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Low-Dose Candesartan Enhances Molecular Mediators of Neuroplasticity and Subsequent Functional Recovery After Ischemic Stroke in Rats

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Abstract

We have previously reported that angiotensin type 1 receptor (AT1R) blockade with candesartan exerts neurovascular protection after experimental cerebral ischemia. Here, we tested the hypothesis that a low, subhypotensive dose of candesartan enhances neuroplasticity and subsequent functional recovery through enhanced neurotrophic factor expression in rats subjected to ischemia reperfusion injury. Male Wistar rats (290–300 g) underwent 90 min of middle cerebral artery occlusion (MCAO) and received candesartan (0.3 mg/kg) or saline at reperfusion and then once every 24 h for 7 days. Functional deficits were assessed in a blinded manner at 1, 3, 7, and 14 days after MCAO. Animals were sacrificed 14-day post-stroke and the brains perfused for infarct size by cresyl violet. Western blot and immunohistochemistry were used to assess the expression of growth factors and synaptic proteins. Candesartan-treated animals showed a significant reduction in the infarct size [t (13) = −5.5, P = 0.0001] accompanied by functional recovery in Bederson [F (1, 13) = 7.9, P = 0.015], beam walk [F (1, 13) = 6.7, P = 0.023], grip strength [F (1, 13) = 15.2, P = 0.0031], and rotarod performance [F (1, 14) = 29.8, P < 0.0001]. In addition, candesartan-treated animals showed significantly higher expression of active metalloproteinase-3 (MMP-3), laminin, and angiopoietin-1 (Ang-1). The expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) and its receptor was significantly increased in the animals treated with candesartan. Also, we observed significant increases in neuroplasticity markers, synaptophysin, and PSD-95. These results indicate that low-dose candesartan had a large and enduring effect on measures of plasticity, and this accompanied the functional recovery after ischemic stroke.

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Abbreviations

ANOVA:

Analysis of variance

Ang-1:

Angiopoietin-1

AT1R:

Angiotensin II type 1 receptor

BP:

Blood pressure

BDNF:

Brain-derived neurotrophic factor

MMP-3:

Matrix metalloproteinase-3

MCAO:

Middle cerebral artery occlusion

PSD-95:

Postsynaptic density protein-95

TrkB:

Tropomyosin-related kinase-B

VEGF:

Vascular endothelial growth factor

ARBs:

Angiotensin receptor blockers

MABP:

Mean arterial blood pressure

tPA:

Tissue plasminogen activator

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Acknowledgments

This study was supported in part by the Veterans Affairs Merit Review (SCF, BX000891 and AE, BX000347) and NIH–NINDS (SCF, NS063965 and AE, NS054688). Adviye Ergul is a research career scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia.

Conflict of Interest

SCF is a consultant for and has received funding from Pfizer. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

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

    Tauheed Ishrat, Bindu Pillai, Sahar Soliman, Abdelrahman Y. Fouda, Anna Kozak, Adviye Ergul & Susan C. Fagan

  2. Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, HM 1212, 1120 15th St., Augusta, GA, 30912, USA

    Tauheed Ishrat, Bindu Pillai, Sahar Soliman, Abdelrahman Y. Fouda, Anna Kozak, Adviye Ergul & Susan C. Fagan

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

    Adviye Ergul

  4. Department of Biostatistics, Georgia Regents University, Augusta, GA, USA

    Maribeth H. Johnson

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

    Susan C. Fagan

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  1. Tauheed Ishrat
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Ishrat, T., Pillai, B., Soliman, S. et al. Low-Dose Candesartan Enhances Molecular Mediators of Neuroplasticity and Subsequent Functional Recovery After Ischemic Stroke in Rats. Mol Neurobiol 51, 1542–1553 (2015). https://doi.org/10.1007/s12035-014-8830-6

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