Acute Treatment with Candesartan Reduces Early Injury After Permanent Middle Cerebral Artery Occlusion

Abstract

We have shown that reduction of blood pressure (BP) immediately after the onset of reperfusion reduced neurovascular damage and improved functional outcome after experimental cerebral ischemia and candesartan is particularly effective in improving long-term functional outcome. In this study, we sought to determine if early BP lowering with candesartan, in the presence of an occluded cerebral artery, will reduce injury and improve outcome after experimental stroke. Male Wistar rats underwent 24 h or 7 days of middle cerebral artery occlusion (MCAO). A single dose of 1 mg/kg candesartan was administered intravenously at 3 h after MCAO. Animals received neurobehavioral testing at 3 h, 24 h, and 7 days, and blood pressure was measured by telemetry. Animals had brain tissue collected for infarct size (24 h and 7 days), hemoglobin content, matrix metalloproteinase (MMP) activity, and vascular endothelial growth factor (VEGF) expression (24 h only). Candesartan significantly decreased blood pressure, infarct size (−20%; p=0.021), hemoglobin excess (−50%; p=0.0013), and edema (−35%; p=0.0005) at 24 h after MCAO. This resulted in a reduced cerebral perfusion deficit (p=0.034) in the ischemic hemisphere compared with saline and significantly improved Bederson scores and paw grasp. MMP-2, MMP-9, and VEGF were significantly increased by MCAO, but there were no differences between candesartan- and saline-treated animals. There were no significant differences in behavioral outcome at day 7. BP lowering with candesartan reduces early brain injury after experimental stroke even when the artery remains occluded. The early benefits were not sustained at 7 days, as seen in reperfused animals, however. The neuroprotection and neurorestorative properties of candesartan may occur by separate distinct mechanisms.

Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

“…Inhibition of metalloproteinase (MMP)-2 and MMP-9 reduces neuronal and glial apoptosis [59]. Furthermore, Guan et al reported that MMP-2, MMP-9, and vascular endothelial growth factor (VEGF) are significantly increased by MCAO, but candesartan fails to reduce MMP-2, MMP-9, and VEGF in the rat MCAO model [60]. These findings show that telmisartan, irbesartan, and candesartan reduce infarct size and improve neurological outcome in ischemic stroke model rats.…”

Candesartan, an Angiotensin II AT1-Receptor Blocker and PPAR-γ Agonist, Reduces Lesion Volume and Improves Motor and Memory Function After Traumatic Brain Injury in Mice

“…The difference in the efficacy of 1 mg/kg/day between our data and that of Timaru-Kast et al (2012) may be explained by different mechanisms of administration. There is a significant drop in blood pressure following TBI that could be detrimental (Guan et al, 2011;Sookplung et al, 2011). Thus, medication that lowers blood pressure further may be problematic in treating TBI.…”

“…We hypothesized that treatment with candesartan may improve the behavioral and neurological outcome after TBI, in a manner similar to that observed in rodent models and in humans affected by stroke (Awad, 2011;Guan et al, 2011;Ito et al, 2001;Liu et al, 2008;Stenman and Edvinsson, 2004). We therefore investigated the effect of administering candesartan to mice just before they received a controlled cortical impact (CCI) injury to determine whether short-or long-term inhibition of central AT 1 Rs would reduce the cortical and hippocampal damage and hence protect against cognitive impairment.…”

Comparative Analysis of Different Methods of Ischemia/Reperfusion in Hyperglycemic Stroke Outcomes: Interaction with tPA

“…Scanning laser Doppler (Pim-3, Perimed, ST) was used to confirm a similar degree of drop in CBF among groups. The percent drop in CBF after stroke was determined by comparing to baseline [24]. To monitor the ability of tPA to resolve the blood clots and restore blood flow, CBF was measured 30, 60 and 120 minutes after tPA administration in animals subjected to thromboembolic occlusion.…”