Neurochemical Research

, Volume 38, Issue 12, pp 2668–2677 | Cite as

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
Original Paper

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.

Keywords

Candesartan Embolic stroke Matrix metalloproteinases Tissue plasminogen activator Hemorrhage 

Abbreviations

eMCAO

Embolic middle cerebral artery occlusion

tPA

Tissue plasminogen activator

PE

Polyethylene

NF-κB

Nuclear factor kappa-B

TNF-α

Tumor necrosis factor-α

(p-eNOS)

Phospho endothelial nitric oxide synthase

MMP

Matrix metalloproteinase

AT1R

Angiotensin II type 1 receptor

Hb

Hemoglobin

TTC

2, 3, 5-triphenyltetrazolium chloride

SEM

Standard error of the mean

CBF

Cerebral blood flow

HT

Hemorrhagic transformation

LRP

Low-density lipoprotein receptor-related protein

BBB

Blood brain-barrier

NO

Nitric oxide

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Tauheed Ishrat
    • 1
    • 2
  • Bindu Pillai
    • 1
    • 2
  • Adviye Ergul
    • 1
    • 2
    • 3
  • Sherif Hafez
    • 1
    • 2
  • Susan C. Fagan
    • 1
    • 2
    • 4
  1. 1.Charlie Norwood VA Medical CenterAugustaUSA
  2. 2.Center for Pharmacy and Experimental TherapeuticsUniversity of Georgia College of PharmacyAugustaUSA
  3. 3.Department of Physiology, Medical College of GeorgiaGeorgia Regents UniversityAugustaUSA
  4. 4.Department of Neurology, Medical College of GeorgiaGeorgia Regents UniversityAugustaUSA

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