Summary
Background. Though cerebral vasospasm is one of the most serious complications of subarachnoid haemorrhage (SAH), its complex pathogenesis is poorly understood and available clinical treatment options are unsatisfactory. This study was designed to examine the efficacy of leflunomide, an immunomodulatory agent with inhibitory properties, on vascular smooth muscle cell proliferation and inflammation in a rabbit cerebral vasospasm model.
Methods. Twenty-two adult New-Zealand rabbits were assigned to 4 groups: control, SAH, SAH plus vehicle, SAH plus leflunomide. Subarachnoid haemorrhage was induced by administration of 1 ml of fresh unheparinised autologous arterial blood into the cisterna magna. Oral leflunomide (2 mg/kg) or vehicle treatment was started 12 h after the induction of subarachnoid haemorrhage and administered once a day. Three days later, the animals were sacrificed and the basilar artery was examined histologically for the lumen area and the thickness of the vessel wall. Inflammatory reaction was also examined by counting white blood cells within the vessel wall by means of light microscopic examination using haematoxylin and eosin staining.
Findings. Severe and moderate vasospasms were detected in the basilar artery of the SAH and SAH plus vehicle treated groups, respectively. Leflunomide effectively reduced the vasospasm of the basilar artery. Compared to the vehicle treated group, leflunomide significantly reduced the lumen area (p < 0.01) and hyperplasia of the vessel wall (p < 0.01). Although inflammatory response within the vessel wall was reduced in the leflunomide treated group, no statistical significance was found between groups (p = 0.07).
Conclusion. This study demonstrates for the first time that leflunomide treatment attenuates cerebral vasospasm in a rabbit SAH model while inflammatory reaction in the vessel wall is not affected. Although further studies are needed to reveal its molecular mechanisms in relieving vasospasm, leflunomide may provide a therapeutic potential for human cerebral vasospasm induced by SAH.
Similar content being viewed by others
References
CO Borel A McKee A Parra MM Haglund A Solan V Prabhakar H Sheng DS Warner L Niklason (2003) ArticleTitlePossible role for vascular cell proliferation in cerebral vasospasm after subarachnoid hemorrhage Stroke 34 427–433 Occurrence Handle12574555 Occurrence Handle10.1161/01.STR.0000053848.06436.AB Occurrence Handle1:CAS:528:DC%2BD3sXosVOgsA%3D%3D
JF Clark G Pyne-Geithman (2005) ArticleTitleVascular smooth muscle functions: the physiology and pathology of vasoconstriction Pathophysiology 12 35–45 Occurrence Handle15927823 Occurrence Handle10.1016/j.pathophys.2005.02.007 Occurrence Handle1:CAS:528:DC%2BD2MXltVeht7o%3D
M Dougados P Emery EM Lemmel R de la Serna CA Zerbini S Brin P van Riel (2003) ArticleTitleEfficacy and safety of leflunomide and predisposing factors for treatment response in patients with active rheumatoid arthritis: RELIEF 6-month data J Rheumatol 30 2572–2579 Occurrence Handle14719196 Occurrence Handle1:CAS:528:DC%2BD2cXktVCgtbo%3D
AS Dumont RJ Dumont MM Chow CL Lin T Calisaneller KF Lev NF Kassell KS Lee (2003) ArticleTitleCerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation Neurosurgery 53 123–133 Occurrence Handle12823881 Occurrence Handle10.1227/01.NEU.0000068863.37133.9E
N Egemen U Sanlidilek A Zorlutuna M Baskaya S Bilgic S Caglar A Unlu (1992) ArticleTitleTransclival approach to rabbit basilar artery for experimental induction of chronic vasospasm Acta Neurochir (Wien) 115 123–126 Occurrence Handle10.1007/BF01406370 Occurrence Handle1:STN:280:DyaK383psF2nsg%3D%3D
K Fassbender B Hodapp S Rossol T Bertsch J Schmeck S Schutt M Fritzinger P Horn P Vajkoczy S Kreisel J Brunner P Schmiedek M Hennerici (2001) ArticleTitleInflammatory cytokines in subarachnoid hemorrhage: association with abnormal blood flow velocities in basal cerebral arteries J Neurol Neurosurg Psychiatry 70 534–537 Occurrence Handle11254783 Occurrence Handle10.1136/jnnp.70.4.534 Occurrence Handle1:STN:280:DC%2BD3M3os1Kqsg%3D%3D
JM Findlay RL Macdonald BKA Weir (1991) ArticleTitleCurrent concepts of pathophysiology and management of cerebral vasospasm following aneurysmal subarachnoid hemorrhage Cerebrovasc Brain Metab Rev 3 336–361 Occurrence Handle1772740 Occurrence Handle1:STN:280:DyaK387is1Cnug%3D%3D
