title: Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: Protection by angiotensin converting enzyme inhibition.
abstract: Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25μg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50μg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25μg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50μg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition.
authors: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Ruby
authors: R
authors: Goel
authors: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Shahnawaz Ali
authors: SA
authors: Bhat
authors: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), India.
authors: N
authors: N
authors: Rajasekar
authors: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), India.
authors: Kashif
authors: K
authors: Hanif
authors: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), India.
authors: Chandishwar
authors: C
authors: Nath
authors: Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), India. Electronic address: rakeshshukla_cdri@rediffmail.com.
authors: Rakesh
authors: R
authors: Shukla
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril
keywords: Angiotensin converting enzyme; Hypertension; Lipopolysaccharide; Memory impairment; Neuroinflammation; Perindopril