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

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

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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.

Original languageEnglish (US)
Pages (from-to)1542-1553
Number of pages12
JournalMolecular Neurobiology
Volume51
Issue number3
DOIs
StatePublished - Jun 1 2015

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Neuronal Plasticity
Stroke
Middle Cerebral Artery Infarction
trkB Receptor
Angiopoietin-1
Matrix Metalloproteinase 3
Synaptophysin
Angiotensin Type 1 Receptor
Nerve Growth Factors
Hand Strength
candesartan
Reperfusion Injury
Brain Ischemia
Vascular Endothelial Growth Factor A
Reperfusion
Wistar Rats
Intercellular Signaling Peptides and Proteins
Western Blotting
Immunohistochemistry
Brain

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Low-Dose Candesartan Enhances Molecular Mediators of Neuroplasticity and Subsequent Functional Recovery After Ischemic Stroke in Rats. / Ishrat, Tauheed; Pillai, Bindu; Soliman, Sahar; Fouda, Abdelrahman Y.; Kozak, Anna; Johnson, Maribeth H.; Ergul, Adviye; Fagan, Susan C.

In: Molecular Neurobiology, Vol. 51, No. 3, 01.06.2015, p. 1542-1553.

Research output: Contribution to journalArticle

Ishrat, Tauheed ; Pillai, Bindu ; Soliman, Sahar ; Fouda, Abdelrahman Y. ; Kozak, Anna ; Johnson, Maribeth H. ; Ergul, Adviye ; Fagan, Susan C. / Low-Dose Candesartan Enhances Molecular Mediators of Neuroplasticity and Subsequent Functional Recovery After Ischemic Stroke in Rats. In: Molecular Neurobiology. 2015 ; Vol. 51, No. 3. pp. 1542-1553.
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AU - Fouda, Abdelrahman Y.

AU - Kozak, Anna

AU - Johnson, Maribeth H.

AU - Ergul, Adviye

AU - Fagan, Susan C.

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