鞘氨醇激酶/1-磷酸鞘氨醇信号通路在中枢神经系统疾病中的研究进展_Journal of Epilepsy

Authors：

董媛媛 , 冯邦哲 , 孙影 ,  孔庆霞

济宁医学院附属医院神经内科（济宁 272000）;

Corresponding author：

孔庆霞, Email: kxdqy8@sohu.com

Keywords：

中枢神经系统疾病; 癫痫; 鞘氨醇激酶1; 1-磷酸鞘氨醇; 炎症反应; 细胞凋亡; 信号转导

DOI：

10.7507/2096-0247.20180027

Video：

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我国当前约有 900 万以上的癫痫患者，每年新发癫痫患者 65～70 万，其中约 30% 为难治性癫痫。癫痫的发病机制复杂，其病理机制至今尚未完全了解，鞘氨醇激酶（Sphingosine kinase, SphK）/1-磷酸鞘氨醇（Sphingosine-1-phosphate, S1P）通路在癫痫中可能发挥的作用及其机制目前尚不十分清楚。为进一步探索难治性癫痫在分子水平的发病机制，现就 SphK/S1P 信号通路通过调控炎症反应及细胞凋亡参与癫痫发病机制和可能存在的理想治疗靶点作一综述。

Citation： 董媛媛, 冯邦哲, 孙影, 孔庆霞. 鞘氨醇激酶/1-磷酸鞘氨醇信号通路在中枢神经系统疾病中的研究进展. Journal of Epilepsy, 2018, 4(2): 129-134. doi: 10.7507/2096-0247.20180027 Copy

