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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage

Authors: Hao-Liang Xu, Dale A Pelligrino, Chanannait Paisansathan, Fernando D Testai

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Subarachnoid hemorrhage (SAH) is a neurological emergency with limited pharmacological treatment options. Inflammation is increasingly recognized as a key pathogenic contributor to brain injury in this condition. In the present study, we examined the neuroprotective effects of the immunomodulatory agent, fingolimod, in rats subjected to SAH.

Methods

We utilized an endovascular rat perforation model of SAH. Animals were divided into four groups: (1) sham-vehicle; (2) sham-fingolimod; (3) SAH-vehicle; and (4) SAH-fingolimod. Rats received either vehicle solution or fingolimod (0.5 mg/kg) intraperitoneally 3 hours after sham surgery or SAH. A closed cranial window and intravital microscope system was used at 48 hours to assess neuroinflammation, which was represented by rhodamine-6G-labeled leukocyte trafficking in pial venules, and pial arteriolar dilating responses to a variety of vasodilators, including hypercapnia, and topically-applied acetylcholine, adenosine, and S-nitroso-N-acetyl penicillamine. In addition, motor-sensory function was evaluated.

Results

Compared to sham-vehicle rats, SAH-vehicle animals displayed a four-times greater increase in pial venular intraluminal leukocyte adhesion. Treatment with fingolimod largely reduced the intravascular leukocyte adhesion. Vehicle-treated SAH animals displayed a significant decrease in pial arteriolar responses to all the vasodilators tested and vascular reactivity was preserved, to a significant degree, in the presence of fingolimod. In addition, neurological scores obtained at 48 hours post-SAH indicated significant neurological deficits in the vehicle-treated group (versus sham-vehicle surgical control). Those deficiencies were partially reduced by fingolimod (P < 0.0001 compared to the vehicle-treated SAH group).