JM Findlay BKA Weir K Kanamaru F Espinosa (1989) ArticleTitleArterial wall changes in cerebral vasospasm Neurosurgery 25 736–745 Occurrence Handle2586727 Occurrence Handle10.1097/00006123-198911000-00008 Occurrence Handle1:STN:280:DyaK3c%2Fms12qtg%3D%3D
G Grasso (2004) ArticleTitleAn overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage Brain Res Rev 44 49–63 Occurrence Handle14739002 Occurrence Handle10.1016/j.brainresrev.2003.10.003 Occurrence Handle1:CAS:528:DC%2BD2cXltVygtQ%3D%3D
J Grisar M Aringer MD Köller GH Stumvoll D Eselböck B Zwölfer CW Steiner B Zierhut L Wagner P Pietschmann JS Smolen (2004) ArticleTitleLeflunomide inhibits transendothelial migration of peripheral blood mononuclear cells Ann Rheum Dis 63 1632–1637 Occurrence Handle15547088 Occurrence Handle10.1136/ard.2003.018440 Occurrence Handle1:CAS:528:DC%2BD2cXhtFaktbjI
Y Handa T Kubota M Kaneko A Tsuchida H Kobayashi H Kawano T Kubota (1995) ArticleTitleExpression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid hemorrhage in rats Acta Neurochir 132 92–97 Occurrence Handle10.1007/BF01404854 Occurrence Handle1:STN:280:DyaK2M3nsVCrtQ%3D%3D
J Hansen-Schwartz (2004) ArticleTitleCerebral vasospasm: a consideration of the various cellular mechanisms involved in the pathophysiology Neurocrit Care 1 235–246 Occurrence Handle16174921 Occurrence Handle10.1385/NCC:1:2:235 Occurrence Handle1:CAS:528:DC%2BD2cXms1altbY%3D
CG Harrod BR Bendok HH Batjer (2005) ArticleTitlePrediction of cerebral vasospasm in patients presenting with aneurismal subarachnoid hemorrhage: a review Neurosurgery 56 633–654 Occurrence Handle15792502 Occurrence Handle10.1227/01.NEU.0000156644.45384.92
T Jahnke FKW Schäfer H Bolte L Rector PJ Schäfer J Brossmann F Fändrich J Hedderich M Heller S Müller-Hülsbeck (2005) ArticleTitlePeriprocedural oral administration of the leflunomide analogue FK778 inhibits neointima formation in a double-injury rat model of restenosis J Vasc Interv Radiol 16 903–910 Occurrence Handle16002499
T Jayaraman V Berenstein X Li J Mayer M Silane YS Shin Y Niimi T Kilic M Gunel A Berenstein (2005) ArticleTitleTumor necrosis factor alpha is a key modulator of inflammation in cerebral aneurysms Neurosurgery 57 558–564 Occurrence Handle16145536 Occurrence Handle10.1227/01.NEU.0000170439.89041.D6
J Josko (2003) ArticleTitleCerebral angiogenesis and expression of VEGF after subarachnoid hemorrhage in rats Brain Res 981 58–69 Occurrence Handle12885426 Occurrence Handle10.1016/S0006-8993(03)02920-2 Occurrence Handle1:CAS:528:DC%2BD3sXls1Cgtbo%3D
N Kassel M Shaffrey C Shaffrey (1993) Cerebral vasospasm following aneurysmal subarachnoid hemorrhage M Apuzzo (Eds) Brain surgery EditionNumber1 Churchill-Livingstone New York 847–856
K Magari S Miyata F Nishigaki Y Ohkubo S Mutol (2004) ArticleTitleComparison of anti-arthritic properties of leflunomide with methotrexate and FK506: effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis Inflamm Res 53 544–550 Occurrence Handle15597149 Occurrence Handle10.1007/s00011-004-1294-9 Occurrence Handle1:CAS:528:DC%2BD2cXhtVKhtrnP
RV Nair W Cao RE Morris (1996) ArticleTitleThe antiproliferative effect of leflunomide on vascular smooth muscle cells in vitro is mediated by selective inhibition of pyrimidine biosynthesis Transpalnt Proc 28 3081 Occurrence Handle1:CAS:528:DyaK2sXisFGhtA%3D%3D
T Otsuji S Endo Y Hirashima M Nishijima A Takaku (1994) ArticleTitleAn experimental model of symptomatic vasospasm induced by oxyhemoglobin in rabbits Stroke 25 657–662 Occurrence Handle8128522 Occurrence Handle1:CAS:528:DyaK2cXktVKms74%3D
S Park M Yamaguchi C Zhou JW Calvert J Tang JH Zhang (2004) ArticleTitleNeurovascular protection reduces early brain injury after subarachnoid hemorrhage Stroke 35 2412–2417 Occurrence Handle15322302 Occurrence Handle10.1161/01.STR.0000141162.29864.e9 Occurrence Handle1:STN:280:DC%2BD2cvnslOgsQ%3D%3D
T Sasaki NF Kassell M Yamashita S Fujiwara M Zuccarello (1985) ArticleTitleBarrier disruption in the major cerebral arteries following experimental subarachnoid hemorrhage J Neurosurg 63 433–440 Occurrence Handle4020472 Occurrence Handle1:STN:280:DyaL2M3mtlylug%3D%3D Occurrence Handle10.3171/jns.1985.63.3.0433
