TY - JOUR
T1 - Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke
AU - Ishrat, Tauheed
AU - Pillai, Bindu
AU - Ergul, Adviye
AU - Hafez, Sherif
AU - Fagan, Susan C.
N1 - Funding Information:
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 pharmacologist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia.
Funding Information:
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.
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Candesartan
KW - Embolic stroke
KW - Hemorrhage
KW - Matrix metalloproteinases
KW - Tissue plasminogen activator
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U2 - 10.1007/s11064-013-1185-y
DO - 10.1007/s11064-013-1185-y
M3 - Article
C2 - 24194350
AN - SCOPUS:84890309262
SN - 0364-3190
VL - 38
SP - 2668
EP - 2677
JO - Neurochemical Research
JF - Neurochemical Research
IS - 12
ER -