Conclusions

Treatment of rats with fingolimod was associated with a marked limitation in the intravascular adhesion of leukocytes to pial venules, preserved pial arteriolar dilating function, and improved neurological outcome in rats subjected to SAH.
Literature
1.
Huang J, van Gelder JM. The probability of sudden death from rupture of intracranial aneurysms: a meta-analysis. Neurosurgery. 2002;51:1101–5. discussion 1105–7.CrossRefPubMed
2.
Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997;28:660–4.CrossRefPubMed
3.
Mayer SA, Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59:1750–8.CrossRefPubMed
4.
Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006;354:387–96.CrossRefPubMed
5.
Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol. 2009;8:345–54.CrossRefPubMed
6.
Macdonald RL, Jaja B, Cusimano MD, Etminan N, Hanggi D, Hasan D, et al. SAHIT Investigators - on the outcome of some subarachnoid hemorrhage clinical trials. Transl Stroke Res. 2013;4:286–96.CrossRefPubMed
7.
Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10:44–58.CrossRefPubMed
8.
Schneider UC, Schiffler J, Hakiy N, Horn P, Vajkoczy P. Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro. J Neuroinflammation. 2012;9:28. 2094-9-28.CrossRefPubMedCentralPubMed
9.
Kooijman E, Nijboer CH, van Velthoven CT, Mol W, Dijkhuizen RM, Kesecioglu J, et al. Long-term functional consequences and ongoing cerebral inflammation after subarachnoid hemorrhage in the rat. PLoS One. 2014;9:e90584.CrossRefPubMedCentralPubMed
10.
Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014;34:1573–84.CrossRefPubMed
11.
Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schutt S, et al. Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry. 2001;70:534–7.CrossRefPubMedCentralPubMed
12.
Lad SP, Hegen H, Gupta G, Deisenhammer F, Steinberg GK. Proteomic biomarker discovery in cerebrospinal fluid for cerebral vasospasm following subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 2012;21:30–41.CrossRefPubMed
13.
Soliven B, Miron V, Chun J. The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology. 2011;76:S9–14.CrossRefPubMed
14.
Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9:883–97.CrossRefPubMed
15.
Wei Y, Yemisci M, Kim HH, Yung LM, Shin HK, Hwang SK, et al. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol. 2011;69:119–29.CrossRefPubMedCentralPubMed
16.
Rolland 2nd WB, Manaenko A, Lekic T, Hasegawa Y, Ostrowski R, Tang J, et al. FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice. Acta Neurochir Suppl. 2011;111:213–7.CrossRefPubMedCentralPubMed
17.
Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke. 2010;41:368–74.CrossRefPubMedCentralPubMed
18.
Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods. 2008;167:327–34.CrossRefPubMedCentralPubMed
19.
Xu HL, Paisansathan C, Pelligrino DA. Closed cranial window applications in the rat: studies on neurovascular coupling involving pial arterioles and the glia limitans. In: Zhao M et al., editors. Neurovascular coupling methods. New York: Springer Science+Business Media; 2014. p. 179–200.CrossRef
20.
Xu HL, Baughman VL, Pelligrino DA. Estrogen replacement treatment in diabetic ovariectomized female rats potentiates postischemic leukocyte adhesion in cerebral venules. Stroke. 2004;35:1974–8.CrossRefPubMed
21.
Xu HL, Galea E, Santizo RA, Baughman VL, Pelligrino DA. The key role of caveolin-1 in estrogen-mediated regulation of endothelial nitric oxide synthase function in cerebral arterioles in vivo. J Cereb Blood Flow Metab. 2001;21:907–13.CrossRefPubMed
22.
Britz GW, Meno JR, Park IS, Abel TJ, Chowdhary A, Nguyen TS, et al. Time-dependent alterations in functional and pharmacological arteriolar reactivity after subarachnoid hemorrhage. Stroke. 2007;38:1329–35.CrossRefPubMed
23.
Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol. 2013;241:45–55.CrossRefPubMedCentralPubMed
24.
Hasegawa Y, Suzuki H, Altay O, Rolland W, Zhang JH. Role of the sphingosine metabolism pathway on neurons against experimental cerebral ischemia in rats. Transl Stroke Res. 2013;4:524–32.CrossRefPubMed
25.
26.
Liesz A, Sun L, Zhou W, Schwarting S, Mracsko E, Zorn M, et al. FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia. PLoS One. 2011;6:e21312.CrossRefPubMedCentralPubMed
27.
Sabri M, Lass E, Macdonald RL. Early brain injury: a common mechanism in subarachnoid hemorrhage and global cerebral ischemia. Stroke Res Treat. 2013;2013:394036.PubMedCentralPubMed
28.
Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R. The immunology of acute stroke. Nat Rev Neurol. 2012;8:401–10.CrossRefPubMed
29.
30.
