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Moore A, Ritchie MD. Is the Relationship Between Cardiovascular Disease and Alzheimer's Disease Genetic? A Scoping Review. Genes (Basel) 2024; 15:1509. [PMID: 39766777 PMCID: PMC11675426 DOI: 10.3390/genes15121509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Cardiovascular disease (CVD) and Alzheimer's disease (AD) are two diseases highly prevalent in the aging population and often co-occur. The exact relationship between the two diseases is uncertain, though epidemiological studies have demonstrated that CVDs appear to increase the risk of AD and vice versa. This scoping review aims to examine the current identified overlapping genetics between CVDs and AD at the individual gene level and at the shared pathway level. METHODS Following PRISMA-ScR guidelines for a scoping review, we searched the PubMed and Scopus databases from 1990 to October 2024 for articles that involved (1) CVDs, (2) AD, and (3) used statistical methods to parse genetic relationships. RESULTS Our search yielded 2918 articles, of which 274 articles passed screening and were organized into two main sections: (1) evidence of shared genetic risk; and (2) shared mechanisms. The genes APOE, PSEN1, and PSEN2 reportedly have wide effects across the AD and CVD spectrum, affecting both cardiac and brain tissues. Mechanistically, changes in three main pathways (lipid metabolism, blood pressure regulation, and the breakdown of the blood-brain barrier (BBB)) contribute to subclinical and etiological changes that promote both AD and CVD progression. However, genetic studies continue to be limited by the availability of longitudinal data and lack of cohorts that are representative of diverse populations. CONCLUSIONS Highly penetrant familial genes simultaneously increase the risk of CVDs and AD. However, in most cases, sets of dysregulated genes within larger-scale mechanisms, like changes in lipid metabolism, blood pressure regulation, and BBB breakdown, increase the risk of both AD and CVDs and contribute to disease progression.
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Affiliation(s)
- Anni Moore
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Marylyn D. Ritchie
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- Division of Informatics, Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Penn Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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2
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Gouveia F, Fonseca C, Silva A, Camins A, Teresa Cruz M, Ettcheto M, Fortuna A. Intranasal irbesartan reverts cognitive decline and activates the PI3K/AKT pathway in an LPS-induced neuroinflammation mice model. Int Immunopharmacol 2024; 128:111471. [PMID: 38199198 DOI: 10.1016/j.intimp.2023.111471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/13/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND New strategies are urgently needed to manage and delay the development of Alzheimer's disease (AD). Neuroinflammation is a significant contributor to cognitive decline in neurodegenerative diseases, including AD. Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) protect hypertensive patients against AD, but the cellular and molecular mechanisms underlying these effects remain unknown. In light of this, the protective effects of three ARBs and three ACEIs against neuroinflammation and cognitive decline were investigated through comprehensive pharmacologicalin vitro/in vivoscreening. METHODS BV-2 microglia cells were exposed tolipopolysaccharide (LPS) and treated with ARBs and ACEIs to provide initial insights into the anti-inflammatory properties of the drugs. Subsequently, irbesartan was selected, and its efficacy was evaluated inC57/BL6 male miceintranasally administered with irbesartan and injected with LPS. Long-term memory and depressive-like behavior were evaluated; dendritic spines were measured as well as neuroinflammation, neurodegeneration and cognitive decline biomarkers. RESULTS Irbesartan mitigated memory loss and depressive-like behavior in mice treated with LPS, probably because itincreased spine density, ameliorated synapsis dysfunction and activated the PI3K/AKT pathway. Irbesartan elevated the levels of hippocampalsuperoxide dismutase2 andglutathione peroxidaseandsuppressed LPS-induced astrogliosis. CONCLUSIONS Overall, this study provides compelling evidence that multiple intranasal administrations of irbesartan can effectively prevent LPS-induced cognitive decline by activating pathways involved in neuroprotection and anti-inflammatory events. These findings underscore the potential of irbesartan as a preventive strategy against the development of AD and other neurodegenerative conditions associated with neuroinflammation.
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Affiliation(s)
- Filipa Gouveia
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Carla Fonseca
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Ana Silva
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute, Madrid, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - M Teresa Cruz
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute, Madrid, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain.
| | - Ana Fortuna
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
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3
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Yang MH, Ho TC, Chang CC, Su YS, Yuan CH, Chuang KP, Tyan YC. Utilizing Proteomic Approaches to Uncover the Neuroprotective Effects of ACE Inhibitors: Implications for Alzheimer's Disease Treatment. Molecules 2023; 28:5938. [PMID: 37630190 PMCID: PMC10459293 DOI: 10.3390/molecules28165938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/30/2023] [Accepted: 07/18/2023] [Indexed: 08/27/2023] Open
Abstract
Two types of angiotensin-converting enzyme (ACE) inhibitors, lisinopril and benazepril HCl, were tested in neuroblastoma cells and found to upregulate low-density lipoprotein-receptor-related protein 1B (LRP1B) and 14-3-3 protein zeta/delta. Additionally, benazepril HCl was found to increase the expression of calreticulin. The upregulation of these proteins by ACE inhibitors may contribute to the amelioration of cognitive deficits in Alzheimer's disease/dementia, as well as the clinically observed deceleration of functional decline in Alzheimer's patients. This discovery suggests that the supplementation of ACE inhibitors may promote neuronal cell survival independently of their antihypertensive effect. Overall, these findings indicate that ACE inhibitors may be a promising avenue for developing effective treatments for Alzheimer's disease.
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Affiliation(s)
- Ming-Hui Yang
- Division of General & Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tzu-Chuan Ho
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chin-Chuan Chang
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yuh-Shan Su
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Cheng-Hui Yuan
- Mass Spectrometry Laboratory, Department of Chemistry, National University of Singapore, Singapore 119077, Singapore
| | - Kuo-Pin Chuang
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Companion Animal Research Center, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Yu-Chang Tyan
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Nemoto W, Yamagata R, Nakagawasai O, Tan-No K. Angiotensin-Related Peptides and Their Role in Pain Regulation. BIOLOGY 2023; 12:biology12050755. [PMID: 37237567 DOI: 10.3390/biology12050755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/19/2023] [Accepted: 05/20/2023] [Indexed: 05/28/2023]
Abstract
Angiotensin (Ang)-generating system has been confirmed to play an important role in the regulation of fluid balance and blood pressure and is essential for the maintenance of biological functions. Ang-related peptides and their receptors are found throughout the body and exhibit diverse physiological effects. Accordingly, elucidating novel physiological roles of Ang-generating system has attracted considerable research attention worldwide. Ang-generating system consists of the classical Ang-converting enzyme (ACE)/Ang II/AT1 or AT2 receptor axis and the ACE2/Ang (1-7)/MAS1 receptor axis, which negatively regulates AT1 receptor-mediated responses. These Ang system components are expressed in various tissues and organs, forming a local Ang-generating system. Recent findings indicate that changes in the expression of Ang system components under pathological conditions are involved in the development of neuropathy, inflammation, and their associated pain. Here, we summarized the effects of changes in the Ang system on pain transmission in various organs and tissues involved in pain development process.
