Dexmedetomidine (Dex) exerts protective effects on rat neuronal cells injured by cerebral ischemia/reperfusion via regulating the Sphk1/S1P signaling pathway



      To investigate the influence of dexmedetomidine (Dex) on cerebral ischemia/reperfusion (I/R)-injured rat neuronal cells by regulating the Sphk1/S1P pathway.


      The rats were divided into the following groups, with 18 rats in each group categorized on the basis of random number tables: sham (Sham), I/R (I/R), Dex, Sphk1 inhibitor (PF-543), and Dex together with the Sphk1 agonist phorbol-12-myristate-13-acetate (Dex+PMA). The neurological functions of the rats were assessed by the Longa scoring system at 24 h post reperfusion. The area of brain infarction was inspected using 2,3,5-triphenyltetrazolium chloride staining, and the water content of brain tissue was determined by the dry-wet weight method. The morphology of neurons in the CA1 region of the rat hippocampus was inspected using Nissl staining, while the apoptosis of neurons in this region was detected by terminal-deoxynucleotidyl transferase mediated nick end labeling staining. The Sphk1 and S1P protein levels were determined by immunofluorescence and western blotting, respectively.


      Compared to the I/R group, rats in the Dex, PF-543, and Dex+PMA groups had a significantly lower neurological function score, as well as lower brain water content and a decreased infarction area. Moreover, the apoptotic index of the neurons and the Sphk1 and S1P levels in the hippocampal CA1 region were significantly lower in these groups (p<0.05). PMA, an agonist of Sphk1, was able to reverse the protective effects of Dex on I/R-induced neuronal cell injury.


      Dex could protect cerebral I/R-induced neuronal cell injury by suppressing the Sphk1/S1P signaling pathway.


