Role of the Sphingosine Metabolism Pathway on Neurons Against Experimental Cerebral Ischemia in Rats
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ORIGINAL ARTICLE
Role of the Sphingosine Metabolism Pathway on Neurons Against Experimental Cerebral Ischemia in Rats Yu Hasegawa & Hidenori Suzuki & Orhan Altay & William Rolland & John H. Zhang
Received: 5 March 2013 / Revised: 15 April 2013 / Accepted: 18 April 2013 # Springer Science+Business Media New York 2013
Abstract Although there is evidence that sphingosine-1phosphate receptor-1 (S1P1) activation occurs following experimental brain injury, there is little information about its metabolic pathway in cerebral ischemia. The purpose of this study was to evaluate the role of the sphingosine metabolic pathway including S1P1 and sphingosine kinases 1 (SphK1) and 2 (SphK2) in transient middle cerebral artery occlusion (MCAO). Fifty-eight male Sprague–Dawley rats were used to assess temporal profiles of S1P1, SphK1, and SphK2 on neurons in infarct and periinfarct cortices at preinfarct state, 6 h, and 24 h after MCAO. The animals were then treated with vehicle and 0.25 mg/kg FTY720, which is an agonist of S1P receptors, and evaluated regarding neurological function, infarct volume, and S1P1 expression on neurons at 24 h after MCAO. The expressions of S1P1, SphK1, and SphK2 were significantly decreased after MCAO. Labeling of all markers was reduced in the infarct cortex but remained present in the periinfarct cortex and some were found to be on neurons. Significant improvements of neurological function and brain injury were observed in the FTY720 group compared with the vehicle and untreated groups, although S1P1 expression on neurons was reduced in the FTY720 group compared with the vehicle group. We demonstrated that S1P1, SphK1, and SphK2 were downregulated in the infarct cortex, whereas they were preserved in the periinfarct cortex where FTY720 reduced neuronal injury possibly via S1P1 activation. Our findings Y. Hasegawa : H. Suzuki : O. Altay : W. Rolland : J. H. Zhang (*) Department of Physiology, Loma Linda University School of Medicine, Risley Hall, Room 223, Loma Linda, CA 92354, USA e-mail: [email protected] J. H. Zhang Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA
suggest that activation of the sphingosine metabolic pathway may be neuroprotective in cerebral ischemia. Keywords Sphingosine 1-phosphate receptor-1 . Sphingosine kinase 1 . Sphingosine kinase 2 . FTY720 . Transient middle cerebral artery occlusion
Introduction Experimental transient middle cerebral artery occlusion (MCAO) is widely approved as a representative model for cerebral ischemia in humans [1]. MCAO in rodent animal modeling produces an infarct core which is defined as necrosis and a penumbra (periinfarct area) in the frontoparietal cortex, in which apoptotic pathways are mainly implicated [2, 3]. Neurons in the infarct core are undergoing a sudden failure of cellular energy, swelling, and rupture of the organelles, whereas neurons in the periinfarct area are viable targets as they can be rescued with suitable treatments including antiapoptotic drugs [4, 5]. Sphingosine 1-phosph
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