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Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke

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Abstract

Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan’s proangiogenic potential.

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Abbreviations

ARBs:

Angiotensin II type-1 receptor blockers

hCMECs:

Human cerebral microvascular endothelial cells

MCAO:

Middle cerebral artery occlusion

MMPs:

Matrix metalloproteinases

VEGF:

Vascular endothelial growth factor

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Compliance with Ethical Standards

Funding Source

This study was funded by the National Institute of Health (R01-NS063965) and Veterans Affairs Merit Award (BX000891) to SCF and the American Heart Association-Southeast Affiliate (12PRE12030197) to SS.

Conflict of Interest

Authors declare no conflict of interest.

Ethical Approval

All applicable institutional guidelines for the care and use of animals were followed. All experimental protocols were approved by the Care of Experimental Animal Committee of Georgia Regents University/Institutional Animal Care and Use Committee (IACUC) of the Veterans Affairs Medical Center. This article does not contain any studies with human participants performed by any of the authors.

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Authors and Affiliations

  1. Charlie Norwood VA Medical Center, Augusta, GA, USA

    Sahar Soliman, Tauheed Ishrat, Abdelrahman Y. Fouda, Ami Patel, Bindu Pillai & Susan C. Fagan

  2. Program in Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, 30912, USA

    Sahar Soliman, Tauheed Ishrat, Abdelrahman Y. Fouda, Ami Patel, Bindu Pillai & Susan C. Fagan

  3. Department of Neurology, Georgia Regents University, Augusta, GA, USA

    Susan C. Fagan

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  1. Sahar Soliman
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  2. Tauheed Ishrat
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  5. Bindu Pillai
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  6. Susan C. Fagan
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Correspondence to Susan C. Fagan.

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Soliman, S., Ishrat, T., Fouda, A.Y. et al. Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke. Transl. Stroke Res. 6, 309–322 (2015). https://doi.org/10.1007/s12975-015-0408-8

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