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        • Stegner D
        • Klaus V
        • Nieswandt B.
        Platelets as Modulators of Cerebral Ischemia/Reperfusion Injury.
        Front Immunol. 2019; 10: 2505
        • Shen Z
        • Zheng Y
        • Wu J
        • et al.
        PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window.
        Autophagy. 2017; 13: 473-485
        • Hou S
        • Zhao MM
        • Shen PP
        • Liu XP
        • Sun Y
        • Feng JC.
        Neuroprotective effect of salvianolic acids against cerebral ischemia/reperfusion injury.
        Int J Mol Sci. 2016; 17: 1190
        • Wen L
        • Liu L
        • Tong L
        • et al.
        NDRG4 prevents cerebral ischemia/reperfusion injury by inhibiting neuronal apoptosis.
        Genes Dis. 2019; 6: 448-454
        • Guo P
        • Jin Z
        • Wu H
        • et al.
        Effects of irisin on the dysfunction of blood-brain barrier in rats after focal cerebral ischemia/reperfusion.
        Brain Behav. 2019; 9: e01425
        • Fluri F
        • Schuhmann MK
        • Kleinschnitz C.
        Animal models of ischemic stroke and their application in clinical research.
        Drug Des Devel Ther. 2015; 9: 3445-3454
        • Ma R
        • Xie Q
        • Li Y
        • et al.
        Animal models of cerebral ischemia: a review.
        Biomed Pharmacother. 2020; 131110686
        • Kumar A
        • Aakriti Gupta V
        A review on animal models of stroke: an update.
        Brain Res Bull. 2016; 122: 35-44
        • Weerink MAS
        • Struys M
        • Hannivoort LN
        • Barends CRM
        • Absalom AR
        • Colin P
        Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine.
        Clin Pharmacokinet. 2017; 56: 893-913
        • Lee S.
        Dexmedetomidine: present and future directions.
        Korean J Anesthesiol. 2019; 72: 323-330
        • Cai Y
        • Xu H
        • Yan J
        • Zhang L
        • Lu Y.
        Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury.
        Mol Med Rep. 2014; 9: 1542-1550
        • Jiang L
        • Hu M
        • Lu Y
        • Cao Y
        • Chang Y
        • Dai Z.
        The protective effects of dexmedetomidine on ischemic brain injury: a meta-analysis.
        J Clin Anesth. 2017; 40: 25-32
        • Khoei SG
        • Sadeghi H
        • Samadi P
        • Najafi R
        • Saidijam M.
        Relationship between Sphk1/S1P and microRNAs in human cancers.
        Biotechnol Appl Biochem. 2021; 68: 279-287
        • Marfe G
        • Mirone G
        • Shukla A
        • Di Stefano C.
        Sphingosine kinases signalling in carcinogenesis.
        Mini Rev Med Chem. 2015; 15: 300-314
        • Sukocheva OA
        • Furuya H
        • Ng ML
        • et al.
        Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target.
        Pharmacol Ther. 2020; 207107464
        • Carr JM
        • Mahalingam S
        • Bonder CS
        • Pitson SM.
        Sphingosine kinase 1 in viral infections.
        Rev Med Virol. 2013; 23: 73-84
        • Jozefczuk E
        • Guzik TJ
        • Siedlinski M.
        Significance of sphingosine-1-phosphate in cardiovascular physiology and pathology.
        Pharmacol Res. 2020; 156104793
        • van Echten-Deckert G
        • Hagen-Euteneuer N
        • Karaca I
        • Walter J.
        Sphingosine-1-phosphate: boon and bane for the brain.
        Cell Physiol Biochem. 2014; 34: 148-157
        • Han M
        • Sun T
        • Chen H
        • Han M
        • Wang D.
        Potential sphingosine-1-phosphate-related therapeutic targets in the treatment of cerebral ischemia reperfusion injury.
        Life Sci. 2020; 249117542
        • Gyires K
        • Zádori ZS
        • Török T
        • Mátyus P.
        alpha(2)-Adrenoceptor subtypes-mediated physiological, pharmacological actions.
        Neurochem Int. 2009; 55: 447-453
        • Atef RM
        • Agha AM
        • Abdel-Rhaman AA
        • Nassar NN.
        The Ying and Yang of adenosine A(1) and A(2A) receptors on ERK1/2 activation in a rat model of global cerebral ischemia reperfusion injury.
        Mol Neurobiol. 2018; 55: 1284-1298
        • Zhu Y
        • Li S
        • Liu J
        • et al.
        Role of JNK signaling pathway in dexmedetomidine post-conditioning-induced reduction of the inflammatory response and autophagy effect of focal cerebral ischemia reperfusion injury in rats.
        Inflammation. 2019; 42: 2181-2191
        • Wang C
        • Xu T
        • Lachance BB
        • et al.
        Critical roles of sphingosine kinase 1 in the regulation of neuroinflammation and neuronal injury after spinal cord injury.
        J Neuroinflammat. 2021; 18: 50
        • Nakazawa D
        • Tomaru U
        • Suzuki A
        • et al.
        Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps: implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis.
        Arthritis Rheum. 2012; 64: 3779-3787
        • Longa EZ
        • Weinstein PR
        • Carlson S
        • Cummins R.
        Reversible middle cerebral artery occlusion without craniectomy in rats.
        Stroke. 1989; 20: 84-91
        • Liu F
        • McCullough LD.
        Middle cerebral artery occlusion model in rodents: methods and potential pitfalls.
        J Biomed Biotechnol. 2011; 2011464701
        • Chen L
        • Cao J
        • Cao D
        • et al.
        Protective effect of dexmedetomidine against diabetic hyperglycemia-exacerbated cerebral ischemia/reperfusion injury: an in vivo and in vitro study.
        Life Sci. 2019; 235116553
        • Lv M
        • Zhang D
        • Dai D
        • Zhang W
        • Zhang L.
        Sphingosine kinase 1/sphingosine-1-phosphate regulates the expression of interleukin-17A in activated microglia in cerebral ischemia/reperfusion.
        Inflamm Res. 2016; 65: 551-562
        • Su D
        • Cheng Y
        • Li S
        • Dai D
        • Zhang W
        • Lv M.
        Sphk1 mediates neuroinflammation and neuronal injury via TRAF2/NF-κB pathways in activated microglia in cerebral ischemia reperfusion.
        J Neuroimmunol. 2017; 305: 35-41
        • An N
        • Gao Y
        • Si Z
        • et al.
        Regulatory mechanisms of the NLRP3 inflammasome, a novel immune-inflammatory marker in cardiovascular diseases.
        Front Immunol. 2019; 10: 1592
        • Zheng S
        • Wei S
        • Wang X
        • et al.
        Sphingosine kinase 1 mediates neuroinflammation following cerebral ischemia.
        Exp Neurol. 2015; 272: 160-169
        • Salas-Perdomo A
        • Miró-Mur F
        • Gallizioli M
        • et al.
        Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke.
        Sci Rep. 2019; 9: 8309
        • Wang YQ
        • Tang YF
        • Yang MK
        • Huang XZ.
        Dexmedetomidine alleviates cerebral ischemia-reperfusion injury in rats via inhibition of hypoxia-inducible factor-1α.
        J Cell Biochem. 2018;
        • Zhai Y
        • Zhu Y
        • Liu J
        • et al.
        Dexmedetomidine post-conditioning alleviates cerebral ischemia-reperfusion injury in rats by inhibiting high mobility group protein B1 group (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway.
        Med Sci Monit. 2020; 26e918617
        • Song DD
        • Zhou JH
        • Sheng R.
        Regulation and function of sphingosine kinase 2 in diseases.
        Histol Histopathol. 2018; 33: 433-445
        • Cartier A
        • Hla T.
        Sphingosine 1-phosphate: Lipid signaling in pathology and therapy.
        Science. 2019; 366