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Deterioration of cognitive function after transient cerebral ischemia with amyloid-? infusion-possible amelioration of cognitive function by AT2 receptor activation.

ABSTRACT: To promote understanding of the pathogenesis of cognitive impairment or dementia, we explored the potential interaction between transient cerebral ischemia and amyloid-? (A?) infusion in mediating cognitive decline and examined the possible ameliorative effect of angiotensin II type 2 (AT2) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit. Adult male wild-type mice (WT) and mice with VSMC-specific AT2 receptor overexpression (smAT2) were subjected to intracerebroventricular (ICV) injection of A?1-40. Transient cerebral ischemia was induced by 15 min of bilateral common carotid artery occlusion (BCCAO) 24 h after A? injection. A? injection in WT induced a cognitive decline, whereas BCCAO did not cause a significant cognitive deficit. In contrast, WT with BCCAO following A? injection exhibited more marked cognitive decline compared to A? injection alone, in concert with increases in superoxide anion production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and expression of p22phox, p40phox, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-1? in the hippocampus, and upregulation of RAGE (receptor for advanced glycation end product), an A? transporter. BCCAO following A? injection further enhanced neuronal pyknosis in the hippocampus, compared with BCCAO or A? injection alone. In contrast, smAT2 did not show a cognitive decline, increase in oxidative stress, inflammation, and RAGE level or neuronal pyknosis, which were induced by BCCAO with/without A? injection in WT. Transient cerebral ischemia might worsen A? infusion-mediated cognitive decline and vice versa, with possible involvement of amplified oxidative stress and inflammation and impairment of the RAGE-mediated A? clearance system, contributing to exaggerated neuronal degeneration. AT2 receptor activation in VSMC could play an inhibitory role in this cognitive deficit.

SUBMITTER: Min LJ

PROVIDER: S-EPMC7140348 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Deterioration of cognitive function after transient cerebral ischemia with amyloid-β infusion-possible amelioration of cognitive function by AT<sub>2</sub> receptor activation.

Min Li-Juan LJ Iwanami Jun J Shudou Masachika M Bai Hui-Yu HY Shan Bao-Shuai BS Higaki Akinori A Mogi Masaki M Horiuchi Masatsugu M

Journal of neuroinflammation 20200407 1

<h4>Background</h4>To promote understanding of the pathogenesis of cognitive impairment or dementia, we explored the potential interaction between transient cerebral ischemia and amyloid-β (Aβ) infusion in mediating cognitive decline and examined the possible ameliorative effect of angiotensin II type 2 (AT<sub>2</sub>) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit.<h4>Methods</h4>Adult male wild-type mice (WT) and mice with VSMC-specific AT<sub>2</sub> rec ...[more]

PMID: 32264971

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Project description:Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10-15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 ± 3.1%, P = 0.016) and postconditioning pigs (47.6 ± 3.9%, P = 0.008) versus controls (53.8 ± 4.1%). Late MVO was significantly reduced by cyclosporine (13.9 ± 9.6%, P = 0.047) but not postconditioning (23.6 ± 11.7%, P = 0.66) when compared with controls (32.0 ± 16.9%). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R(2) = 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (-7.9 ± 2.4%, P = 0.008) but not postconditioning (-12.0 ± 5.5%, P = 0.22) when compared with controls (-16.4 ± 5.5%). In the three groups, infarct size (β = -0.69, P < 0.001) and late MVO (β = -0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R(2) = 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.

Dataset Information

Deterioration of cognitive function after transient cerebral ischemia with amyloid-? infusion-possible amelioration of cognitive function by AT2 receptor activation.

Publications

Deterioration of cognitive function after transient cerebral ischemia with amyloid-β infusion-possible amelioration of cognitive function by AT<sub>2</sub> receptor activation.

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