW7821 can be partly attributed to the interruption of the vicious cycle of abnormal S1P metabolism and neuro-inflammation. The close imitation of the FTY720 effects by SW2871 in Aβ-induced neuro-inflammation may highlight the attractive role of S1P1 as a potential target to restore S1P metabolism and inhibit inflammatory processes.
BACKGROUND: Recent evidence suggests that an extreme shift may occur in sphingosine metabolism in neuroinflammatory contexts. Sphingosine 1-phosphate (S1P)-metabolizing enzymes (SMEs) regulate the level of S1P. We recently found that FTY720, a S1P analogue, and SEW2871, a selective S1P receptor 1 (S1P1) agonist, provide protection against neural damage and memory deficit in amyloid beta (Aβ)-injected animals. This study aimed to evaluate the effects of these two analogues on the expression of SMEs as well as their anti-inflammatory roles. METHODS:Rats were treated with intracerebrallipopolysaccharide (LPS) or Aβ. Memory impairment was assessed by Morris water maze and the effects of drugs on SMEs as well as inflammatory markers, TNF- α and COX-II, were determined by immunoblotting. RESULTS: Aβ and LPS differentially altered the expression profile of SMEs. In Aβ-injected animals, FTY720 and SEW2871 treatments exerted anti-inflammatory effects and restored the expression profile of SMEs, in parallel to our previous findings. In LPS animals however, in spite of anti-inflammatory effects of the two analogues, only FTY720 restored the levels of SMEs and prevented memory deficit. CONCLUSION: The observed ameliorating effects of FTY720 and SEW7821 can be partly attributed to the interruption of the vicious cycle of abnormal S1P metabolism and neuro-inflammation. The close imitation of the FTY720 effects by SW2871 in Aβ-induced neuro-inflammation may highlight the attractive role of S1P1 as a potential target to restore S1P metabolism and inhibit inflammatory processes.
Authors: Irene Maeve Rea; David S Gibson; Victoria McGilligan; Susan E McNerlan; H Denis Alexander; Owen A Ross Journal: Front Immunol Date: 2018-04-09 Impact factor: 7.561
Authors: Vijay R Varma; Anup M Oommen; Sudhir Varma; Ramon Casanova; Yang An; Ryan M Andrews; Richard O'Brien; Olga Pletnikova; Juan C Troncoso; Jon Toledo; Rebecca Baillie; Matthias Arnold; Gabi Kastenmueller; Kwangsik Nho; P Murali Doraiswamy; Andrew J Saykin; Rima Kaddurah-Daouk; Cristina Legido-Quigley; Madhav Thambisetty Journal: PLoS Med Date: 2018-01-25 Impact factor: 11.069