T Sasaki NF Kassell M Zuccarello T Nagakomi S Fujiwara AR Colohan M Lehman (1986) ArticleTitleBarrier disruption in the major cerebral arteries during the acute stage after experimental subarachnoid hemorrhage Neurosurgery 19 177–184 Occurrence Handle3748347 Occurrence Handle10.1097/00006123-198608000-00002 Occurrence Handle1:STN:280:DyaL28zhtFOhtQ%3D%3D
J Savikko E Von Willebrand P Hayry (2003) ArticleTitleLeflunomide analogue FK778 is vasculoprotective independent of its immunosuppressive effect: potential applications for restenosis and chronic rejection Transplantation 76 455–458 Occurrence Handle12923428 Occurrence Handle10.1097/01.TP.0000076382.87978.73 Occurrence Handle1:CAS:528:DC%2BD3sXmtl2lurg%3D
R Secombe YRT Dinh P Gomis (2002) ArticleTitleCerebrovascular inflammation following subarachnoid hemorrhage Jpn J Pharmacol 88 227–249 Occurrence Handle10.1254/jjp.88.227
A Spallone FS Pastore (1989) ArticleTitleCerebral vasospasm in a double-injection model in rabbit Surg Neurol 32 408–417 Occurrence Handle2636794 Occurrence Handle10.1016/0090-3019(89)90002-5 Occurrence Handle1:STN:280:DyaK3c3ms1aqug%3D%3D
E Tani (2002) ArticleTitleMolecular mechanisms involved in development of cerebral vasospasm Neurosurg Focus 12 ECP1 Occurrence Handle16212317 Occurrence Handle10.3171/foc.2002.12.3.8
MM Treggiari-Venzi PM Suter JA Romand (2001) ArticleTitleReview of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care Neurosurgery 48 249–261 Occurrence Handle11220367 Occurrence Handle10.1097/00006123-200102000-00001 Occurrence Handle1:STN:280:DC%2BD3M3ksVCrsw%3D%3D
P Vergne-Salle DY Léger P Bertin R Trèves JL Beneytout B Liagre (2005) ArticleTitleEffects of active metabolite of leflunomide, A77 1726, on cytokine release and the MAPK signaling pathway in human rheumatoid arthritis synoviocytes Cytokine 31 335–348 Occurrence Handle16099671 Occurrence Handle10.1016/j.cyto.2005.06.002 Occurrence Handle1:CAS:528:DC%2BD2MXpsVWhtLo%3D
DG Vollmer M Takayasu RG Dacey SuffixJr (1992) ArticleTitleAn in vitro comparative study of conducting vessels and penetrating arterioles after experimental subarachnoid hemorrhage in the rabbit J Neurosurg 77 113–119 Occurrence Handle1607952 Occurrence Handle1:STN:280:DyaK38zgtVClug%3D%3D
P Vorkapic JA Bevan RD Bevan (1991) ArticleTitleTwo indices of functional damage of the artery wall parallel the time course of irreversible narrowing in experimental vasospasm in the rabbit Blood Vessels 28 179–182 Occurrence Handle2001468 Occurrence Handle1:STN:280:DyaK3M7lvFKltw%3D%3D
P Vorkapic JA Bevan RD Bevan (1991) ArticleTitleLongitudinal in vivo and in vitro time-course study of chronic cerebrovasospasm in the rabbit basilar artery Neurosurg Rev 14 215–219 Occurrence Handle1944936 Occurrence Handle10.1007/BF00310660 Occurrence Handle1:STN:280:DyaK38%2FltValsQ%3D%3D
P Vorkapic RD Bevan JA Bevan (1990) ArticleTitlePharmacologic irreversible narrowing in chronic cerebrovasospasm in rabbits is associated with functional damage Stroke 21 1478–1484 Occurrence Handle2219213 Occurrence Handle1:STN:280:DyaK3M%2FitVaktg%3D%3D
WJ Waldman A Bickerstaff G Gordillo K Orosz DA Knight CG Orosz (2001) ArticleTitleInhibition of angiogenesis-related endotheial activity by the experimental immunosuppressive agent leflunomide Transplantation 72 1578–1582 Occurrence Handle11707749 Occurrence Handle10.1097/00007890-200111150-00018 Occurrence Handle1:CAS:528:DC%2BD3MXpt1SqtL8%3D
Y Yan E Verbeken L Yu O Rutgeerts J Goebels C Segers Y Lin W Mark (2005) ArticleTitleEffects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection Transplantation 79 135–141 Occurrence Handle15665760 Occurrence Handle10.1097/01.TP.0000147464.63188.4B Occurrence Handle1:CAS:528:DC%2BD2MXmt1Oqsw%3D%3D
HW Yao J Li JQ Chen SY Xu (2004) ArticleTitleInhibitory effect of leflunomide on hepatic fibrosis induced by CCl4 in rats Acta Pharmacol Sin 25 915–920 Occurrence Handle15210065 Occurrence Handle1:CAS:528:DC%2BD2cXlslejt74%3D
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Belen, D., Besalti, Ö., Yiğitkanlı, K. et al. Leflunomide prevents vasospasm secondary to subarachnoid haemorrhage. Acta Neurochir (Wien) 149, 1041–1048 (2007). https://doi.org/10.1007/s00701-007-1275-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00701-007-1275-1