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Affiliation(s)
- Wataru Nemoto
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Ryota Yamagata
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Osamu Nakagawasai
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
| | - Koichi Tan-No
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
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MacLachlan R, Evans CE, Chai SY, Good MA, Kehoe PG, Miners JS. Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer's disease pathology in mouse models of Alzheimer's disease. AGING BRAIN 2023; 3:100062. [PMID: 36911263 PMCID: PMC9997187 DOI: 10.1016/j.nbas.2022.100062] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/26/2022] [Accepted: 12/20/2022] [Indexed: 12/30/2022] Open
Abstract
An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer's disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline. Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1-7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD - 2, 6, and 12 months of age; Apd9 - 3-4, 12, and 18 months of age; Tg2576 - 3-4 and 24 months of age; and PDAPP - 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls. ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age. These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aβ, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aβ deposition.
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Affiliation(s)
- Robert MacLachlan
- Dementia Research Group, Clinical Neurosciences, Bristol Medical School, University of Bristol, Learning and Research Building, Southmead Hospital, BS10 5NB, United Kingdom
| | - Charles E Evans
- School of Psychology, Cardiff University, Cardiff CF10 3AT, United Kingdom
| | - Siew Yeen Chai
- Monash Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
| | - Mark A Good
- School of Psychology, Cardiff University, Cardiff CF10 3AT, United Kingdom
| | - Patrick Gavin Kehoe
- Dementia Research Group, Clinical Neurosciences, Bristol Medical School, University of Bristol, Learning and Research Building, Southmead Hospital, BS10 5NB, United Kingdom
| | - J Scott Miners
- Dementia Research Group, Clinical Neurosciences, Bristol Medical School, University of Bristol, Learning and Research Building, Southmead Hospital, BS10 5NB, United Kingdom
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6
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Tada AM, Hamezah HS, Pahrudin Arrozi A, Abu Bakar ZH, Yanagisawa D, Tooyama I. Pharmaceutical Potential of Casein-Derived Tripeptide Met-Lys-Pro: Improvement in Cognitive Impairments and Suppression of Inflammation in APP/PS1 Mice. J Alzheimers Dis 2022; 89:835-848. [PMID: 35964178 PMCID: PMC9535549 DOI: 10.3233/jad-220192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Background: Tripeptide Met-Lys-Pro (MKP), a component of casein hydrolysates, has effective angiotensin-converting enzyme (ACE) inhibitory activity. Brain angiotensin II enzyme activates the NADPH oxidase complex via angiotensin II receptor type 1 (AT1) and enhances oxidative stress injury. ACE inhibitors improved cognitive function in Alzheimer’s disease (AD) mouse models and previous clinical trials. Thus, although undetermined, MKP may be effective against pathological amyloid-β (Aβ) accumulation-induced cognitive impairment. Objective: The current study aimed to investigate the potential of MKP as a pharmaceutical against AD by examining MKP’s effect on cognitive function and molecular changes in the brain using double transgenic (APP/PS1) mice. Methods: Experimental procedures were conducted in APP/PS1 mice (n = 38) with a C57BL/6 background. A novel object recognition test was used to evaluate recognition memory. ELISA was used to measure insoluble Aβ40, Aβ42, and TNF-α levels in brain tissue. Immunohistochemical analysis allowed the assessment of glial cell activation in MKP-treated APP/PS1 mice. Results: The novel object recognition test revealed that MKP-treated APP/PS1 mice showed significant improvement in recognition memory. ELISA of brain tissue showed that MKP significantly reduced insoluble Aβ40, Aβ42, and TNF-α levels. Immunohistochemical analysis indicated the suppression of the marker for microglia and reactive astrocytes in MKP-treated APP/PS1 mice. Conclusion: Based on these results, we consider that MKP could ameliorate pathological Aβ accumulation-induced cognitive impairment in APP/PS1 mice. Furthermore, our findings suggest that MKP potentially contributes to preventing cognitive decline in AD.
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Affiliation(s)
- Asuka Matsuzaki Tada
- Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan.,Functional Food Ingredients Group, Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., Zama, Japan
| | - Hamizah Shahirah Hamezah
- Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan.,Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, Malaysia
| | - Aslina Pahrudin Arrozi
- Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan
| | | | - Daijiro Yanagisawa
- Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan
| | - Ikuo Tooyama
- Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan
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7
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Kabel AM, Atef A, Borg HM, El-Sheikh AAK, Al Khabbaz HJ, Arab HH, Estfanous RS. Perindopril/Ambrosin Combination Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice: Crosstalk between Toll-Like Receptor 4, the Pro-Inflammatory Pathways, and SIRT1/PPAR-γ Signaling. Pharmaceuticals (Basel) 2022; 15:600. [PMID: 35631426 PMCID: PMC9143999 DOI: 10.3390/ph15050600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/02/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
Colitis is one of the inflammatory states that affect the intestinal wall and may even predispose to malignancy due to chronic irritation. Although the etiology of colitis is not yet fully explored, a combination of genetic and environmental factors is strongly incriminated. Perindopril is an angiotensin-converting enzyme inhibitor that is used for the management of a wide range of cardiovascular diseases. Ambrosin is a sesquiterpene lactone that was proven to have beneficial effects in disorders characterized by inflammatory nature. The objective of this study is to make a comparison between the effects of perindopril or ambrosin on dextran sulfate sodium (DSS)-induced colitis in mice and to explore the effect of their combination. The present findings indicate that each ambrosin or perindopril alone or in combination is able to ameliorate oxidative stress and suppress the proinflammatory pathways in the colonic tissues of DSS-treated mice via mechanisms related to toll-like receptor 4/nuclear factor kappa B signaling and modulation of peroxisome proliferator-activated receptor gamma/sirtuin-1 levels. In addition, each ambrosin or perindopril alone or in combination inhibits apoptosis and augments the mediators of autophagy in DSS-treated mice. These effects are reflected in the amelioration of the histopathological and electron microscopic changes in the colonic tissues. Interestingly, the most remarkable effects are those encountered with the perindopril/ambrosin combination compared to the groups treated with each of these agents alone. In conclusion, the perindopril/ambrosin combination might represent an effective modality for mitigation of the pathogenic events and the clinical sequelae of colitis.
