| Chronic cerebral hypoperfusion(CCH)is usually caused by vascular and metabolic diseases including hypertension,diabetes and atherosclerosis,and is considered to be the important risk factors of vascular dementia(Va D)and Alzheimer’s disease(AD).Studies have shown that CCH can lead to a series of pathological changes after brain ischemia and hypoxia,such as amyloid-β(Aβ)deposition,tau protein hyperphosphorylation(p-tau),inflammatory reaction,oxidative stress,etc.These pathological changes can accelerate the process of learning and memory impairment in patients,leading to the progression and deterioration of dementia.To date,there is no effective treatment for these CCH-related neuropathological changes in the brain.The rat model of bilateral common carotid artery ligation can better simulate vascular cognitive dysfunction,and the model generally does not show obvious focal necrosis of brain tissue,which can largely mimic the pathological state after CCH in human brain.It is used as amore ideal experimental model for CCH study.The renin-angiotensin system(RAS)was identified as a key component of the circulatory system,regulating water and sodium homeostasis.In some areas and structures of the brain,independent local RAS has been discovered and is thought to be involved in some brain physiological functions and the pathogenesis of some neurological diseases,including ischemic stroke,Parkinson’s disease,Va D and AD.As an important component of brain RAS,angiotensin IV(Ang IV)has been reported to bind to type 4 Angiotensin IV receptor(AT4R),can restore cognitive impairment caused by various central injuries including CCH.However,to date,there have beenfew studies on whether this hexapeptide has a beneficial effect on CCH-related neuropathological changes.In the present study,we hypothesized that exogenous Ang IV infusion may affect CCH-related neuropathological changes in a dose-dependent manner,such as Aβ,hyperphosphorylated tau(p-tau)and inflammatory response markers and oxidative stress levels.To assess this hypothesis,a CCH rat model induced by bilateral common carotid artery(CCAs)ligation was used.We first found that Ang IV inhibited the inflammatory response and oxidative stress levels in a dose-dependent manner through the AT4 receptor in the brain of CCH rats,while the expression levels of Aβand p-tau were not affected.This beneficial effect of Ang IV appears to be independent of blood pressure.Inshort,these findings suggest that the Ang IV/AT4 receptor may be one of the potential therapeutic targets for CCH-associated neurological diseases.Objective: This study was aimed to evaluate the influence of central angiotensin IV(Ang IV)infusion on chronic neuropathic hypoperfusion(CCH)-related neuropathological changes including amyloid-β(Aβ),hyperphosphorylated tau(p-tau),inflammatory response and oxidative stress levels.Methods: Rats with CCH received central infusion of Ang IV,its receptor AT4 R antagonist divalinal-Ang IV or artificial cerebrospinal fluid for 6 weeks.During this procedure,the blood pressure was monitored,and the levels of Aβ42,p-tau,pro-inflammatory cytokines and oxidative stress levels in the brain were assessed.Results: Rats with CCH exhibited higher levels of Aβ42,p-tau,pro-inflammatory cytokines and oxidative stress in the brain when compared with controls.Infusion of Ang IV significantly reduced the expression of pro-inflammatory cytokines and related oxidative stress in the brain of rats with CCH.Meanwhile,the reduction of pro-inflammatory cytokines levels and oxidative stress levels caused by Ang IV was reversed by divalinal-Ang IV.During the treatment,the blood pressure of rats was not significantly altered.Conclusion: This study demonstrates for the first time that Ang IV dose-dependently suppresses inflammation and oxidative stress levels through AT4 R in the brain of rats with CCH,which is independent from the blood pressure.These findings suggest that Ang IV/AT4 R may represent a potential therapeutic target for CCH-related neurological diseases. |
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