Protective effects of fingolimod on secondary nerve injury after thalamic-ventricle hemorrhage in rats_West China Medical Journal

Authors：

GAN Qi ¹ , ZHANG Hanmei ² , MA Weichao ¹ ,  LIU Yi ¹

1. Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIU Yi, Email: neurosurgeon@live.cn

Keywords：

Fingolimod; Thalamic-ventricle hemorrhage; Neuroprotection; Apoptosis; Autophagy; Rat

DOI：

10.7507/1002-0179.201805035

Video：

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ObjectiveTo explore the effect of fingolimod (FTY720) on secondary nerve injury after thalamic-ventricle hemorrhage (TH-IVH) in rats.MethodsAdult male Sprague Dawley rats (clean animal) were randomly divided into 3 groups: sham group, TH-IVH group, and intervention group (FTY720 group), with 6 rats in each group. TH-IVH model was established in both TH-IVH group and FTY720 group, but only the rats in FTY720 group were treated with FTY720. The observation was conducted at the 1st, 3rd and 7th day after modeling. The main observation index included scores of neurological function, change of body weight, water content of brain tissue, the activation of inflammatory cells, the degree of neuronal degeneration and apoptosis, and the level of cell autophagy.ResultsAt the 1st, 3rd and 7th day after modeling, the change of body weight, the neurological score, brain edema and microglia activation in TH-IVH group were statistically different from those in sham group and FTY720 group (P<0.05). The number of degenerated neurons and the number of apoptotic cells in TH-IVH group were statistically different from those in sham group and FTY720 group at the 1st and 3rd day after modeling (P<0.05). The differences in the ratio of LC3Ⅱ/LC3Ⅰ protein expression andBcl-2/Bax expression were statistically significant between FTY720 group and TH-IVH group at the 1st and 3rd day after modeling (P<0.05).ConclusionsFTY720 can improve neurological function of the TH-IVH model in the acute phase, and has certain neuroprotective effect. The neuroprotective effect of FTY720 may be associated with neuronal autophagy and apoptosis regulation and immunosuppression.

Citation： GAN Qi, ZHANG Hanmei, MA Weichao, LIU Yi. Protective effects of fingolimod on secondary nerve injury after thalamic-ventricle hemorrhage in rats. West China Medical Journal, 2018, 33(6): 736-743. doi: 10.7507/1002-0179.201805035 Copy

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2.	Zahuranec BD, Lisabeth LD, Sánchez BN, et al. Intracerebral hemorrhage mortality is not changing despite declining incidence. Neurology, 2014, 82(24): 2180-2186.
3.	Lema PP, Girard C, Vachon P. High doses of methylprednisolone are required for the treatment of collagenase-induced intracerebral hemorrhage in rats. Can J Vet Res, 2005, 69(4): 253-259.
4.	Iniaghe LO, Krafft PR, Klebe DW, et al. Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage. Neurobiol, 2015, 82: 349-358.
5.	Ang LC, Gillett JM, Kaufmann JC. Neuropathology of heart transplantation. Can J Neurol Sci, 1989, 16(3): 291-298.
6.	. Pitman MR, Woodcock JM, Lopez AF et al. Molecular targets of FTY720(fingolimod). Curr Mol Med, 2012, 12(10): 1207-1219.
7.	Patmanathan SN, Yap LF, Murray PG, et al. The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod. J Cell Mol Med, 2015, 19(10): 2329-2340.
8.	Azuma H, Takahara S, Ichimaru N, et al. Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. Cancer Res, 2002, 62(5): 1410-1419.
9.	Chua CW, Lee DT, Ling MT, et al. FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer. Int J Cancer, 2005, 117(6): 1039-1048.
10.	Schmid G, Guba M, Papyan A, et al. FTY720 inhibits tumor growth and angiogenesis. Transplant Proc, 2005, 37(1): 110-111.
11.	Wei Y, Yemisci M, Kim HH, et al. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol, 2011, 69(1): 119-129.
12.	Hasegawa Y, Suzuki H, Sozen T, et al. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke, 2010, 41(2): 368-374.
13.	Zhang Z, Zhang Z, Fauser U, et al. FTY720 attenuates accumulation of EMAP-Ⅱ⁺ and MHC-Ⅱ⁺ monocytes in early lesions of rat traumatic brain injury. J Cell Mol Med, 2007, 11(2): 307-314.
14.	Rolland WB 2nd, Manaenko A, Lekic T, et al. FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice. Acta Neurochir Suppl, 2011, 111: 213-217.
15.	. Lekic T, Rolland W, Manaenko A, et al. Evaluation of the hematoma consequences, neurobehavioral profiles, and histopathology in a rat model of pontine hemorrhage. J Neurosurg, 2013, 118(2): 465-477.
16.	Kennedy PC, Zhu R, Huang T, et al. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther, 2011, 338(3): 879-889.
17.	Takasugi N, Sasaki T, Ebinuma I, et al. FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. PLoS One, 2013, 8(5): e64050.
18.	Lu L, Barfejani AH, Qin T, et al. Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res, 2014, 1555: 89-96.
19.	Li JY, Chang GQ, Liu Y, et al. Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage. Neurosci Bull, 2015, 31(6): 755-762.
20.	Rolland WB, Lekic T, Krafft PR, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol, 2013, 241: 45-55.
21.	Qureshi AI. Apoptosis as a form of cell death in intracerebral hemorrhage. Neurosurgery, 2003, 52(5): 1041-1047.
22.	Krajewski S, Krajewska M, Shabaik S, et al. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol, 1994, 145(6): 1323-1336.
23.	Creagh EM. Caspase crosstallk: integration of apoptotic and innate immune signalliing pathways. Trends Immunol, 2014, 35(12): 631-640.
24.	Kuranaga E. Beyond apoptosis: caspase regulatory mechanisms and functions in vivo. Genes Cells, 2012, 17(2): 83-97.
25.	Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol, 1962, 12: 198-202.
26.	Marzella L, Ahlberg J, Glaumann H. Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation. Virchows Arch B Cell Pathol Incl Mol Pathol, 1981, 36(2-3): 219-234.
27.	Eisenberg-Lerner A, Bialik S, Simon HU, et al. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ, 2009, 16(7): 966-975.
28.	Zhu H, Zhang Y. Life and death partners in Post-PCI restenosis: apoptosis, autophagy, and the cross-talk between them. Curr Drug Targets, 2016.

1. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol, 2010, 9(2): 167-176.
2. Zahuranec BD, Lisabeth LD, Sánchez BN, et al. Intracerebral hemorrhage mortality is not changing despite declining incidence. Neurology, 2014, 82(24): 2180-2186.
3. Lema PP, Girard C, Vachon P. High doses of methylprednisolone are required for the treatment of collagenase-induced intracerebral hemorrhage in rats. Can J Vet Res, 2005, 69(4): 253-259.
4. Iniaghe LO, Krafft PR, Klebe DW, et al. Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage. Neurobiol, 2015, 82: 349-358.
5. Ang LC, Gillett JM, Kaufmann JC. Neuropathology of heart transplantation. Can J Neurol Sci, 1989, 16(3): 291-298.
6. . Pitman MR, Woodcock JM, Lopez AF et al. Molecular targets of FTY720(fingolimod). Curr Mol Med, 2012, 12(10): 1207-1219.
7. Patmanathan SN, Yap LF, Murray PG, et al. The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod. J Cell Mol Med, 2015, 19(10): 2329-2340.
8. Azuma H, Takahara S, Ichimaru N, et al. Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. Cancer Res, 2002, 62(5): 1410-1419.
9. Chua CW, Lee DT, Ling MT, et al. FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer. Int J Cancer, 2005, 117(6): 1039-1048.
10. Schmid G, Guba M, Papyan A, et al. FTY720 inhibits tumor growth and angiogenesis. Transplant Proc, 2005, 37(1): 110-111.
11. Wei Y, Yemisci M, Kim HH, et al. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol, 2011, 69(1): 119-129.
12. Hasegawa Y, Suzuki H, Sozen T, et al. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke, 2010, 41(2): 368-374.
13. Zhang Z, Zhang Z, Fauser U, et al. FTY720 attenuates accumulation of EMAP-Ⅱ⁺ and MHC-Ⅱ⁺ monocytes in early lesions of rat traumatic brain injury. J Cell Mol Med, 2007, 11(2): 307-314.
14. Rolland WB 2nd, Manaenko A, Lekic T, et al. FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice. Acta Neurochir Suppl, 2011, 111: 213-217.
15. . Lekic T, Rolland W, Manaenko A, et al. Evaluation of the hematoma consequences, neurobehavioral profiles, and histopathology in a rat model of pontine hemorrhage. J Neurosurg, 2013, 118(2): 465-477.
16. Kennedy PC, Zhu R, Huang T, et al. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther, 2011, 338(3): 879-889.
17. Takasugi N, Sasaki T, Ebinuma I, et al. FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. PLoS One, 2013, 8(5): e64050.
18. Lu L, Barfejani AH, Qin T, et al. Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res, 2014, 1555: 89-96.
19. Li JY, Chang GQ, Liu Y, et al. Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage. Neurosci Bull, 2015, 31(6): 755-762.
20. Rolland WB, Lekic T, Krafft PR, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol, 2013, 241: 45-55.
21. Qureshi AI. Apoptosis as a form of cell death in intracerebral hemorrhage. Neurosurgery, 2003, 52(5): 1041-1047.
22. Krajewski S, Krajewska M, Shabaik S, et al. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol, 1994, 145(6): 1323-1336.
23. Creagh EM. Caspase crosstallk: integration of apoptotic and innate immune signalliing pathways. Trends Immunol, 2014, 35(12): 631-640.
24. Kuranaga E. Beyond apoptosis: caspase regulatory mechanisms and functions in vivo. Genes Cells, 2012, 17(2): 83-97.
25. Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol, 1962, 12: 198-202.
26. Marzella L, Ahlberg J, Glaumann H. Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation. Virchows Arch B Cell Pathol Incl Mol Pathol, 1981, 36(2-3): 219-234.
27. Eisenberg-Lerner A, Bialik S, Simon HU, et al. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ, 2009, 16(7): 966-975.
28. Zhu H, Zhang Y. Life and death partners in Post-PCI restenosis: apoptosis, autophagy, and the cross-talk between them. Curr Drug Targets, 2016.

West China Medical Journal

Protective effects of fingolimod on secondary nerve injury after thalamic-ventricle hemorrhage in rats

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