Perindopril Attenuates Lipopolysaccharide-Induced Amyloidogenesis and Memory Impairment by Suppression of Oxidative Stress and RAGE Activation

Abstract

Clinical and preclinical studies account hypertension as a risk factor for dementia. We reported earlier that angiotensin-converting enzyme (ACE) inhibition attenuated the increased vulnerability to neurodegeneration in hypertension and prevented lipopolysaccharide (LPS)-induced memory impairment in normotensive wistar rats (NWRs) and spontaneously hypertensive rats (SHRs). Recently, a receptor for advanced glycation end products (RAGE) has been reported to induce amyloid beta (Aβ1-42) deposition and memory impairment in hypertensive animals. However, the involvement of ACE in RAGE activation and amyloidogenesis in the hypertensive state is still unexplored. Therefore, in this study, we investigated the role of ACE on RAGE activation and amyloidogenesis in memory-impaired NWRs and SHRs. Memory impairment was induced by repeated (on days 1, 4, 7, and 10) intracerebroventricular (ICV) injections of LPS in SHRs (25 μg) and NWRs (50 μg). Our data showed that SHRs exhibited increased oxidative stress (increased gp91-phox/NOX-2 expression and ROS generation), RAGE, and β-secretase (BACE) expression without Aβ1-42 deposition. LPS (25 μg, ICV) further amplified oxidative stress, RAGE, and BACE activation, culminating in Aβ1-42 deposition and memory impairment in SHRs. Similar changes were observed at the higher dose of LPS (50 μg, ICV) in NWRs. Further, LPS-induced oxidative stress was associated with endothelial dysfunction and reduction in cerebral blood flow (CBF), more prominently in SHRs than in NWRs. Finally, we showed that perindopril (0.1 mg/kg, 15 days) prevented memory impairment by reducing oxidative stress, RAGE activation, amyloidogenesis, and improved CBF in both SHRs and NWRs. These findings suggest that perindopril might be used as a therapeutic strategy for the early stage of dementia.

Modulation of advanced glycation endproducts (AGEs) signaling in experimentally induced stroke in mice.

“…Benfotiamine was shown to reduce AGEs formation (Nagai,Shirakawa et al 2014) and reduce diabetic vascular complications (Bozic, Savic et al 2015). ACE inhibition by perindopril was shown to reduce accumulation of AGEs, increase sRAGE (Forbes, Thorpe et al 2005) and reduce oxidative stress and RAGE activation in rats (Goel, Bhat et al 2016). Although perindopril was previously shown to increase sRAGE (Forbes, Thorpe et al 2005) in diabetic patients, however, in the current study similar action was not shown which might be attributed to the difference in disease model, species and dose administered.…”

Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF‐κB‐p65/TLR‐4, JAK1/STAT‐3, Nrf‐2, and PI3K/Akt/mTOR Signaling Pathways

“…This may also explains, at least partly, the hepatic oxidative stress and histological changes observed in IR‐subjected rats. PER was previously reported to possess protective effects against oxidative damage in a number of experimental models (Yang et al, ; Goel et al, ). In agreement, data of the present study provide clearly a direct evidence for the antioxidant activity of PER.…”

Targeting Renin–Angiotensin System Against Alzheimer’s Disease

“…The protective effect of ACE inhibitors could be explained partly via suppressing brain derived neurotrophic factor decline and TNF-α release. They were also found to ameliorate oxidonitrosative stress and nitrotyrosine production ( Ali et al, 2016 ) with that in turn reduces amyloidogenesis and subsequent Aβ deposition ( Goel et al, 2016 ). However, further investigations are required to see if the contradicting reports were intrinsic to the specific inherent nature of the drug or methodological issue.…”