title: Prophylactic angiotensin type 1 receptor antagonism confers neuroprotection in an aged rat model of postoperative cognitive dysfunction.
abstract: Postoperative cognitive dysfunction (POCD) is a common geriatric complication, although its exact neuropathogenesis remains elusive. Blockers of the renin-angiotensin system (RAS) ameliorate cognitive deficits in inflammatory brain disorders, with its effects on POCD not yet fully elucidated. The aim of the present study was to investigate regulation of the brain RAS and the effect of angiotensin II receptor type 1 (AT1) inhibition on surgery-induced cognitive impairment in a well-established rat POCD model. We observed upregulation of angiotensin II protein expression and AT1 subtype B transcript levels in the hippocampus after laparotomy, suggesting surgical stress activates the hippocampal RAS in aged rats. Chronic pretreatment with 0.1 mg/kg/day candesartan, an AT1 antagonist, significantly attenuated surgery-induced cognitive deficits in the Morris water maze task without altering blood pressure. Candesartan also decreased hippocampal blood-brain barrier (BBB) permeability. Concomitant with these functional benefits, we observed significant inhibition of hippocampal neuroinflammation, evidenced by decreased glial reactivity and phosphorylation of the NF-κB p65 subunit, as well as marked reductions in interleukin-1β, tumor necrosis factor-α, and cyclooxygenase-2. Our results are the first to show that activation of the brain RAS after surgery contributes to POCD in aged rats. Chronic treatment with low doses of candesartan may elicit blood pressure-independent neuroprotective effects in POCD by improving BBB function and promoting resolution of neuroinflammation.
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Zhengqian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Lunxu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Yaoxian
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Tian
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Na
authors.initials: N
authors.lastname: Mo
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Chui
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China. Electronic address: puthmzk@163.com.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Guo
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D003072:Cognition Disorders / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011183:Postoperative Complications / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C524087:Agtrap protein, rat; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C081643:candesartan
keywords: Angiotensin II receptor type 1; Blood–brain barrier; Neuroinflammation; Postoperative cognitive dysfunction; Renin–angiotensin system