Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke

Tauheed Ishrat, Bindu Pillai, Adviye Ergul, Sherif Hafez, Susan C. Fagan

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We have previously reported that angiotensin receptor blockade reduces reperfusion hemorrhage in a suture occlusion model of stroke, despite increasing matrix metalloproteinase (MMP-9) activity. We hypothesized that candesartan will also decrease hemorrhage associated with delayed (6 h) tissue plasminogen activator (tPA) administration after embolic stroke, widening the therapeutic time window of tPA. Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) and treated with either candesartan (1 mg/kg) alone early at 3 h, delayed tPA (10 mg/kg) alone at 6 h, the combination of candesartan and tPA, or vehicle control. Rats were sacrificed at 24 and 48 h post-eMCAO and brains perfused for evaluation of neurological deficits, cerebral hemorrhage in terms of hemoglobin content, occurrence rate of hemorrhage, infarct size, tissue MMP activity and protein expression. The combination therapy of candesartan and tPA after eMCAO reduced the brain hemorrhage, and improved neurological outcome compared with rats treated with tPA alone. Further, candesartan in combination with tPA increased activity of MMP-9 but decreased MMP-3, nuclear factor kappa-B and tumor necrosis factor-α expression and enhanced activation of endothelial nitric oxide synthase. An activation of MMP-9 alone is insufficient to cause increased hemorrhage in embolic stroke. Combination therapy with acute candesartan plus tPA may be beneficial in ameliorating tPA-induced hemorrhage after embolic stroke.

Original languageEnglish (US)
Pages (from-to)2668-2677
Number of pages10
JournalNeurochemical Research
Volume38
Issue number12
DOIs
StatePublished - Dec 1 2013

Fingerprint

Tissue Plasminogen Activator
Rats
Stroke
Hemorrhage
Matrix Metalloproteinases
Middle Cerebral Artery Infarction
Brain
Chemical activation
candesartan
Angiotensin Receptors
Intracranial Hemorrhages
NF-kappa B
Nitric Oxide Synthase Type III
Matrix Metalloproteinase 9
Cerebral Hemorrhage
Sutures
Reperfusion
Wistar Rats
Hemoglobins
Therapeutics

Keywords

  • Candesartan
  • Embolic stroke
  • Hemorrhage
  • Matrix metalloproteinases
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry

Cite this

Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke. / Ishrat, Tauheed; Pillai, Bindu; Ergul, Adviye; Hafez, Sherif; Fagan, Susan C.

In: Neurochemical Research, Vol. 38, No. 12, 01.12.2013, p. 2668-2677.

Research output: Contribution to journalArticle

Ishrat, Tauheed ; Pillai, Bindu ; Ergul, Adviye ; Hafez, Sherif ; Fagan, Susan C. / Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke. In: Neurochemical Research. 2013 ; Vol. 38, No. 12. pp. 2668-2677.
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