nach oben

Acta Neurochirurgica

Erschienen in:

01.08.2010 | Experimental research

RETRACTED ARTICLE: 6-Mercaptopurine exerts an immunomodulatory and neuroprotective effect on permanent focal cerebral occlusion in rats

verfasst von: Chih-Zen Chang, Aij-Lie Kwan, Shen-Long Howng

Erschienen in: Acta Neurochirurgica | Ausgabe 8/2010

Einloggen, um Zugang zu erhalten

Abstract

Background

A bursting cascade of inflammation imposes progressive neurological deterioration after experimental stroke has been demonstrated. In our study, 6-mercaptopurine (6-mp) has been successful in alleviating cerebral infarct in a rodent permanent middle cerebral artery occlusion (pMCAO) model. The present study was aimed to examine the effect of 6-mp on cytokine levels in experimental stroke.

Methods

The rodent pMCAO model was employed. A dose of 2 mg/kg 6-mp or vehicle (0.1 mol/L PBS) was administered intraperitoneally 30 min after the induction of pMCAO. Neurological score, serum, and cerebrospinal fluid (CSF) cytokines such as IL-1β, IL-6, and TNF-α and infarct volume were determined 48 h after pMCAO.

Results

Cerebral infarction volume was significantly decreased in animals treated with 6-mp (74.3%, p < 0.01), and the ratio of tissue edema was also decreased in 6-mp-treated groups (71%). Animals receiving 6-mp thus showed a significant decrease in IL-1 and TNF-α (18/43% and 48/64% in CSF/serum, respectively) when compared with the pMCAO groups (p < 0.01).

Conclusion

This study demonstrates that 6-mp interposes the production of IL-1 and TNF-α in CSF and serum, attenuates ischemic brain injury, and thus alleviates neurological deficits in the pMCAO animals. These findings also offer first evidence that 6-mp may attenuate TNF-α-related neuron apoptosis and also support the notion that 6-mp and other anti-inflammatory agents could potentially have therapeutic uses in cases of cerebral infarct.

Adams HP Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, Grubb RL, Higashida R, Kidwell C, Kwiatkowski TG, Marler JR, Hademenos GJ, Stroke Council of the American Stroke Association (2003) Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke 34:1056–1083CrossRefPubMed

Arfors KE, Lundberg C, Lindbom L, Lundberg K, Beatty PG, Harlan JM (1987) A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood 69:338–340CrossRefPubMed

Barone FC, Ohlstein EH, Hunter AJ, Campbell CA, Hadingham SH, Parsons AA, Yang Y, Shohami E (2000) Selective antagonism of endothelin-A-receptors improves outcome in both head trauma and focal stroke in rat. J Cardiovasc Pharmacol 36:S357–361CrossRefPubMed

Bernadi P (1996) The permeability transition pore: control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. Biochem Biophys Acta 1275:5–9

Butcher EC (1991) Leukocyte–endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67:1033–1036CrossRefPubMed

Butcher KS, Parsons M, MacGregor L, Barber PA, Chalk J, Bladin C, Levi C, Kimber T, Schultz D, Fink J, Tress B, Donnan G, Davis S, EPITHET Investigators (2005) Refining the perfusion–diffusion mismatch hypothesis. Stroke 36:1153–1159CrossRefPubMed

Chang CZ, Winardi D, Lin CL, Kwan AL, Jeng AY, Kassell NF, Howng SL, Lee KS (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 58:181–188CrossRefPubMed

Chang CZ, Winardi D, Loh JK, Kung SS, Howng SL, Jeng AY, Kwan AL (2002) Alteration of ischemic reperfusion injury in the rat neocortex by a potent antioxidant mexiletine. Acta Neurochir (Wien) 144(2):189–193, discussion 193CrossRefPubMed

Chang CZ, Yen CP, Winadi D, Wu SC, Howng SL, Lin TK, Jeng AY, Kassell NF, Kwan AL (2004) Neuroprotective effect of CGS 26303, an endothelin-converting enzyme inhibitor, on transient middle cerebral artery occlusion in rats. J Cardiovasc Pharmacol 44(Suppl 1):S487–9CrossRefPubMed

10.

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 137:557–558CrossRefPubMed

11.

Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 32:219–229CrossRefPubMed

12.

Davis RJ (2000) Signal tranduction by the JNK group of MAP kinases. Cell 103:239–252CrossRefPubMed

13.

Doran JF, Jackson P, Kynoch PA, Thompson RJ (1983) Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis. J Neurochem 40:1542–1547CrossRefPubMed

14.

Flaris NA, Densmore TL, Molleston MC, Hickey WF (1993) Characterization of microglia and macrophages in the central nervous system of rats: definition of the differential expression of molecules using standard and novel monoclonal antibodies in normal CNS and in four models of parenchymal reaction. GLIA 7:34–40CrossRefPubMed

15.

Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan PH (1998) Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 18:1239–1247CrossRefPubMed

16.

Graham SH, Chen J (2001) Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 21:99–109CrossRefPubMed

17.

Gray CS, French JM, Bates D, Cartlidge NE, Venables GS, James OF (2004) Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke. Age Ageing 33(1):71–77CrossRefPubMed

18.

Hiramatsu K, Kassell NF, Goto Y, Soleau S, Lee KS (1993) A reproducible model of reversible, focal, neocortical ischemia in Sprague–Dawley rat. Acta Neurochir 120:66–71CrossRefPubMed

19.

