title: 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.
authors.affiliation: Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Ruby
authors.initials: R
authors.lastname: Goel
authors.affiliation: Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Shahnawaz Ali
authors.initials: SA
authors.lastname: Bhat
authors.affiliation: Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
authors.affiliation: Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Chandishwar
authors.initials: C
authors.lastname: Nath
authors.affiliation: Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000139:chemically induced / Q000188:drug therapy*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism; D020913:Perindopril / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; C075222:amyloid beta-protein (1-42); D008550:Melatonin; D020913:Perindopril
keywords: Hypertension; amyloidogenesis; angiotensin-converting enzyme; memory impairment; oxidative stress; perindopril