Suppressing inflammation by inhibiting the NF‐κB pathway contributes to the neuroprotective effect of angiotensin‐(1‐7) in rats with permanent cerebral ischaemia

Abstract

BACKGROUND AND PURPOSEAngiotensin-(1-7) [Ang-(1-7)] has anti-inflammatory effects in peripheral organs, but its effects in ischaemic stroke are unclear as yet. We investigated whether its anti-inflammatory effect contributes to the neuroprotection induced by Ang-(1-7) in a rat model of permanent middle cerebral artery occlusion (pMCAO). EXPERIMENTAL APPROACHWe infused Ang-(1-7), Mas receptor antagonist A-779, angiotensin II type 2 receptor antagonist PD123319 or artificial CSF into the right lateral ventricle of male Sprague-Dawley rats from 48 h before onset of pMCAO until the rats were killed. Twenty-four hours after pMCAO, the neuroprotective effect of Ang-(1-7) was analysed by evaluating infarct volume and neurological deficits. The levels of oxidative stress were detected by spectrophotometric assay. The activation of NF-kB was assessed by Western blot and immunohistochemistry analysis. The level of COX-2 was tested by Western blot analysis and concentrations of pro-inflammatory cytokines were measured by ELISA. KEY RESULTSInfusion of Ang-(1-7), i.c.v., significantly reduced infarct volume and improved neurological deficits. It decreased the levels of oxidative stress and suppressed NF-kB activity, which was accompanied by a reduction of pro-inflammatory cytokines and COX-2 in the peri-infarct regions. These effects of Ang-(1-7) were reversed by A-779 but not by PD123319. Additionally, infusion of A-779 alone increased oxidative stress levels and enhanced NF-kB activity, which was accompanied by an up-regulation of pro-inflammatory cytokines and COX-2. CONCLUSION AND IMPLICATIONSOur findings indicate that suppressing NF-kB dependent pathway via Mas receptor may represent one mechanism that contributes to the anti-inflammatory effects of Ang-(1-7) in rats with pMCAO.Abbreviations aCSF, artificial CSF; Ang II, angiotensin II; Ang-(1-7), angiotensin-(1-7); CBF, cerebral blood flow; MDA, malondialdehyde; pMCAO, permanent middle cerebral artery occlusion; RAS, renin-angiotensin system; ROS, reactive oxygen species; SOD, superoxide dismutase BJP British Journal of Pharmacology

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