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Experimental & Translational Stroke Medicine

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Open Access 01-12-2011 | Research

Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke

Authors: Md Nasrul Hoda, Weiguo Li, Ajmal Ahmad, Safia Ogbi, Marina A Zemskova, Maribeth H Johnson, Adviye Ergul, William D Hill, David C Hess, Irina Y Sazonova

Published in: Experimental & Translational Stroke Medicine | Issue 1/2011

Abstract

Background

Minocycline provides neurovascular protection reducing acute cerebral injury. However, it is unclear whether minocycline is effective in females. We tested minocycline in both sexes and aged animals using a novel embolic stroke model in mice that closely mimics acute thromboembolic stroke in humans.

Methods

Five groups of mice were subjected to thromboembolic stroke: adult males, aged males, adult females, aged females, and adult ovariectomized females. They were treated with phosphate saline (vehicle) or minocycline (6 mg/kg) immediately after stroke onset. Behavioral outcomes, infarct volumes and cerebral blood flow were assessed. The effect of minocycline on expression and activity of MMP-9 was analyzed.

Results

The model resulted in reproducible infarct in the experimental groups. As expected, adult females were significantly more resistant to cerebral ischemic injury than males. This advantage was abolished by aging and ovariectomy. Minocycline significantly reduced the infarct volume (P < 0.0001) and also improved neurologic score (P < 0.0001) in all groups. Moreover, minocycline treatment significantly reduced mortality at 24 hours post stroke (P = 0.037) for aged mice (25% versus 54%). Stroke up-regulated MMP-9 level in the brain, and acute minocycline treatment reduced its expression in both genders (P < 0.0001).

Conclusion

In a thromboembolic stroke model minocycline is neuroprotective irrespective of mouse sex and age.

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Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD: Gender-linked brain injury in experimental stroke. Stroke 1998,29(1):159–165. discussion 66 10.1161/01.STR.29.1.159PubMedCrossRef

Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE, Guida E, Broughton BR, Drummond GR, Sobey CG: Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 2010,30(7):1306–1317. 10.1038/jcbfm.2010.14PubMedCentralPubMedCrossRef

Liu F, McCullough LD: Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J Biomed Biotechnol 2011, 2011: 464701.PubMedCentralPubMed

Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD, Miller VM: Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 2000,31(1):161–168. 10.1161/01.STR.31.1.161PubMedCrossRef

McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD: Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 2005,25(4):502–512. 10.1038/sj.jcbfm.9600059PubMedCrossRef

Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A: Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide. J Cereb Blood Flow Metab 2006,26(3):414–420. 10.1038/sj.jcbfm.9600196PubMedCrossRef

Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH, STAIR Group: Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations. Stroke 2009,40(6):2244–2250. 10.1161/STROKEAHA.108.541128PubMedCentralPubMedCrossRef

Liu S, Zhen G, Meloni BP, Campbell K, Winn HR: Rodent Stroke Model Guidelines for Preclinical Stroke Trials (1st Edition). J Exp Stroke Transl Med 2009,2(2):2–27.PubMedCentralPubMedCrossRef

del Zoppo GJ: Clinical trials in acute stroke: why have they not been successful? Neurology 1998,51(3 Suppl 3):S59–61.PubMedCrossRef

10.

Zhang Z, Chopp M, Zhang RL, Goussev A: A mouse model of embolic focal cerebral ischemia. J Cereb Blood Flow Metab 1997,17(10):1081–1088.PubMedCrossRef

11.

Wang X, Xu L, Wang H, Grzanna R, Zhan Y, Knabb RM, Luettgen JM, Bozarth TA, Galemmo RA, Wong PC, Bernard R, Vargas H, Chopp M, Friedman SM, Feuerstein GZ: Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats. Stroke 2003,34(2):468–474. 10.1161/01.STR.0000049765.81774.A3PubMedCrossRef

12.

Aoki T, Sumii T, Mori T, Wang X, Lo EH: Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke 2002,33(11):2711–2717. 10.1161/01.STR.0000033932.34467.97PubMedCrossRef

13.

Kriz J, Gowing G, Julien JP: Efficient three-drug cocktail for disease induced by mutant superoxide dismutase. Ann Neurol 2003,53(4):429–436. 10.1002/ana.10500PubMedCrossRef

14.

Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, Hess DC, Waller JL, Fagan SC: Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke 2009,40(9):3028–3033. 10.1161/STROKEAHA.109.556852PubMedCentralPubMedCrossRef

15.

Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH: Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 2008,39(12):3372–3377. 10.1161/STROKEAHA.108.514026PubMedCentralPubMedCrossRef

16.

Wang CX, Yang T, Noor R, Shuaib A: Delayed minocycline but not delayed mild hypothermia protects against embolic stroke. BMC Neurol 2002, 2: 2. 10.1186/1471-2377-2-2PubMedCentralPubMedCrossRef

17.

Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC: Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol 2004, 4: 7. 10.1186/1471-2377-4-7PubMedCentralPubMedCrossRef

18.

Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG: Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke 2006,37(4):1087–1093. 10.1161/01.STR.0000206281.77178.acPubMedCrossRef

19.

Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J: A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999,96(23):13496–13500. 10.1073/pnas.96.23.13496PubMedCentralPubMedCrossRef

20.

Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, Hall CE, Switzer JA, Ergul A, Hess DC: Minocycline to Improve Neurologic Outcome in Stroke (MINOS). A Dose-Finding Study. Stroke 2010,41(10):2283–2287. 10.1161/STROKEAHA.110.582601PubMedCentralPubMedCrossRef

21.

Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M: Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007,69(14):1404–1410. 10.1212/01.wnl.0000277487.04281.dbPubMedCrossRef

22.

Alano CC, Kauppinen TM, Valls AV, Swanson RA: Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA 2006,103(25):9685–9690. 10.1073/pnas.0600554103PubMedCentralPubMedCrossRef

23.

Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC: Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci 2006, 7: 56. 10.1186/1471-2202-7-56PubMedCentralPubMedCrossRef

24.

Li J, McCullough LD: Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab 2009,29(4):670–674. 10.1038/jcbfm.2009.3PubMedCentralPubMedCrossRef

25.

Liu F, Li Z, Li J, Siegel C, Yuan R, McCullough LD: Sex Differences in Caspase Activation After Stroke. Stroke 2009,40(5):1842–1848. 10.1161/STROKEAHA.108.538686PubMedCentralPubMedCrossRef

26.

Nelson JF, Felicio LS, Randall PK, Sims C, Finch CE: A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology. Biol Reprod 1982,27(2):327–339. 10.1095/biolreprod27.2.327PubMedCrossRef

27.

Zhang Z, Zhang RL, Jiang Q, Raman SB, Cantwell L, Chopp M: A new rat model of thrombotic focal cerebral ischemia. J Cereb Blood Flow Metab 1997,17(2):123–135.PubMedCrossRef

28.

Ergul A, Elgebaly MM, Middlemore ML, Li W, Elewa H, Switzer JA, Hall C, Kozak A, Fagan SC: Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes. BMC Neurol 2007, 7: 33. 10.1186/1471-2377-7-33PubMedCentralPubMedCrossRef

29.

Li W, Kelly-Cobbs AI, Mezzetti EM, Fagan SC, Ergul A: Endothelin-1-mediated cerebrovascular remodeling is not associated with increased ischemic brain injury in diabetes. Can J Physiol Pharmacol 2010,88(8):788–795. 10.1139/Y10-040PubMedCentralPubMedCrossRef

30.

Sugawara J, Hayashi K, Kurachi S, Tanaka T, Yokoi T, Kurachi K: Age-related effects of regular physical activity on hemostatic factors in men. J Thromb Thrombolysis 2008,26(3):203–210. 10.1007/s11239-007-0092-yPubMedCrossRef

31.

Stout RW, Crawford VL, McDermott MJ, Rocks MJ, Morris TC: Seasonal changes in haemostatic factors in young and elderly subjects. Age Ageing 1996,25(3):256–258. 10.1093/ageing/25.3.256PubMedCrossRef

32.

Lacroix KA, Bean C, Box L, Wagner K: A study of the fibrinolytic response in healthy men and women following a brief exposure to venous occlusion. Thromb Res 1996,81(1):133–143. 10.1016/0049-3848(95)00221-9PubMedCrossRef

33.

Savitz SI, Schlaug G, Caplan L, Selim M: Arterial occlusive lesions recanalize more frequently in women than in men after intravenous tissue plasminogen activator administration for acute stroke. Stroke 2005,36(7):1447–1451. 10.1161/01.STR.0000170647.42126.a8PubMedCrossRef

34.

Dinapoli VA, Rosen CL, Nagamine T, Crocco T: Selective MCA occlusion: a precise embolic stroke model. J Neurosci Methods 2006,154(1–2):233–238. 10.1016/j.jneumeth.2005.12.026PubMedCrossRef

35.

Sanchez C, Alonso de Lecinana M, Diez-Tejedor E, Carceller F, Vega A, Roda JM: Treatment of embolic cerebral infarct via thrombolysis and cytoprotection with U-74389-G in rats. Rev Neurol 1998,27(158):653–658.PubMed

36.

Heo JH, Kim SH, Lee KY, Kim EH, Chu CK, Nam JM: Increase in plasma matrix metalloproteinase-9 in acute stroke patients with thrombolysis failure. Stroke 2003,34(6):e48–50. 10.1161/01.STR.0000073788.81170.1CPubMedCrossRef

37.

Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S: Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke 2003,34(9):2165–2170. 10.1161/01.STR.0000088062.86084.F2PubMedCrossRef

38.

Montaner J, Alvarez-Sabin J, Molina CA, Angles A, Abilleira S, Arenillas J, Monasterio J: Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 2001,32(12):2762–2767. 10.1161/hs1201.99512PubMedCrossRef

39.

Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabín J: Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003,107(4):598–603. 10.1161/01.CIR.0000046451.38849.90PubMedCrossRef

40.

Montaner J, Rovira A, Molina CA, Arenillas JF, Ribo M, Chacon P, Monasterio J, Alvarez-Sabín J: Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. J Cereb Blood Flow Metab 2003,23(12):1403–1407.PubMedCrossRef

41.

Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM, Fagan SC: Matrix Metalloproteinase-9 in an Exploratory Trial of Intravenous Minocycline for Acute Ischemic Stroke. Stroke 2011,42(9):2633–2633. 10.1161/STROKEAHA.111.618215PubMedCentralPubMedCrossRef

Title: Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke
Authors: Md Nasrul Hoda
Weiguo Li
Ajmal Ahmad
Safia Ogbi
Marina A Zemskova
Maribeth H Johnson
Adviye Ergul
William D Hill
David C Hess
Irina Y Sazonova
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Experimental & Translational Stroke Medicine / Issue 1/2011
Electronic ISSN: 2040-7378
DOI: https://doi.org/10.1186/2040-7378-3-16

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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