Hirata Y, Matsunaga T, Ando K, Furukawa T, Tsukagoshi H, Marumo F (1990) Presence of endothelin-1-like immunoreactivity in human cerebrospinal fluid. Biochem Biophys Res Commun 166:1274–1278CrossRefPubMed

20.

Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemia injury. J Cereb Blood Flow Metab 22(6):631–647CrossRefPubMed

21.

Kim JS (1996) Cytokines and adhesion moleculaes in stroke and related diseases. J Neurol Sci 137:69–78CrossRefPubMed

22.

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):352CrossRef

23.

Kutlu N, Vatansever HS, Bayazit TO, Ekerbicer N, Tan U (2002) Blood brain barrier in right- and left-pawed female rats assessed by a new staining method. Int J Neurosci 112(9):1037–1046CrossRefPubMed

24.

Li CY, Lazcano-Villareal O, Pierre RV, Yam LT (1987) Immunocytochemical identification of cells in serous effusions. Technical considerations. Am J Clin Pathol 88:696–706CrossRefPubMed

25.

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

26.

Markgraf CG, Green EJ, Hurwitz BE, Morikawa E, Dietrich WD, McCabe PM, Ginsberg MD, Schneiderman N (1992) Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res 575(2):238–246CrossRefPubMed

27.

Maruyama K, Tsukada T, Ohkura N, Bandoh S, Hosono T, Yamaguchi K (1998) The NGFI-B subfamily of the nuclear receptor superfamily. Int J Oncol 12(6):1237–1243PubMed

28.

Mazzotta G, Sarchielli P, Caso V, Paciaroni M, Floridi A, Gallai V (2004) Different cytokines levels in thrombolysis patients as predictors for clinical outcome. Euro J Neuro 11:377–381CrossRef

29.

McPherson JA, Barringhaus KG, Bishop GG, Sanders JM, Rieger JM, Hesselbacher SE, Gimple LW, Powers ER, Macdonald T, Sullivan G, Linden J, Sarembock IJ (2001) Adenosine A(2A) receptor stimulation reduces inflammation and neointimal growth in a murine carotid ligation model. Arterioscler Thromb Vasc Biol 21:791–796CrossRefPubMed

30.

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(27):24791–24799CrossRefPubMed

31.

Pawlinski R, Pedersen B, Kehrle B, Aird WC, Frank RD, Guha M, Mackman N (2003) Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model. Blood 101:3940–3947CrossRefPubMed

32.

Perini F, Morra M, Alecci M, Galloni E, Marchi M, Toso V (2001) Temperal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischemic stroke patients. Neurol Sci 22:289–296CrossRefPubMed

33.

Soriano MA, Tessier M, Certa U, Gil R (2000) Parallel gene expression monitoring using oligonucleotide probe arrays of multiple transcripts with an animal model of focal ischemia. J Cereb Blood Flow Metab 20:1045–1055CrossRefPubMed

34.

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(1):49–56CrossRefPubMed

35.

Toyoda T, Kassell NF, Lee KS (1997) Attenation of ischemia reperfusion injury in the rat neocortex by the hydroxylradical scavergen nicarave. Neurosurgery 40:372–378CrossRefPubMed

36.

von Andrian UH, Chambers JD, McEvoy LM, Bargatze RF, Arfors KE, Butcher EC (1991) Two-step model of leukocyte–endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo. Proc Natl Acad Sci U S A 88:7538–7542CrossRef

37.

Woronicz JD, Calnan B, Ngo V, Winoto A (1994) Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367(6460):277–281CrossRefPubMed

38.

Yan SF, Fujita T, Lu J, Okada K, Shan Zou Y, Mackman N, Pinsky DJ, Stern DM (2000) Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nature Med 6:1355–1361CrossRefPubMed

39.

Yi JH, Park SW, Kapadia R, Vemuganti R (2007) Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage. Neurochem Int 50:1014–1027CrossRefPubMedPubMedCentral

40.

Zong W-X, Lindsten T, Ross AJ, MacGregor GR, Thompson CB (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15:1481–1486CrossRefPubMedPubMedCentral

Titel: RETRACTED ARTICLE: 6-Mercaptopurine exerts an immunomodulatory and neuroprotective effect on permanent focal cerebral occlusion in rats
verfasst von: Chih-Zen Chang
Aij-Lie Kwan
Shen-Long Howng
Publikationsdatum: 01.08.2010
Verlag: Springer Vienna
Erschienen in: Acta Neurochirurgica / Ausgabe 8/2010
Print ISSN: 0001-6268
Elektronische ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-010-0608-7

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Viel Bewegung in der Parkinsonforschung

25.04.2024 Parkinson-Krankheit Nachrichten

Neue arznei- und zellbasierte Ansätze, Frühdiagnose mit Bewegungssensoren, Rückenmarkstimulation gegen Gehblockaden – in der Parkinsonforschung tut sich einiges. Auf dem Deutschen Parkinsonkongress ging es auch viel um technische Innovationen.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Background

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2010

Superficial siderosis of the central nervous system: secondary progression despite successful surgical treatment, mimicking amyotrophic lateral sclerosis. Case report and review

Acute intracranial hypertension and shunt dependency following treatment of intracranial arachnoid cyst in a child: a case report and review of the literature

Clinical article: mortality associated with severe head injury in the elderly

Surgical treatment for hemangioblastomas in the medulla oblongata

The first 50s: can we achieve acceptable results in vestibular schwannoma surgery from the beginning?