Compound 21is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke

Ahmed Alhusban, Abdelrahman Y. Fouda, Bindu Pillai, Tauheed Ishrat, Sahar Soliman, Susan C. Fagan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Introduction: Angiotensin II type 2 receptor (AT2R) stimulation is neuroprotective after experimental stroke. However, the therapeutic utility of AT2R stimulation has been hampered by the lack of a specific agonist with favourable bioavailability. Compound 21 (C21) - the first non-peptide AT2R agonist - offers a potential option to enhance stroke recovery. This study aimed to investigate the effect of C21 administration on early and late stroke outcomes, and the molecular mediators involved.

Methods: Rats were subjected to 3 h or 90 min of middle cerebral artery occlusion (MCAO) and randomized to intraperitoneal C21 (0.03 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 h or 7 days and brains were collected for molecular analysis and immunostaining, respectively. Functional outcome at days 1, 4 and 7 was assessed blindly. C21 angiogenic potential was assessed in vitro.

Results: After 3 h of MCAO, C21 treatment reduced infarct size and improved behavioural outcome at 24 h without affecting blood pressure. Co-administration of the AT2R antagonist (PD123319) blocked these effects. On the molecular level, C21 decreased brain haemoglobin content, down-regulated apoptotic and oxidative markers, and increased pro-survival molecules in the brain. After 90 min of MCAO, C21 treatment resulted in sustained functional improvement at 7 days, together with increased vascular density in the ischemic penumbra. In vitro, C21 showed a pro-angiogenic effect that was blocked with brain-derived neurotrophic factor neutralization.

Conclusion: These findings demonstrate that a single dose of C21 is neurovascular-protective and improves stroke outcome possibly through increasing neurotrophin activity, mitigating brain inflammation, and promoting antioxidant and pro-angiogenic effects.

Original languageEnglish (US)
Pages (from-to)170-180
Number of pages11
JournalJournal of Hypertension
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Angiotensin Type 2 Receptor
Middle Cerebral Artery Infarction
Stroke
Brain
Angiotensin II Type 2 Receptor Blockers
Brain-Derived Neurotrophic Factor
Nerve Growth Factors
Encephalitis
Biological Availability
Reperfusion
Blood Vessels
Hemoglobins
Antioxidants
Blood Pressure
In Vitro Techniques
Therapeutics

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Compound 21is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke. / Alhusban, Ahmed; Fouda, Abdelrahman Y.; Pillai, Bindu; Ishrat, Tauheed; Soliman, Sahar; Fagan, Susan C.

In: Journal of Hypertension, Vol. 33, No. 1, 01.01.2015, p. 170-180.

Research output: Contribution to journalArticle

Alhusban, Ahmed ; Fouda, Abdelrahman Y. ; Pillai, Bindu ; Ishrat, Tauheed ; Soliman, Sahar ; Fagan, Susan C. / Compound 21is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke. In: Journal of Hypertension. 2015 ; Vol. 33, No. 1. pp. 170-180.
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