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2.	Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol, 2003, 4(5): 397-407.
3.	Ishii I, Fukushima N, Ye X, et al. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem, 2004, 73: 321-354.
4.	Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta, 2006, 1758(12): 2016-2026.
5.	Obinata H, Hla T. Sphingosine-1-phosphate in coagulation andinflammation. Semin Immunopathol, 2012, 34(1): 73-91.
6.	Kohama T, Olivera A, Edsall L, et al. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem, 1998, 273(37): 23722-23728.
7.	Xie Z, Liu H, Geng M. Targeting sphingosine-1-phosphate signaling for cancer therapy. Sci China Life Sci, 2017, 60(6): 585-600.
8.	Aarthi JJ, Darendeliler MA, pushparaj PN. Dissecting the role of the S1P/S1PR axis in health and disease. J Dent Res, 2011, 90(7): 841-854.
9.	Huang YL, Chang CL, Tang CH, et al. Extrinsic sphingosine 1-phosphate activates S1P5 and induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells. Cell Signal, 2014, 26(3): 611-618.
10.	Hinkovska-Galcheva V, Vanway SM, Shanley TP, et al. The role of sphingosine-1-phosphate and ceramide-1-phosphate in Calcium homeostasis. Curr Opin Investig Drugs, 2008, 9(11): 1192-1205.
11.	Li Q, Chen B, Zeng C, et al. Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells. Exp Physiol, 2014, 100(1): 95-107.
12.	Kamiya T, Nagaoka T, Omae T, et al. Role of Ca2+-dependent and Ca2+-sensitive mechanisms in sphingosine 1-phosphate-induced constriction of isolated porcine retinal arterioles in vitro. Exp Eye Res, 2014: 94-101.
13.	Goetzl EJ. Regulation of immunity by lysosphingolipids and their G protein-coupled receptors. J Clin Invest, 2004, 114(11): 1531-1537.
14.	Zheng Y, Voice JK, Kong Y. Altered expression and functional profile of lysophosphatidic acid receptors in mitogen-activated human blood T lymphocytes. FASEB J, 2000, 14(15): 2387-2389.
15.	Graeler M. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J, 2002, 16(14): 1874-1878.
16.	Goetzl EJ. Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T lymphocytes. J Leukoc Biol, 2004, 76(1): 30-35.
17.	Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature, 2004, 427(6972): 355-360.
18.	Allende ML, Dreier JL, Mandala S. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem, 2004, 279(15): 15396-15401.
19.	Yopp AC, Ochando JC, Mao M, et al. Sphingosine 1-phosphate receptors regulate chemokine-driven transendothelial migration of lymph node but not splenic T cells. J Immunol, 2005, 175(5): 2913-2924.
20.	Spiegel S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol, 2003, 4(5): 397-407.
21.	Olivera A, Kohama T, Edsall L, et al. Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol, 1999, 147(3): 545-558.
22.	Shu X, Wu W, Mosteller RD. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol, 2002, 22(22): 7758-7768.
23.	Xia P, Gamble JR, Wang L, et al. An oncogenic role of sphingosine kinase. Curr Biol, 2000, 10(23): 1527-1530.
24.	Nava VE, Hobson JP, Murthy S, et al. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp Cell Res, 2002, 281(1): 115-127.
25.	Sukocheva OA, Wang L, Albanese N, et al. Sphingosine kinase transmits estrogensignaling in human breast cancer cells. Mol Endocrinol, 2003, 17(10):2002-2012.
26.	Pitson SM, Xia P, Leclercq TM, et al. Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med, 2005, 201(1): 49-54.
27.	French KJ, Schrecengost RS, Lee BD, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res, 2003, 63(18): 5962-5969.
28.	Johnson KR, Johnson KY, Crellin HG, et al. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem, 2005, 53(9): 1159-1166.
29.	Wu W, Shu X, Hovsepyan H, et al. VEGF receptor expression and signaling in human bladder tumors. Oncogene, 2003, 22(22): 3361-3370.
30.	Sarkar S, Maceyka M, Hait NC, et al. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett, 2005, 579(24): 5313-5317.
31.	Van Brocklyn JR, Jackson CA, Pearl DK, et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol, 2005, 64(8): 695-705.
32.	Liu H, Toman RE, Goparaju SK, et al. Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem, 2003, 278(41): 40330-40336.
33.	Igarashi N, Okada T, Hayashi S, et al. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem, 2003, 278(47): 46832-46839.
