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6-Mercaptopurine attenuates adhesive molecules in experimental vasospasm

  • Experimental research
  • Published:
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Abstract

Objective

Adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important inflammatory mediators which are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The authors previously found that 6-mercaptopurine (6-mp) was effective in preventing and reversing arterial narrowing in a rodent SAH model. The present study was to examine whether levels of adhesion molecules were altered after treatment with 6-mp in this animal model.

Materials and methods

Animals were each injected with autologous blood into the cisterna magna, and intraperitoneal treatment with 6-mp (2 mg/kg) was initiated 1 h before (prevention) or later (treatment). The compound was subsequently administered at 24 and 48 h post-SAH. Blood samples were collected at 72 h post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. The basilar arteries were harvested and sliced, and their cross-sectional areas were measured. Morphologically, convolution of the internal elastic lamina, distorted endothelial wall, and myonecrosis of the smooth muscle were prominently observed in the SAH only and vehicle-treated SAH groups, but not in the 6-mp-treated SAH group or in healthy controls. No significant differences were found in the levels of VCAM-1 among all groups. However, the levels of E-selectin were increased in all animals subjected to SAH (SAH only and SAH plus vehicle groups) compared with healthy controls (no SAH), but not in the 6-mp group (SAH plus 6-mp treatment and preventive treatment with 6-mp).Likewise, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and pretreatment and treatment with 6-mp reduced ICAM-1 to control levels.

Conclusion

These results show that ICAM-1 and E-selectin may play a role in mediating SAH-induced vasospasm and that a reduction of both adhesive molecules after SAH may partly contribute to the antispastic effect of 6-mp.

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Abbreviations

BA:

Basilar artery

ICAM-1:

Intercellular adhesion molecule-1

IEL:

Internal elastic lamina

PBS:

Phosphate-buffered saline

PECAM:

Platelet-endothelial adhesion molecule

SAH:

Subarachnoid hemorrhage

References

  1. Aihara Y, Kasuya H, Onda H, Hori T, Takeda J (2001) Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage. Stroke 32:212–217

    CAS  PubMed  Google Scholar 

  2. Bavbek M, Polin R, Kwan AL, Arthur AS, Kassell NF, Lee KS (1998) Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Stroke 29(9):1930–1935, discussion 1935–1936

    CAS  PubMed  Google Scholar 

  3. Bowman G, Dixit S, Bonneau RH, Chinchilli VM, Cockroft KM (2004) Neutralizing antibody against interleukin-6 attenuates posthemorrhagic vasospasm in the rat femoral artery model. Neurosurgery 54:719–725, discussion 725–726

    Article  PubMed  Google Scholar 

  4. Chang CZ, Yen CP, Winadi D, Wu SC, Howng SL, Lin TK, Jeng AY, Kassell NF, Kwan AL (2002) Attenuation of hemolysate-induced cerebrovascular endothelial cell injury and of production of endothelin-1 and big endothelin-1 by an endothelin converting enzyme inhibitor. Surg Neurol 58:181–187, discussion 187–188

    Article  PubMed  Google Scholar 

  5. Cintra A, Fuxe K, Anggård E, Tinner B, Staines W, Agnati LF (1989) Increased endothelin-like immunoreactivity in ibotenic acid lesioned hippocampal formation of the rat brain. Acta Physiol Scand 137:557–558

    Article  CAS  PubMed  Google Scholar 

  6. Clatterbuck RE, Gailloud P, Ogata L, Gebremariam A, Dietsch GN, Murphy KJ, Tamargo RJ (2003) Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates. J Neurosurg 99:376–382

    Article  CAS  PubMed  Google Scholar 

  7. Davies MR, Harding CJ, Raines S, Tolley K, Parker AE, Downey-Jones M, Needham MR (2005) Nurr1 dependent regulation of pro-inflammatory mediators in immortalized synovial fibroblasts. J Inflam 2:15

    Article  Google Scholar 

  8. Denis B, Franck P, Mattihias C, Irene JV, Gilles N (2005) Upregulation of TNF-α-induced ICAM-1 surface expression by adenylate cyclase-dependent pathway in human endothelial cells. J Cell Physiol 202:434–441

    Article  Google Scholar 

  9. Dukes M, Chan WC, Willoughby DA (1973) The effect of various immunosuppressive agents on the vascular and cellular response to carrageenan in the rat. J Pathol 109:151–161

    Article  CAS  PubMed  Google Scholar 

  10. Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, Kassell NF, Lee KS (2003) Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 53:123–133, discussion 133–135

    Article  PubMed  Google Scholar 

  11. Frazier JL, Pradilla G, Wang PP, Tamargo RJ (2004) Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage. J Neurosurg 101:93–98

    Article  CAS  PubMed  Google Scholar 

  12. Frijns CJ, Kappelle LJ (2002) Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 33:2115–2122

    Article  CAS  PubMed  Google Scholar 

  13. Gaetani P, Tartara F, Pignatti P, Tancioni F, Rodriguez y Baena R, De Benedetti F (1998) Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Neurol Res 20:337–342

    CAS  PubMed  Google Scholar 

  14. Gearing AJ, Newman W (1993) Circulating adhesion molecules in disease. Immunol Today 14:506–512

    Article  CAS  PubMed  Google Scholar 

  15. Grosso G (2004) An overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage. Brain Res Rev 44:49–63

    Article  Google Scholar 

  16. Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G (1995) Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 15:42–51

    CAS  PubMed  Google Scholar 

  17. Konstantopoulou M, Belgi A, Griffiths KD, Seale JR, Macfarlane AW (2005) Azathioprine-induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte thiopurine methyltransferase. BMJ 330(7487):350–351