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Affiliation(s)
- Ahmed M. Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
| | - Aliaa Atef
- Department of Pathology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
| | - Hany M. Borg
- Physiology Department, Faculty of Medicine, Kafrelsheikh University, Kafr El-Shaikh 33516, Egypt;
| | - Azza A. K. El-Sheikh
- Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Hana J. Al Khabbaz
- Biochemistry Division, College of Pharmacy, Riyadh Elm University, Riyadh 11681, Saudi Arabia;
| | - Hany H. Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Remon S. Estfanous
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
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Gouveia F, Camins A, Ettcheto M, Bicker J, Falcão A, Cruz MT, Fortuna A. Targeting brain Renin-Angiotensin System for the prevention and treatment of Alzheimer's disease: Past, present and future. Ageing Res Rev 2022; 77:101612. [PMID: 35346852 DOI: 10.1016/j.arr.2022.101612] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 02/09/2022] [Accepted: 03/16/2022] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a well-known neurodegenerative disease characterized by the presence of two main hallmarks - Tau hyperphosphorylation and Aβ deposits. Notwithstanding, in the last few years the scientific evidence about the drivers of AD have been changing and nowadays age-related vascular alterations and several cardiovascular risk factors have been shown to trigger the development of AD. In this context, drugs targeting the Renin Angiotensin System (RAS), commonly used for the treatment of hypertension, are evidencing a high potential to delay AD development due to their action on brain RAS. Indeed, the ACE 1/Ang II/AT1R axis is believed to be upregulated in AD and to be responsible for deleterious effects such as increased oxidative stress, neuroinflammation, blood-brain barrier (BBB) hyperpermeability, astrocytes dysfunction and a decrease in cerebral blood flow. In contrast, the alternative axis - ACE 1/Ang II/AT2R; ACE 2/Ang (1-7)/MasR; Ang IV/ AT4R(IRAP) - seems to counterbalance the deleterious effects of the principal axis and to exert beneficial effects on memory and cognition. Accordingly, retrospective studies demonstrate a reduced risk of developing AD among people taking RAS medication as well as several in vitro and in vivo pre-clinical studies as it is herein critically reviewed. In this review, we first revise, at a glance, the pathophysiology of AD focused on its classic hallmarks. Secondly, an overview about the impact of the RAS on the pathophysiology of AD is also provided, focused on their four essential axes ACE 1/Ang II/AT2R; ACE 2/Ang (1-7)/MasR; Ang IV/ AT4R(IRAP) and ACE 1/Ang II/AT1R. Finally, the therapeutic potential of available drugs targeting RAS on AD, namely angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs), is highlighted and data supporting this hope will be presented, from in vitro and in vivo pre-clinical to clinical studies.
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9
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Yang M, Sun D, Wang Y, Yan M, Zheng J, Ren J. Cognitive Impairment in Heart Failure: Landscape, Challenges, and Future Directions. Front Cardiovasc Med 2022; 8:831734. [PMID: 35198608 PMCID: PMC8858826 DOI: 10.3389/fcvm.2021.831734] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 12/30/2021] [Indexed: 12/20/2022] Open
Abstract
Heart failure (HF) is a major global healthcare problem accounting for substantial deterioration of prognosis. As a complex clinical syndrome, HF often coexists with multi-comorbidities of which cognitive impairment (CI) is particularly important. CI is increasing in prevalence among patients with HF and is present in around 40%, even up to 60%, of elderly patients with HF. As a potent and independent prognostic factor, CI significantly increases the hospitalization and mortality and decreases quality of life in patients with HF. There has been a growing awareness of the complex bidirectional interaction between HF and CI as it shares a number of common pathophysiological pathways including reduced cerebral blood flow, inflammation, and neurohumoral activations. Research that focus on the precise mechanism for CI in HF is still ever insufficient. As the tremendous adverse consequences of CI in HF, effective early diagnosis of CI in HF and interventions for these patients may halt disease progression and improve prognosis. The current clinical guidelines in HF have begun to emphasize the importance of CI. However, nearly half of CI in HF is underdiagnosed, and few recommendations are available to guide clinicians about how to approach CI in patients with HF. This review aims to synthesize knowledge about the link between HF and cognitive dysfunction, issues pertaining to screening, diagnosis and management of CI in patients with HF, and emerging therapies for prevention. Based on data from current studies, critical gaps in knowledge of CI in HF are identified, and future research directions to guide the field forward are proposed.
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Affiliation(s)
- Mengxi Yang
- Heart Failure Center, China-Japan Friendship Hospital, Beijing, China
- Department of Cardiology, China-Japan Friendship Hospital, Beijing, China
| | - Di Sun
- Heart Failure Center, China-Japan Friendship Hospital, Beijing, China
- Department of Cardiology, China-Japan Friendship Hospital, Beijing, China
| | - Yu Wang
- Department of Neurology, China-Japan Friendship Hospital, Beijing, China
| | - Mengwen Yan
- Heart Failure Center, China-Japan Friendship Hospital, Beijing, China
- Department of Cardiology, China-Japan Friendship Hospital, Beijing, China
| | - Jingang Zheng
- Heart Failure Center, China-Japan Friendship Hospital, Beijing, China
- Department of Cardiology, China-Japan Friendship Hospital, Beijing, China
| | - Jingyi Ren
- Heart Failure Center, China-Japan Friendship Hospital, Beijing, China
- Department of Cardiology, China-Japan Friendship Hospital, Beijing, China
- Vascular Health Research Center of Peking University Health Science Center, Beijing, China
- *Correspondence: Jingyi Ren
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10
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Recent Advances in the Endogenous Brain Renin-Angiotensin System and Drugs Acting on It. J Renin Angiotensin Aldosterone Syst 2021; 2021:9293553. [PMID: 34925551 PMCID: PMC8651430 DOI: 10.1155/2021/9293553] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/14/2021] [Accepted: 10/23/2021] [Indexed: 12/22/2022] Open
Abstract
The RAS (renin-angiotensin system) is the part of the endocrine system that plays a prime role in the control of essential hypertension. Since the discovery of brain RAS in the seventies, continuous efforts have been put by the scientific committee to explore it more. The brain has shown the presence of various components of brain RAS such as angiotensinogen (AGT), converting enzymes, angiotensin (Ang), and specific receptors (ATR). AGT acts as the precursor molecule for Ang peptides—I, II, III, and IV—while the enzymes such as prorenin, ACE, and aminopeptidases A and N synthesize it. AT1, AT2, AT4, and mitochondrial assembly receptor (MasR) are found to be plentiful in the brain. The brain RAS system exhibits pleiotropic properties such as neuroprotection and cognition along with regulation of blood pressure, CVS homeostasis, thirst and salt appetite, stress, depression, alcohol addiction, and pain modulation. The molecules acting through RAS predominantly ARBs and ACEI are found to be effective in various ongoing and completed clinical trials related to cognition, memory, Alzheimer's disease (AD), and pain. The review summarizes the recent advances in the brain RAS system highlighting its significance in pathophysiology and treatment of the central nervous system-related disorders.
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Tran S, Kuruppu S, Rajapakse NW. Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia? J Alzheimers Dis 2021; 85:943-955. [PMID: 34897090 DOI: 10.3233/jad-215231] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.