34.	Huang DC. BH3-Only proteins-essential initiators of apoptotic cell death. Cell, 2000, 103(6): 839-842.
35.	Maceyka M, Sankala H, Hait NC, et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem, 2005, 280(44): 37118-37129.
36.	Berridge MJ, Lipp P. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol, 2000, 1(1): 11-21.
37.	Pinton P, Ferrari D, Rapizzi E, et al. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J, 2001, 20(11): 2690-2701.
38.	Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science, 2003, 300(5616): 135-139.
39.	Nutt LK, Chandra J, Pataer A, et al. Bax-mediated Ca2+ mobilization promotes cytochrome c release during apoptosis. J Biol Chem, 2002, 277(23): 20301-20308.
40.	Toman RE, Movsesyan V, Murthy SK, et al. Ceramide-induced cell death in primary neuronal cultures: upregulation of ceramide levels during neuronal apoptosis. J Neurosci Res, 2002, 68(3): 323-330.
41.	Jaillard C, Harrison S, Stankoff B, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci, 2005, 25(6): 1459-1469.
42.	Johnson JR, Chu AK. Possible role of CREB in the stimulation of oligodendrocyte precursor cell proliferation by neurotrophin-3. J Neurochem, 2000, 74(4): 1409-1417.
43.	Saini HS, Gorse KM, Boxer LM. Neurotrophin-3 and a CREB-mediated signaling pathway regulate Bcl-2 expression in oligodendrocyte progenitor cells. J Neurochem, 2004, 89(4): 951-961.
44.	Saini HS, Coelho RP, Goparaju SK, et al. Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J Neurochem, 2005, 95(5): 1298-1310.
45.	Sato K, Ui M, Okajima F. Differential roles of Edg-1 and Edg-5, sphingosine 1-phosphate receptors, in the signaling pathways in C6 glioma cells. Brain Res Mol Brain Res, 2000, 85(1-2): 151-160.
46.	Harada J, Foley M, Moskowitz MA. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J Neurochem, 2004, 88(4): 1026-1039.
47.	Edsall LC, Cuvillier O, Twitty S, et al. Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J Neurochem, 2001, 76(5): 1573-1584.
48.	Bassi R, Anelli V, Giussani P, et al. Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi-protein-coupled receptors. Glia, 2006, 53(6): 621-630.
49.	Leo A, Citraro R, Marra R, et al. The sphingosine 1-phosphate signaling pathway in epilepsy: A possible role for the immunomodulator drug fingolimod in epilepsy treatment. CNS Neurol Disord Drug Targets, 2017, 16(3): 311-325.
50.	Chan JP, Sieburth D. Localized sphingolipid signaling at presynaptic terminals is regulated by calcium influx and promotes recruitment of priming factors. J Neurosci, 2012, 32(49): 17909-17920.
51.	Alemany R, Kleuser B, Ruwisch L, et al. Depolarisation induces rapid and transient formation of intracellular sphingosine-1-phosphate. FEBS Lett, 2001, 509(2): 239-244.
52.	Blom T, Bergelin N, Slotte JP, et al. Sphingosine kinase regulates voltage operated calcium channels in GH4C1 rat pituitary cells. Cell Signal, 2006, 18(9): 1366-1375.
53.	Kim MY, Liang GH, Kim JA, et al. Sphingosine-1-phosphate activates BKCa channels independently of G protein-coupled receptor in human endothelial cells. Am J Physiol Cell Physiol, 2006, 290(4): C1000-1008.
54.	陈璇, 王罗俊, 邓艳春. 钙离子通道基因突变与癫痫. 癫痫杂志, 2016, 2(4): 344-348.
55.	Leo A, Citraro R, Constanti A, et al. Are big potassium-type Ca(2+)-activated potassium channels a viable target for the treatment of epilepsy?. Exp Opin Therc Targ, 2015, 19(7): 911-926.
56.	Kajimoto T, Okada T, Yu H, et al. Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol, 2007, 27(9): 3429-3440.
57.	Kanno T, Nishizaki T. Endogenous sphingosine 1-phosphate regulates spontaneous glutamate release from mossy fiber terminals via S1P(3) receptors. Life Sci, 2011, 89(3-4): 137-140.
58.	Wang GX, Wang DW, Liu Y, et al. Intractable epilepsy and the P-glycoprotein hypothesis. Int J Neurosci, 2016, 126(5): 385-392.
59.	Yu N, Liu H, Zhang YF, et al. Effects of brain IKKbeta gene silencing by small interfering RNA on P-glycoprotein expression and brain damage in the rat kainic acid-induced seizure model. CNS Neurol Disord Drug Targ, 2014, 13(4): 661-672.
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1. 杨华俊, 郭安臣, 王群. 癫痫的发病机制研究. 癫痫杂志, 2017, 3(2): 132-136.
2. Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol, 2003, 4(5): 397-407.