    Article  CAS  PubMed  Google Scholar 

  18. Lin CL, Dumont AS, Calisaneller T, Kwan AL, Hwong SL, Lee KS (2005) Monoclonal antibody against E selectin attenuates subarachnoid hemorrhage-induced cerebral vasospasm. Surg Neurol 64:201–206

    Article  PubMed  Google Scholar 

  19. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25:1481–1488

    CAS  PubMed  Google Scholar 

  20. Macdonald RL (2001) Pathophysiology and molecular genetics of vasospasm. Acta Neurochir Suppl 77:7–11

    CAS  PubMed  Google Scholar 

  21. Nishizawa S, Laher I (2005) Signaling mechanisms in cerebral vasospasm. Trends Cardiovasc Med 15:24–34

    Article  CAS  PubMed  Google Scholar 

  22. Nissen JJ, Mantle D, Gregson B, Mendelow AD (2001) Serum concentration of adhesion molecules in patients with delayed ischaemic neurological deficit after aneurysmal subarachnoid haemorrhage: the immunoglobulin and selectin superfamilies. J Neurol Neurosurg Psychiatry 71:329–333

    Article  CAS  PubMed  Google Scholar 

  23. Onda H, Kasuya H, Takakura K, Hori T, Imaizumi T, Takeuchi T, Inoue I, Takeda J (1999) Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage. J Cereb Blood Flow Metab 19:1279–1288

    Article  CAS  PubMed  Google Scholar 

  24. Ordentlich P, Yan Y, Zhou S, Heyman RA (2003) Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem 278:24791–24799

    Article  CAS  PubMed  Google Scholar 

  25. Ostrowski RP, ColohanAR ZJH (2006) Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 28:399–414

    Article  CAS  PubMed  Google Scholar 

  26. Rothoerl RD, Axmann C, Pina AL, Woertgen C, Brawanski A (2006) Possible role of the C-reactive protein and white blood cell count in the pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol 18:68–72

    Article  PubMed  Google Scholar 

  27. Sasaki T, Kasuya H, Onda H, Sasahara A, Goto S, Hori T, Inoue I (2004) Role of p38 mitogen-activated protein kinase on cerebral vasospasm after subarachnoid hemorrhage. Stroke 35:1466–1470

    Article  CAS  PubMed  Google Scholar 

  28. Springer TA (1995) Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 57:827–872

    Article  CAS  PubMed  Google Scholar 

  29. Stet EH, De Abreu RA, Bökkerink JP, Lambooy LH, Vogels-Mentink TM, Keizer-Garritsen JJ, Trijbels FJ (1995) Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine. Biochem Pharmacol 49:49–56

    Article  CAS  PubMed  Google Scholar 

  30. Takizawa T, Tada T, Kitazawa K, Tanaka Y, Hongo K, Kameko M, Uemura KI (2001) Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res 23:724–730

    Article  CAS  PubMed  Google Scholar 

  31. Thai QA, Oshiro EM, Tamargo RJ (1999) Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. Stroke 30:140–147

    CAS  PubMed  Google Scholar 

  32. Yoshimoto Y, Tanaka Y, Hoya K (2001) Acute systemic inflammatory response syndrome in subarachnoid hemorrhage. Stroke 32(9):1989–1993

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

CZC and ALK contributed equally to this work.

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There are no conflicts of interest related to this paper.

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Authors and Affiliations

  1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang

  2. Department of Neurosurgery, Kaohsiung Medical University, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang, Chih-Lung Lin, Aij-Lie Kwan & Shen-Long Howng

  3. Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA

    Neal F. Kassel & Aij-Lie Kwan

  4. Department of Neurosurgery, Kuo General Hospital, Tainan, Taiwan, Republic of China

    Chih-Zen Chang

  5. Department of Surgery, Kaohsiung Municipal Ta Tung Hospital, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang

Authors
  1. Chih-Zen Chang
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  2. Chih-Lung Lin
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  3. Neal F. Kassel
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  4. Aij-Lie Kwan
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  5. Shen-Long Howng
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Corresponding author

Correspondence to Chih-Zen Chang.

Additional information

The authors have carefully built an animal study trying to find out the effects 6-mp may have in the levels of adhesion molecules resulting from the inflammation associated with SAH and vasospasm. Their results seem to demonstrate that when 6-mp is administered to rats prior or immediately after SAH, the levels of two of the three tested adhesion molecules (ICAM-1 and E-Selectin) are diminished. No explanation is given as to why no effect was found with VCAM-1.

This is yet another laboratory study pursuing the key to the resilient latch of SAH. Since inflammation is likely to play a determinant role in the process of vasospasm, results from studies such as these may prove to be rather important in the design of drugs designed to fight this treacherous complication of SAH. The effort is to be commended and we wait for further developments

Manuel Cunha e Sá, M.D.

Lisbon, Portugal

This is an interesting paper adding another valuable piece of information on the role of inflammation in the pathogenesis of post-SAH vasospasm. Given the validity of the model, the soundness of results, and the long-lasting expertise of the senior author in this field, I recommend the authors to produce more experimental work in this setting.

Domenico d’Avella

Padova, Italy

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Chang, CZ., Lin, CL., Kassel, N.F. et al. 6-Mercaptopurine attenuates adhesive molecules in experimental vasospasm. Acta Neurochir 152, 861–867 (2010). https://doi.org/10.1007/s00701-010-0602-0

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  • DOI: https://doi.org/10.1007/s00701-010-0602-0

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