Kubota T, Handa Y, Tsuchida A, Kaneko M, Kobayashi H, Kubota T. The kinetics of lymphocyte subsets and macrophages in subarachnoid space after subarachnoid hemorrhage in rats. Stroke. 1993;24:1993–2000. discussion 2000–1.CrossRefPubMed
31.
Kooijman E, Nijboer CH, van Velthoven CT, Kavelaars A, Kesecioglu J, Heijnen CJ. The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies. J Neuroinflammation. 2014;11:2. 2094-11-2.CrossRefPubMedCentralPubMed
32.
Kasius KM, Frijns CJ, Algra A, Rinkel GJ. Association of platelet and leukocyte counts with delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis. 2010;29:576–83.CrossRefPubMed
33.
McMahon CJ, Hopkins S, Vail A, King AT, Smith D, Illingworth KJ, et al. Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg. 2013;5:512–7.CrossRefPubMedCentralPubMed
34.
Xu HL, Garcia M, Testai F, Vetri F, Barabanova A, Pelligrino DA, et al. Pharmacologic blockade of vascular adhesion protein-1 lessens neurologic dysfunction in rats subjected to subarachnoid hemorrhage. Brain Res. 2014;1586:83–9.CrossRefPubMed
35.
Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8.CrossRefPubMed
36.
Gomis P, Graftieaux JP, Sercombe R, Hettler D, Scherpereel B, Rousseaux P. Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2010;112:681–8.CrossRefPubMed
37.
Chyatte D, Fode NC, Nichols DA, Sundt Jr TM. Preliminary report: effects of high dose methylprednisolone on delayed cerebral ischemia in patients at high risk for vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery. 1987;21:157–60.CrossRefPubMed
38.
Chyatte D, Sundt Jr TM. Response of chronic experimental cerebral vasospasm to methylprednisolone and dexamethasone. J Neurosurg. 1984;60:923–6.CrossRefPubMed
39.
Pradilla G, Chaichana KL, Hoang S, Huang J, Tamargo RJ. Inflammation and cerebral vasospasm after subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21:365–79.CrossRefPubMed
40.
Chaichana KL, Pradilla G, Huang J, Tamargo RJ. Role of inflammation (leukocyte-endothelial cell interactions) in vasospasm after subarachnoid hemorrhage. World Neurosurg. 2010;73:22–41.CrossRefPubMed
41.
Pradilla G, Wang PP, Legnani FG, Ogata L, Dietsch GN, Tamargo RJ. Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. J Neurosurg. 2004;101:88–92.CrossRefPubMed
42.
Friedrich B, Muller F, Feiler S, Scholler K, Plesnila N. Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab. 2012;32:447–55.CrossRefPubMedCentralPubMed
43.
Sun BL, Zheng CB, Yang MF, Yuan H, Zhang SM, Wang LX. Dynamic alterations of cerebral pial microcirculation during experimental subarachnoid hemorrhage. Cell Mol Neurobiol. 2009;29:235–41.CrossRefPubMed
44.
Ostergaard L, Aamand R, Karabegovic S, Tietze A, Blicher JU, Mikkelsen IK, et al. The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2013;33:1825–37.CrossRefPubMedCentralPubMed
45.
Tolle M, Levkau B, Keul P, Brinkmann V, Giebing G, Schonfelder G, et al. Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3. Circ Res. 2005;96:913–20.CrossRefPubMed
46.
Hait NC, Wise LE, Allegood JC, O’Brien M, Avni D, Reeves TM, et al. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci. 2014;17:971–80.CrossRefPubMedCentralPubMed
47.
Brunkhorst R, Vutukuri R, Pfeilschifter W. Fingolimod for the treatment of neurological diseases-state of play and future perspectives. Front Cell Neurosci. 2014;8:283.CrossRefPubMedCentralPubMed
48.
49.
Campos F, Qin T, Castillo J, Seo JH, Arai K, Lo EH, et al. Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model. Stroke. 2013;44:505–11.CrossRefPubMedCentralPubMed
50.
Fu Y, Hao J, Zhang N, Ren L, Sun N, Li YJ, et al. Fingolimod for the treatment of intracerebral hemorrhage: A 2-arm proof-of-concept study. JAMA Neurol. 2014;71:1092–101.CrossRefPubMed
51.
Sarrafzadeh A, Schlenk F, Meisel A, Dreier J, Vajkoczy P, Meisel C. Immunodepression after aneurysmal subarachnoid hemorrhage. Stroke. 2011;42:53–8.CrossRefPubMed
52.
Pfeilschifter W, Czech-Zechmeister B, Sujak M, Foerch C, Wichelhaus TA, Pfeilschifter J. Treatment with the immunomodulator FTY720 does not promote spontaneous bacterial infections after experimental stroke in mice. Exp Transl Stroke Med. 2011;3:2. 7378-3-2.CrossRefPubMedCentralPubMed
53.
Fu Y, Zhang N, Ren L, Yan Y, Sun N, Li YJ, et al. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A. 2014;111:18315–20.CrossRefPubMedCentralPubMed
Metadata
Title
Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage
Authors
Hao-Liang Xu
Dale A Pelligrino
Chanannait Paisansathan
Fernando D Testai
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0234-7

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