3. Ishii I, Fukushima N, Ye X, et al. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem, 2004, 73: 321-354.
4. Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta, 2006, 1758(12): 2016-2026.
5. Obinata H, Hla T. Sphingosine-1-phosphate in coagulation andinflammation. Semin Immunopathol, 2012, 34(1): 73-91.
6. Kohama T, Olivera A, Edsall L, et al. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem, 1998, 273(37): 23722-23728.
7. Xie Z, Liu H, Geng M. Targeting sphingosine-1-phosphate signaling for cancer therapy. Sci China Life Sci, 2017, 60(6): 585-600.
8. Aarthi JJ, Darendeliler MA, pushparaj PN. Dissecting the role of the S1P/S1PR axis in health and disease. J Dent Res, 2011, 90(7): 841-854.
9. Huang YL, Chang CL, Tang CH, et al. Extrinsic sphingosine 1-phosphate activates S1P5 and induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells. Cell Signal, 2014, 26(3): 611-618.
10. Hinkovska-Galcheva V, Vanway SM, Shanley TP, et al. The role of sphingosine-1-phosphate and ceramide-1-phosphate in Calcium homeostasis. Curr Opin Investig Drugs, 2008, 9(11): 1192-1205.
11. Li Q, Chen B, Zeng C, et al. Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells. Exp Physiol, 2014, 100(1): 95-107.
12. Kamiya T, Nagaoka T, Omae T, et al. Role of Ca2+-dependent and Ca2+-sensitive mechanisms in sphingosine 1-phosphate-induced constriction of isolated porcine retinal arterioles in vitro. Exp Eye Res, 2014: 94-101.
13. Goetzl EJ. Regulation of immunity by lysosphingolipids and their G protein-coupled receptors. J Clin Invest, 2004, 114(11): 1531-1537.
14. Zheng Y, Voice JK, Kong Y. Altered expression and functional profile of lysophosphatidic acid receptors in mitogen-activated human blood T lymphocytes. FASEB J, 2000, 14(15): 2387-2389.
15. Graeler M. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J, 2002, 16(14): 1874-1878.
16. Goetzl EJ. Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T lymphocytes. J Leukoc Biol, 2004, 76(1): 30-35.
17. Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature, 2004, 427(6972): 355-360.
18. Allende ML, Dreier JL, Mandala S. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem, 2004, 279(15): 15396-15401.
19. Yopp AC, Ochando JC, Mao M, et al. Sphingosine 1-phosphate receptors regulate chemokine-driven transendothelial migration of lymph node but not splenic T cells. J Immunol, 2005, 175(5): 2913-2924.
20. Spiegel S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol, 2003, 4(5): 397-407.
21. Olivera A, Kohama T, Edsall L, et al. Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol, 1999, 147(3): 545-558.
22. Shu X, Wu W, Mosteller RD. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol, 2002, 22(22): 7758-7768.
23. Xia P, Gamble JR, Wang L, et al. An oncogenic role of sphingosine kinase. Curr Biol, 2000, 10(23): 1527-1530.
24. Nava VE, Hobson JP, Murthy S, et al. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp Cell Res, 2002, 281(1): 115-127.
25. Sukocheva OA, Wang L, Albanese N, et al. Sphingosine kinase transmits estrogensignaling in human breast cancer cells. Mol Endocrinol, 2003, 17(10):2002-2012.
26. Pitson SM, Xia P, Leclercq TM, et al. Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med, 2005, 201(1): 49-54.
27. French KJ, Schrecengost RS, Lee BD, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res, 2003, 63(18): 5962-5969.
28. Johnson KR, Johnson KY, Crellin HG, et al. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem, 2005, 53(9): 1159-1166.
29. Wu W, Shu X, Hovsepyan H, et al. VEGF receptor expression and signaling in human bladder tumors. Oncogene, 2003, 22(22): 3361-3370.
30. Sarkar S, Maceyka M, Hait NC, et al. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett, 2005, 579(24): 5313-5317.
31. Van Brocklyn JR, Jackson CA, Pearl DK, et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol, 2005, 64(8): 695-705.
32. Liu H, Toman RE, Goparaju SK, et al. Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem, 2003, 278(41): 40330-40336.
33. Igarashi N, Okada T, Hayashi S, et al. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem, 2003, 278(47): 46832-46839.
34. Huang DC. BH3-Only proteins-essential initiators of apoptotic cell death. Cell, 2000, 103(6): 839-842.
35. Maceyka M, Sankala H, Hait NC, et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem, 2005, 280(44): 37118-37129.