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Affiliation(s)
- Shirley Tran
- School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, Australia
| | - Sanjaya Kuruppu
- School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, Australia.,Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Niwanthi W Rajapakse
- School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, Australia
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12
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Zhao L, Li J, Kälviäinen R, Jolkkonen J, Zhao C. Impact of drug treatment and drug interactions in post-stroke epilepsy. Pharmacol Ther 2021; 233:108030. [PMID: 34742778 DOI: 10.1016/j.pharmthera.2021.108030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 12/21/2022]
Abstract
Stroke is a huge burden on our society and this is expected to grow in the future due to the aging population and the associated co-morbidities. The improvement of acute stroke care has increased the survival rate of stroke patients, and many patients are left with permanent disability, which makes stroke the main cause of adult disability. Unfortunately, many patients face other severe complications such as post-stroke seizures and epilepsy. Acute seizures (ASS) occur within 1 week after the stroke while later occurring unprovoked seizures are diagnosed as post-stroke epilepsy (PSE). Both are associated with a poor prognosis of a functional recovery. The underlying neurobiological mechanisms are complex and poorly understood. There are no universal guidelines on the management of PSE. There is increasing evidence for several risk factors for ASS/PSE, however, the impacts of recanalization, drugs used for secondary prevention of stroke, treatment of stroke co-morbidities and antiseizure medication are currently poorly understood. This review focuses on the common medications that stroke patients are prescribed and potential drug interactions possibly complicating the management of ASS/PSE.
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Affiliation(s)
- Lanqing Zhao
- Department of Sleep Medicine Center, The Shengjing Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
| | - Jinwei Li
- Department of Stroke Center, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
| | - Reetta Kälviäinen
- Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital, Full Member of ERN EpiCARE, Kuopio, Finland; Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jukka Jolkkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
| | - Chuansheng Zhao
- Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
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13
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Brain Renin-Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms221810139. [PMID: 34576302 PMCID: PMC8468637 DOI: 10.3390/ijms221810139] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/12/2021] [Accepted: 09/14/2021] [Indexed: 12/15/2022] Open
Abstract
The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer's disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.
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14
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Prieto Santamaría L, Ugarte Carro E, Díaz Uzquiano M, Menasalvas Ruiz E, Pérez Gallardo Y, Rodríguez-González A. A data-driven methodology towards evaluating the potential of drug repurposing hypotheses. Comput Struct Biotechnol J 2021; 19:4559-4573. [PMID: 34471499 PMCID: PMC8387760 DOI: 10.1016/j.csbj.2021.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/08/2021] [Accepted: 08/03/2021] [Indexed: 12/14/2022] Open
Abstract
Drug repurposing has become a widely used strategy to accelerate the process of finding treatments. While classical de novo drug development involves high costs, risks, and time-consuming paths, drug repurposing allows to reuse already-existing and approved drugs for new indications. Numerous research has been carried out in this field, both in vitro and in silico. Computational drug repurposing methods make use of modern heterogeneous biomedical data to identify and prioritize new indications for old drugs. In the current paper, we present a new complete methodology to evaluate new potentially repurposable drugs based on disease-gene and disease-phenotype associations, identifying significant differences between repurposing and non-repurposing data. We have collected a set of known successful drug repurposing case studies from the literature and we have analysed their dissimilarities with other biomedical data not necessarily participating in repurposing processes. The information used has been obtained from the DISNET platform. We have performed three analyses (at the genetical, phenotypical, and categorization levels), to conclude that there is a statistically significant difference between actual repurposing-related information and non-repurposing data. The insights obtained could be relevant when suggesting new potential drug repurposing hypotheses.
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Key Words
- ACE, Angiotensin I Converting Enzyme
- AHR, Aryl Hydrocarbon Receptor
- ALK, Anaplastic Lymphoma Kinase
- API, Application Programming Interface
- CMap, Connectivity Map
- COX-2, Cyclooxygenase 2
- CUI, Concept Unique Identifier
- DISNET knowledge base
- DR, Drug Repurposing or Drug Repositioning
- DRD3, Dopamine Receptor D3
- Data integration
- Disease understanding
- Drug repositioning
- Drug repurposing
- Drug-disease validation
- ESR1, Estrogen Receptor 1
- ESR2, Estrogen Receptor 2
- FCGR2A, Fc Fragment Of IgG Receptor IIa
- FCGR3A, Fc Fragment Of IgG Receptor IIIa
- FCGR3B, Fc Fragment Of IgG Receptor IIIb
- GDA, Gene Disease Association
- ICD-10-CM, International Classification of Diseases, 10th revision, Clinical Modification
- ID, Identifier
- KDR, Kinase insert Domain Receptor
- LTα, Lymphotoxin alpha
- MeSH-PA, Medical Subject Headings – Pharmacological Action
- ND, New Disease
- NLM, National Library of Medicine
- OD, Original Disease
- PTGS2, Prostaglandin-endoperoxidase synthase 2
- SM, Supplementary Material
- SRD5A1, Steroid 5 Alpha-Reductase 1
- SRD5A2, Steroid 5 Alpha-Reductase 2
- TNFα, Tumour Necrosis Factor alpha
- UMLS, Unified Medical Language System
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Affiliation(s)
- Lucía Prieto Santamaría
- Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain.,ETS Ingenieros Informáticos, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain.,Ezeris Networks Global Services S.L., 28028 Madrid, Spain
| | - Esther Ugarte Carro
- Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain
| | - Marina Díaz Uzquiano
- Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain
| | - Ernestina Menasalvas Ruiz
- Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain.,ETS Ingenieros Informáticos, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain
| | | | - Alejandro Rodríguez-González
- Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain.,ETS Ingenieros Informáticos, Universidad Politécnica de Madrid, 28660 Boadilla del Monte, Madrid, Spain
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15
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Mitchell CS, Premaratna SD, Bennett G, Lambrou M, Stahl LA, Jois M, Barber E, Antoniadis CP, Woods SC, Cameron-Smith D, Weisinger RS, Begg DP. Inhibition of the Renin-Angiotensin System Reduces Gene Expression of Inflammatory Mediators in Adipose Tissue Independent of Energy Balance. Front Endocrinol (Lausanne) 2021; 12:682726. [PMID: 34149621 PMCID: PMC8206808 DOI: 10.3389/fendo.2021.682726] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/12/2021] [Indexed: 12/30/2022] Open
Abstract
Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD ad libitum (AL), as well as receiving HFD limited to the amount of calories eaten by controls (pair-fed (PF) group). Body weight, food intake, adiposity and plasma leptin were lower in ACE inhibitor or ARB-treated groups over 28 days compared with HFD untreated mice. Short-term treatment with captopril led to increased EE relative to the level in the PF group. After 28 days, EE was lower in both captopril-treated and PF mice compared with AL, but the effect was greater in the captopril-treated group. Adiponectin was elevated in captopril-treated mice, but not in PF mice, after both 2 and 28 days. Additionally, acute RAS blockade in HFD-fed mice reduced mRNA expression for MCP-1, IL-6, TLR4, and leptin in adipose tissue relative to values in untreated groups. These data demonstrate that ACE inhibition and angiotensin receptor blockade reduce food intake to produce weight loss and suggest that the anti-inflammatory effects of ACE inhibition may be independent of weight loss.
