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Sphingosin-1-phosphate Receptor 1: a Potential Target to Inhibit Neuroinflammation and Restore the Sphingosin-1-phosphate Metabolism

  • Zeynab Kolahdooz (a1), Sanaz Nasoohi (a2), Masoumeh Asle-Rousta (a3), Abolhassan Ahmadiani (a1) (a4) and Leila Dargahi (a5)...

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.

Le récepteur 1 de la sphingosine-1-phosphate : une cible potentielle pour inhiber la neuroinflammation et rétablir le métabolisme de S1P. Contexte: Selon des données récentes, un changement très important pourrait survenir dans le métabolisme de la sphingosine dans le contexte de la neuroinflammation. Les enzymes qui métabolisent la sphingosine-1-phosphate (S1P) régulent le niveau de S1P. Nous avons observé récemment que FTY720, un analogue de S1P, et SEW2871, un agoniste sélectif du récepteur 1 de S1P, protègent contre le dommage neuronal et le déficit mnésique chez des animaux à qui on a injecté de l’amyloïde bêta (Aß). Le but de cette étude était d’évaluer les effets de ces deux analogues sur l’expression d’enzymes qui métabolisent S1P (SMes ainsi que leur rôle antiinflammatoire. Méthode: Des rats ont été traités au moyen de lipopolysaccarides (LPS) ou d’Aß intracérébral. Le déficit mnésique a été évalué au moyen du labyrinthe aquatique de Morris et les effets de médicaments sur les SMEs ainsi que les marqueurs de l’inflammation, TNF-α et COX-II, ont été déterminés par technique de buvardage. Résultats: L’Aß et les LPS modifiaient de façon différente le profil d’expression des SMEs. Chez les animaux à qui l’Aß avait été injectée, le traitement par FTY720 et par SEW2871 avait des effets antiinflammatoires et restauraient le profil d’expression des SMEs, en parallèle à nos observations antérieures. Cependant, chez les animaux ayant reçu des LPS, seul FTY720 restaurait les niveaux de SMEs et prévenait le déficit mnésique, malgré les effets antiinflammatoires des deux analogues. Conclusion: Les effets bénéfiques de FTY720 et de SEW7821 observés peuvent être partiellement attribués à l’interruption du cycle infernal du métabolisme anormal de S1P et de la neuroinflammation. Les effets très semblables de FTY720 et de SEW2871 sur la neuroinflammation induite par l’Aß pourraient mettre en lumière le rôle important de S1P1 comme cible potentielle pour restaurer le métabolisme de S1P et inhiber le processus inflammatoire.

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Corresponding author

Correspondence to: Leila Dargahi, NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email: l.dargahi@sbmu.ac.ir

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