36. Berridge MJ, Lipp P. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol, 2000, 1(1): 11-21.
37. Pinton P, Ferrari D, Rapizzi E, et al. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J, 2001, 20(11): 2690-2701.
38. Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science, 2003, 300(5616): 135-139.
39. Nutt LK, Chandra J, Pataer A, et al. Bax-mediated Ca2+ mobilization promotes cytochrome c release during apoptosis. J Biol Chem, 2002, 277(23): 20301-20308.
40. Toman RE, Movsesyan V, Murthy SK, et al. Ceramide-induced cell death in primary neuronal cultures: upregulation of ceramide levels during neuronal apoptosis. J Neurosci Res, 2002, 68(3): 323-330.
41. Jaillard C, Harrison S, Stankoff B, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci, 2005, 25(6): 1459-1469.
42. Johnson JR, Chu AK. Possible role of CREB in the stimulation of oligodendrocyte precursor cell proliferation by neurotrophin-3. J Neurochem, 2000, 74(4): 1409-1417.
43. Saini HS, Gorse KM, Boxer LM. Neurotrophin-3 and a CREB-mediated signaling pathway regulate Bcl-2 expression in oligodendrocyte progenitor cells. J Neurochem, 2004, 89(4): 951-961.
44. Saini HS, Coelho RP, Goparaju SK, et al. Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J Neurochem, 2005, 95(5): 1298-1310.
45. Sato K, Ui M, Okajima F. Differential roles of Edg-1 and Edg-5, sphingosine 1-phosphate receptors, in the signaling pathways in C6 glioma cells. Brain Res Mol Brain Res, 2000, 85(1-2): 151-160.
46. Harada J, Foley M, Moskowitz MA. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J Neurochem, 2004, 88(4): 1026-1039.
47. Edsall LC, Cuvillier O, Twitty S, et al. Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J Neurochem, 2001, 76(5): 1573-1584.
48. Bassi R, Anelli V, Giussani P, et al. Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi-protein-coupled receptors. Glia, 2006, 53(6): 621-630.
49. Leo A, Citraro R, Marra R, et al. The sphingosine 1-phosphate signaling pathway in epilepsy: A possible role for the immunomodulator drug fingolimod in epilepsy treatment. CNS Neurol Disord Drug Targets, 2017, 16(3): 311-325.
50. Chan JP, Sieburth D. Localized sphingolipid signaling at presynaptic terminals is regulated by calcium influx and promotes recruitment of priming factors. J Neurosci, 2012, 32(49): 17909-17920.
51. Alemany R, Kleuser B, Ruwisch L, et al. Depolarisation induces rapid and transient formation of intracellular sphingosine-1-phosphate. FEBS Lett, 2001, 509(2): 239-244.
52. Blom T, Bergelin N, Slotte JP, et al. Sphingosine kinase regulates voltage operated calcium channels in GH4C1 rat pituitary cells. Cell Signal, 2006, 18(9): 1366-1375.
53. Kim MY, Liang GH, Kim JA, et al. Sphingosine-1-phosphate activates BKCa channels independently of G protein-coupled receptor in human endothelial cells. Am J Physiol Cell Physiol, 2006, 290(4): C1000-1008.
54. 陈璇, 王罗俊, 邓艳春. 钙离子通道基因突变与癫痫. 癫痫杂志, 2016, 2(4): 344-348.
55. Leo A, Citraro R, Constanti A, et al. Are big potassium-type Ca(2+)-activated potassium channels a viable target for the treatment of epilepsy?. Exp Opin Therc Targ, 2015, 19(7): 911-926.
56. Kajimoto T, Okada T, Yu H, et al. Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol, 2007, 27(9): 3429-3440.
57. Kanno T, Nishizaki T. Endogenous sphingosine 1-phosphate regulates spontaneous glutamate release from mossy fiber terminals via S1P(3) receptors. Life Sci, 2011, 89(3-4): 137-140.
58. Wang GX, Wang DW, Liu Y, et al. Intractable epilepsy and the P-glycoprotein hypothesis. Int J Neurosci, 2016, 126(5): 385-392.
59. Yu N, Liu H, Zhang YF, et al. Effects of brain IKKbeta gene silencing by small interfering RNA on P-glycoprotein expression and brain damage in the rat kainic acid-induced seizure model. CNS Neurol Disord Drug Targ, 2014, 13(4): 661-672.
60. Cannon RE, Peart JC, Hawkins BT, et al. Targeting blood-brain barrier sphingolipid signaling reduces basal Pglycoprotein activity and improves drug delivery to the brain. Proc Nat Acad Sci USA, 2012, 109(39): 15930-15935.
61. Zheng S, Wei S, Wang X. et al. Sphingosine kinase 1 mediates neuroinflammation following cerebral ischemia.ExpNeurol, 2015, 272:160-169.
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