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Affiliation(s)
| | - Shirmila D. Premaratna
- Department of Animal, Plant and Soil Sciences, School of Life Sciences, La Trobe University, Melbourne, VIC, Australia
| | - Garth Bennett
- School of Psychological Science, La Trobe University, Melbourne, VIC, Australia
| | - Maria Lambrou
- School of Psychological Science, La Trobe University, Melbourne, VIC, Australia
| | - Lauren A. Stahl
- School of Psychological Science, La Trobe University, Melbourne, VIC, Australia
| | - Markandeya Jois
- Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC, Australia
| | - Elizabeth Barber
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
| | | | - Stephen C. Woods
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States
| | - David Cameron-Smith
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore
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16
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Law CSW, Yeong KY. Repurposing Antihypertensive Drugs for the Management of Alzheimer's Disease. Curr Med Chem 2021; 28:1716-1730. [PMID: 32164502 DOI: 10.2174/0929867327666200312114223] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/04/2020] [Accepted: 02/18/2020] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that has affected millions of people worldwide. However, currently, there is no treatment to cure the disease. The AD drugs available in the market only manage the disease symptomatically and the effects are usually short-term. Thus, there is a need to look at alternatives AD therapies. This literature review aims to shed some light on the potential of repurposing antihypertensives to treat AD. Mid-life hypertension has not only been recognised as a risk factor for AD, but its relation with AD has also been well established. Hence, antihypertensives were postulated to be beneficial in managing AD. Four classes of antihypertensives, as well as their potential limitations and prospects in being utilised as AD therapeutics, were discussed in this review.
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Affiliation(s)
- Christine Shing Wei Law
- School of Science, Monash University Malaysia Campus, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia
| | - Keng Yoon Yeong
- School of Science, Monash University Malaysia Campus, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia
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17
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Jinawong K, Apaijai N, Chattipakorn N, Chattipakorn SC. Cognitive impairment in myocardial infarction and heart failure. Acta Physiol (Oxf) 2021; 232:e13642. [PMID: 33656800 DOI: 10.1111/apha.13642] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/28/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022]
Abstract
Myocardial infarction (MI) occurs when coronary blood flow is decreased due to an obstruction/occlusion of the vessels, leading to myocardial death and progression to heart failure (HF). Cognitive impairment, anxiety, depression and memory loss are the most frequent mental health problems among patients with HF. The most common cause of cognitive decline is cardiac systolic dysfunction, which leads to reduced cerebral perfusion. Several in vivo and clinical studies provide information regarding the underlying mechanisms of HF in brain pathology. Neurohormonal activation, oxidative stress, inflammation, glial activation, dendritic spine loss and brain programmed cell death are all proposed as contributors of cognitive impairment in HF. Furthermore, several investigations into the effects of various medications on brain pathology utilizing MI models have been reported. In this review, potential mechanisms involving HF-associated cognitive impairment, as well as neuroprotective interventions in HF models, are discussed and summarized. In addition, gaps in the surrounding knowledge, including the types of brain cell death and the effects of cell death inhibitors in HF, are presented and discussed. This review provides valuable information that will suggest the potential therapeutic strategies for cognitive impairment in patients with HF.
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Affiliation(s)
- Kewarin Jinawong
- Neurophysiology Unit Cardiac Electrophysiology Research and Training Center Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University Chiang Mai Thailand
- Cardiac Electrophysiology Unit Department of Physiology Faculty of Medicine Chiang Mai University Chiang Mai Thailand
| | - Nattayaporn Apaijai
- Neurophysiology Unit Cardiac Electrophysiology Research and Training Center Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University Chiang Mai Thailand
- Cardiac Electrophysiology Unit Department of Physiology Faculty of Medicine Chiang Mai University Chiang Mai Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit Cardiac Electrophysiology Research and Training Center Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University Chiang Mai Thailand
- Cardiac Electrophysiology Unit Department of Physiology Faculty of Medicine Chiang Mai University Chiang Mai Thailand
| | - Siriporn C. Chattipakorn
- Neurophysiology Unit Cardiac Electrophysiology Research and Training Center Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University Chiang Mai Thailand
- Department of Oral Biology and Diagnostic Sciences Faculty of Dentistry Chiang Mai University Chiang Mai Thailand
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18
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Hernandez AR, Banerjee A, Carter CS, Buford TW. Angiotensin (1-7) Expressing Probiotic as a Potential Treatment for Dementia. FRONTIERS IN AGING 2021; 2:629164. [PMID: 34901930 PMCID: PMC8663799 DOI: 10.3389/fragi.2021.629164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/05/2021] [Indexed: 12/12/2022]
Abstract
Increasing life expectancies are unfortunately accompanied by increased prevalence of Alzheimer's disease (AD). Regrettably, there are no current therapeutic options capable of preventing or treating AD. We review here data indicating that AD is accompanied by gut dysbiosis and impaired renin angiotensin system (RAS) function. Therefore, we propose the potential utility of an intervention targeting both the gut microbiome and RAS as both are heavily involved in proper CNS function. One potential approach which our group is currently exploring is the use of genetically-modified probiotics (GMPs) to deliver therapeutic compounds. In this review, we specifically highlight the potential utility of utilizing a GMP to deliver Angiotensin (1-7), a beneficial component of the renin-angiotensin system with relevant functions in circulation as well as locally in the gut and brain.
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Affiliation(s)
- Abbi R. Hernandez
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Anisha Banerjee
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Christy S. Carter
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, United States
- Nathan Shock Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Thomas W. Buford
- Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, United States
- Nathan Shock Center, University of Alabama at Birmingham, Birmingham, AL, United States
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19
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Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Rescue Memory Defects in Drosophila-Expressing Alzheimer's Disease-Related Transgenes Independently of the Canonical Renin Angiotensin System. eNeuro 2020; 7:ENEURO.0235-20.2020. [PMID: 33060184 PMCID: PMC7768280 DOI: 10.1523/eneuro.0235-20.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 01/09/2023] Open
Abstract
Alzheimer's disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, we used a genetic and pharmacological approach to evaluate the beneficial effects of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila, other RAS components are not conserved. We show that captopril, an ACE-I, and losartan, an ARB, can suppress a rough eye phenotype and brain cell death in flies expressing a mutant human C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human Aβ42 and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of Aβ42 Importantly, neither drug rescued brain cell death in Drosophila expressing human Tau, suggesting that RAS inhibitors specifically target the amyloid pathway. Of note, we also observed reduced cell death and a complete rescue of memory deficits when we crossed a null mutation in Drosophila Acer into each transgenic line demonstrating that the target of captopril in Drosophila is Acer. Together, these studies demonstrate that captopril and losartan are able to modulate AD related phenotypes in the absence of the canonical RAS pathway and suggest that both drugs have additional targets that can be identified in Drosophila.
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20
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Panariello F, Cellini L, Speciani M, De Ronchi D, Atti AR. How Does SARS-CoV-2 Affect the Central Nervous System? A Working Hypothesis. Front Psychiatry 2020; 11:582345. [PMID: 33304284 PMCID: PMC7701095 DOI: 10.3389/fpsyt.2020.582345] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 10/07/2020] [Indexed: 12/15/2022] Open
Abstract
Interstitial pneumonia was the first manifestation to be recognized as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, in just a few weeks, it became clear that the coronavirus disease-2019 (COVID-19) overrun tissues and more body organs than just the lungs, so much so that it could be considered a systemic pathology. Several studies reported the involvement of the conjunctiva, the gut, the heart and its pace, and vascular injuries such as thromboembolic complications and Kawasaki disease in children and toddlers were also described. More recently, it was reported that in a sample of 214 SARS-CoV-2 positive patients, 36.4% complained of neurological symptoms ranging from non-specific manifestations (dizziness, headache, and seizures), to more specific symptoms such hyposmia or hypogeusia, and stroke. Older individuals, especially males with comorbidities, appear to be at the highest risk of developing such severe complications related to the Central Nervous System (CNS) involvement. Neuropsychiatric manifestations in COVID-19 appear to develop in patients with and without pre-existing neurological disorders. Growing evidence suggests that SARS-CoV-2 binds to the human Angiotensin-Converting Enzyme 2 (ACE2) for the attachment and entrance inside host cells. By describing ACE2 and the whole Renin Angiotensin Aldosterone System (RAAS) we may better understand whether specific cell types may be affected by SARS-CoV-2 and whether their functioning can be disrupted in case of an infection. Since clear evidences of neurological interest have already been shown, by clarifying the topographical distribution and density of ACE2, we will be able to speculate how SARS-CoV-2 may affect the CNS and what is the pathogenetic mechanism by which it contributes to the specific clinical manifestations of the disease. Based on such evidences, we finally hypothesize the process of SARS-CoV-2 invasion of the CNS and provide a possible explanation for the onset or the exacerbation of some common neuropsychiatric disorders in the elderly including cognitive impairment and Alzheimer disease.
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Affiliation(s)
- Fabio Panariello
- Department of Mental Health, Local Health Authorities, Bologna, Italy
| | - Lorenzo Cellini
- Department of Biomedical and Neuromotor Sciences, Psychiatry, Bologna University, Bologna, Italy
| | - Maurizio Speciani
- Department of Biomedical and Neuromotor Sciences, Psychiatry, Bologna University, Bologna, Italy
| | - Diana De Ronchi
- Department of Biomedical and Neuromotor Sciences, Psychiatry, Bologna University, Bologna, Italy
| | - Anna Rita Atti
- Department of Biomedical and Neuromotor Sciences, Psychiatry, Bologna University, Bologna, Italy
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21
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Hegazy N, Rezq S, Fahmy A. Mechanisms Involved in Superiority of Angiotensin Receptor Blockade over ACE Inhibition in Attenuating Neuropathic Pain Induced in Rats. Neurotherapeutics 2020; 17:1031-1047. [PMID: 32804335 PMCID: PMC7609714 DOI: 10.1007/s13311-020-00912-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Although previous reports described the beneficial role of angiotensin-converting enzyme inhibitors (ACE-Is) or AT1 receptor blockers (ARBs) in attenuating neuropathic pain (NP), no study has yet explored the exact underlying mechanisms, as well as the superiority of using centrally versus peripherally acting renin-angiotensin-aldosterone system (RAAS) drugs in NP. We investigated the effects of 14 days of treatment with centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) acting ARBs and ACE-Is, respectively, in attenuating peripheral NP induced by sciatic nerve chronic constriction injury (CCI) in rats. We also compared these with the effects of pregabalin, the standard treatment for NP. Behavioral changes, inflammatory markers (NFкB, TNF-α, COX-2, PGE2, and bradykinin), oxidative stress markers (NADPH oxidase and catalase), STAT3 activation, levels of phosphorylated P38-MAPK, ACE, AT1 receptor (AT1R), and AT2 receptor (AT2R), as well as histopathological features, were assessed in the brainstem and sciatic nerve. CCI resulted in clear pain-related behavior along with increased levels of inflammatory and oxidative stress markers, and STAT3 activity, as well as increased levels of phosphorylated P38-MAPK, ACE, AT1R, and AT2R, along with worsened histopathological findings in both the brainstem and sciatic nerve. ARBs improved both animal behavior and all measured parameters in CCI rats and were more effective than ACE-Is. At the tested doses, centrally acting ARBs or ACE-Is were not superior to the peripherally acting drugs of the same category. These findings suggest that ARBs (centrally or peripherally acting) are an effective treatment modality for NP.
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Affiliation(s)
- Nora Hegazy
- Department of Pharmacology and Toxicology, School of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Samar Rezq
- Department of Pharmacology and Toxicology, School of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, 39216, MS, USA.
| | - Ahmed Fahmy
- Department of Pharmacology and Toxicology, School of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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22
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Oboh G, Adedayo BC, Adetola MB, Oyeleye IS, Ogunsuyi OB. Characterization and neuroprotective properties of alkaloid extract ofVernonia amygdalinaDelile in experimental models of Alzheimer’s disease. Drug Chem Toxicol 2020; 45:731-740. [DOI: 10.1080/01480545.2020.1773845] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Ganiyu Oboh
- Functional Foods and Nutraceuticals Unit of Biochemistry Department, Federal University of Technology, Akure, Nigeria
| | - Bukola Christiana Adedayo
- Functional Foods and Nutraceuticals Unit of Biochemistry Department, Federal University of Technology, Akure, Nigeria
| | - Mayowa Blessing Adetola
- Functional Foods and Nutraceuticals Unit of Biochemistry Department, Federal University of Technology, Akure, Nigeria
| | - Idowu Sunday Oyeleye
- Functional Foods and Nutraceuticals Unit of Biochemistry Department, Federal University of Technology, Akure, Nigeria
- Department of Biomedical Technology, Federal University of Technology, Akure, Nigeria
| | - Opeyemi Babatunde Ogunsuyi
- Functional Foods and Nutraceuticals Unit of Biochemistry Department, Federal University of Technology, Akure, Nigeria
- Department of Biomedical Technology, Federal University of Technology, Akure, Nigeria
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23
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Banu N, Panikar SS, Leal LR, Leal AR. Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications. Life Sci 2020; 256:117905. [PMID: 32504757 PMCID: PMC7832382 DOI: 10.1016/j.lfs.2020.117905] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023]
Abstract
In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication.
Protective role of ACE2 in the organs and system Downregulation of ACE2 expression by SARS-CoV-2 leads to Ang II-induced organ damage. The appearance of MAS in COVID-19 patient Suggested treatment to diminish the deleterious effect of Ang II or appearance of MAS
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Affiliation(s)
- Nehla Banu
- Instituto de Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sandeep Surendra Panikar
- Centro de Física Aplicada y Tecnología Avanzada, Universidad Nacional Autonoma de México (UNAM), Apartado Postal 1-1010, Queretaro, Queretaro 76000, Mexico
| | - Lizbeth Riera Leal
- Hospital General Regional número 45, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Annie Riera Leal
- UC DAVIS Institute for Regenerative Cure, Department of Dermatology, University of California, 2921 Stockton Blvd, Rm 1630, 95817 Sacramento, CA, USA.
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24
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Raven PB, Young BE, Fadel PJ. Arterial Baroreflex Resetting During Exercise in Humans: Underlying Signaling Mechanisms. Exerc Sport Sci Rev 2020; 47:129-141. [PMID: 30921029 DOI: 10.1249/jes.0000000000000190] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The arterial baroreflex (ABR) resets during exercise in an intensity-dependent manner to operate around a higher blood pressure with maintained sensitivity. This review provides a historical perspective of ABR resetting and the involvement of other neural reflexes in mediating exercise resetting. Furthermore, we discuss potential underlying signaling mechanisms that may contribute to exercise ABR resetting in physiological and pathophysiological conditions.
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Affiliation(s)
- Peter B Raven
- Department of Integrative Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth
| | - Benjamin E Young
- Department of Kinesiology, University of Texas at Arlington, Arlington, TX
| | - Paul J Fadel
- Department of Kinesiology, University of Texas at Arlington, Arlington, TX
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25
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Ayabe T, Fukuda T, Ano Y. Improving Effects of Hop-Derived Bitter Acids in Beer on Cognitive Functions: A New Strategy for Vagus Nerve Stimulation. Biomolecules 2020; 10:E131. [PMID: 31940997 PMCID: PMC7022854 DOI: 10.3390/biom10010131] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/10/2020] [Accepted: 01/11/2020] [Indexed: 12/22/2022] Open
Abstract
Dementia and cognitive decline are global public health problems. Moderate consumption of alcoholic beverages reduces the risk of dementia and cognitive decline. For instance, resveratrol, a polyphenolic compound found in red wine, has been well studied and reported to prevent dementia and cognitive decline. However, the effects of specific beer constituents on cognitive function have not been investigated in as much detail. In the present review, we discuss the latest reports on the effects and underlying mechanisms of hop-derived bitter acids found in beer. Iso-α-acids (IAAs), the main bitter components of beer, enhance hippocampus-dependent memory and prefrontal cortex-associated cognitive function via dopamine neurotransmission activation. Matured hop bitter acids (MHBAs), oxidized components with β-carbonyl moieties derived from aged hops, also enhance memory functions via norepinephrine neurotransmission-mediated mechanisms. Furthermore, the effects of both IAAs and MHBAs are attenuated by vagotomy, suggesting that these bitter acids enhance cognitive function via vagus nerve stimulation. Moreover, supplementation with IAAs attenuates neuroinflammation and cognitive impairments in various rodent models of neurodegeneration including Alzheimer's disease. Daily supplementation with hop-derived bitter acids (e.g., 35 mg/day of MHBAs) may be a safe and effective strategy to stimulate the vagus nerve and thus enhance cognitive function.
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Affiliation(s)
- Tatsuhiro Ayabe
- Research Laboratories for Health Science & Food Technologies, Kirin Company Ltd., 1-13-5 Fukuura Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan; (T.F.); (Y.A.)
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26
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Telmisartan Protects Against Aluminum-Induced Alzheimer-like Pathological Changes in Rats. Neurotox Res 2019; 37:275-285. [PMID: 31332715 DOI: 10.1007/s12640-019-00085-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 06/23/2019] [Accepted: 06/28/2019] [Indexed: 12/23/2022]
Abstract
Currently, there is no effective mean for treatment or prevention of Alzheimer's disease (AD). Commonly used AD drugs have a moderate effect and treat only the associated symptoms, therefore there is a strong need to search for more effective agents. Our goal is to examine telmisartan neuroprotective effect in aluminum-induced cognitive impairment in rats. Aluminum chloride (10 mg/kg, i.p) was administered for 2 months then behavioral tests (Y-maze and Morris water maze) were done. Hippocampal biochemical and histological analysis were then carried out. AD-like histological, biochemical, and behavioral alterations appeared in aluminum-treated rats. Telmisartan improved rats' condition on behavioral and histological levels. It reversed the increase in hippocampal amyloid beta protein, phosphorylated tau protein contents together with augmentation of neprilysin level, it also diminished levels of nuclear factor kappa-B, FAS ligand, tumor necrosis factor-alpha, malondialdehyde, and acetylcholinesterase content.These findings show the protective action of telmisartan against AD-like pathological alterations.
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27
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Kehoe PG. The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment? J Alzheimers Dis 2019; 62:1443-1466. [PMID: 29562545 PMCID: PMC5870007 DOI: 10.3233/jad-171119] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
There is wide recognition of a complex association between midlife hypertension and cardiovascular disease and later development of Alzheimer’s disease (AD) and cognitive impairment. While significant progress has been made in reducing rates of mortality and morbidity due to cardiovascular disease over the last thirty years, progress towards effective treatments for AD has been slower. Despite the known association between hypertension and dementia, research into each disease has largely been undertaken in parallel and independently. Yet over the last decade and a half, the emergence of converging findings from pre-clinical and clinical research has shown how the renin angiotensin system (RAS), which is very important in blood pressure regulation and cardiovascular disease, warrants careful consideration in the pathogenesis of AD. Numerous components of the RAS have now been found to be altered in AD such that the multifunctional and potent vasoconstrictor angiotensin II, and similarly acting angiotensin III, are greatly altered at the expense of other RAS signaling peptides considered to contribute to neuronal and cognitive function. Collectively these changes may contribute to many of the neuropathological hallmarks of AD, as well as observed progressive deficiencies in cognitive function, while also linking elements of a number of the proposed hypotheses for the cause of AD. This review discusses the emergence of the RAS and its likely importance in AD, not only because of the multiple facets of its involvement, but also perhaps fortuitously because of the ready availability of numerous RAS-acting drugs, that could be repurposed as interventions in AD.
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Affiliation(s)
- Patrick Gavin Kehoe
- Dementia Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Southmead Hospital, Bristol, UK
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28
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Quitterer U, AbdAlla S. Improvements of symptoms of Alzheimer`s disease by inhibition of the angiotensin system. Pharmacol Res 2019; 154:104230. [PMID: 30991105 DOI: 10.1016/j.phrs.2019.04.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 04/10/2019] [Accepted: 04/11/2019] [Indexed: 01/30/2023]
Abstract
With ageing of the global society, the frequency of ageing-related neurodegenerative diseases such as Alzheimer`s disease (AD) is on the rise worldwide. Currently, there is no cure for AD, and the four drugs approved for AD only have very small effects on AD symptoms. Consequently, there are enormous efforts worldwide to identify new targets for treatment of AD. Approaches that interfere with classical neuropathologic features of AD, such as extracellular senile plaques formed of aggregated amyloid-beta (Abeta), and intracellular neurofibrillary tangles of hyperphosphorylated tau have not been successful so far. In search for a treatment approach of AD, we found that inhibition of the angiotensin-converting enzyme (ACE) by a centrally acting ACE inhibitor retards symptoms of neurodegeneration, Abeta plaque formation and tau hyperphosphorylation in experimental models of AD. Our approach is currently being investigated in a clinical setting. Initial evidence with AD patients shows that a brain-penetrating ACE inhibitor counteracts the process of neurodegeneration and dementia. Moreover, centrally acting ACE inhibitors given in addition to the standard therapy, cholinesterase inhibition, can improve cognitive function of AD patients for several months. This is one of the most promising results for AD treatment since more than a decade.
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Affiliation(s)
- Ursula Quitterer
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland; Institute of Pharmacology and Toxicology, Department of Medicine, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
| | - Said AbdAlla
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
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29
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Ayabe T, Ohya R, Ano Y. Hop-Derived Iso-α-Acids in Beer Improve Visual Discrimination and Reversal Learning in Mice as Assessed by a Touch Panel Operant System. Front Behav Neurosci 2019; 13:67. [PMID: 31001094 PMCID: PMC6454052 DOI: 10.3389/fnbeh.2019.00067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 03/15/2019] [Indexed: 12/31/2022] Open
Abstract
Dementia and cognitive decline have become worldwide health problems due to rapid growth of the aged population in many countries. We previously demonstrated that single or short-term administration of iso-α-acids, hop-derived bitter acids in beer, improves the spatial memory of scopolamine-induced amnesia model mice in the Y-maze and enhances novel object recognition in normal mice via activation of the vagus nerve and hippocampal dopaminergic system. However, these behavioral tests do not replicate the stimulus conditions or response requirements of human memory tests, and so may have poor translational validity. In this report, we investigated the effects of iso-α-acids on visual discrimination (VD) and reversal discrimination (RD) using a touch panel-based operant system similar to that used for human working memory tests. In the VD task, scopolamine treatment reduced correct response rate and prolonged response latency in mice, deficits reversed by prior oral administration of iso-α-acids. In the RD task, administration of iso-α-acids significantly increased correct response rate compared to vehicle administration. Previous studies have reported that dopamine signaling is involved in both VD and RD learning, suggesting that enhancement of dopamine release contributes to improved memory performance in mice treated with iso-α-acids. Taken together, iso-α-acids improve VD and RD learning, which are considered high-order cognitive functions. Given the translational advantages of the touch panel-based operant system, the present study suggests that iso-α-acids could be effective for improvement of working memory in human dementia patients.
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Affiliation(s)
- Tatsuhiro Ayabe
- Research Laboratories for Health Science & Food Technologies, Kirin Company Ltd., Yokohama, Japan
| | - Rena Ohya
- Research Laboratories for Health Science & Food Technologies, Kirin Company Ltd., Yokohama, Japan
| | - Yasuhisa Ano
- Research Laboratories for Health Science & Food Technologies, Kirin Company Ltd., Yokohama, Japan
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30
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Fouda AY, Fagan SC, Ergul A. Brain Vasculature and Cognition. Arterioscler Thromb Vasc Biol 2019; 39:593-602. [PMID: 30816798 PMCID: PMC6540805 DOI: 10.1161/atvbaha.118.311906] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/15/2019] [Indexed: 12/18/2022]
Abstract
There is a complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of cerebrovascular function and integrity has a central role in this sophisticated communication within the brain, and any derangements can have deleterious acute and chronic consequences. In almost all forms of cognitive impairment, from mild to Alzheimer disease, there are changes in cerebrovascular function and structure leading to decreased cerebral blood flow, which may initiate or worsen cognitive impairment. In this focused review, we discuss the contribution of 2 major vasoactive pathways to cerebrovascular dysfunction and cognitive impairment in an effort to identify early intervention strategies.
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Affiliation(s)
- Abdelrahman Y. Fouda
- Vascular Biology Center, Augusta University, GA
- Charlie Norwood VA Medical Center Augusta, GA
| | - Susan C. Fagan
- Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, GA
- Charlie Norwood VA Medical Center Augusta, GA
| | - Adviye Ergul
- Ralph Johnson Veterans Administration Medical Center, Medical University of South Carolina, Charleston, SC
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
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31
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Matured Hop-Derived Bitter Components in Beer Improve Hippocampus-Dependent Memory Through Activation of the Vagus Nerve. Sci Rep 2018; 8:15372. [PMID: 30337611 PMCID: PMC6194057 DOI: 10.1038/s41598-018-33866-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/05/2018] [Indexed: 12/15/2022] Open
Abstract
Improving and maintaining memory function is effective in preventing cognitive decline and dementia. Previously, we demonstrated that iso-α-acids, the hop-derived bitter components in beer, prevent cognitive impairment in an Alzheimer’s disease mouse model. In this report, we investigated the effects of matured hop bitter acids (MHBA) containing components of oxides derived from α- and β-acids, and structurally similar to iso-α-acids, on cognitive function using behavioral pharmacological procedures. MHBA and the representative components of MHBA, 4′-hydroxyallohumulinone (HAH) and 4′-hydroxy-cis-alloisohumulone (HAIH) improved spatial working memory in scopolamine-induced amnesia mice. MHBA also enhanced episodic memory in the novel object recognition test (NORT). The administration of MHBA increased the amount of norepinephrine (NE) and NE release into cerebrospinal fluid (CSF) in hippocampus. The MHBA activity in improving memory function was attenuated by treatment with a β-adrenergic receptor inhibitor. In addition, vagotomized mice did not display the memory improvement induced by MHBA. Together, our results suggest that MHBA improves memory function via stimulation of the vagus nerve and enhancement of NE release in the hippocampus. Vagus nerve activation by the intake of food materials including MHBA may be a safe and effective approach for improving cognitive function.
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32
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Moralez G, Jouett NP, Tian J, Zimmerman MC, Bhella P, Raven PB. Effect of centrally acting angiotensin converting enzyme inhibitor on the exercise-induced increases in muscle sympathetic nerve activity. J Physiol 2018; 596:2315-2332. [PMID: 29635787 PMCID: PMC6002210 DOI: 10.1113/jp274697] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 03/21/2018] [Indexed: 01/01/2023] Open
Abstract
KEY POINTS The arterial baroreflex's operating point pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. The intraneural pathways and signalling mechanisms that lead to upwards and rightwards resetting of the operating point pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. We tested the hypothesis that the central production of angiotensin II during dynamic exercise mediates the increases in sympathetic outflow and, therefore, the arterial baroreflex operating point pressure resetting during acute and prolonged dynamic exercise. The results identify that perindopril, a centrally acting angiotensin converting enzyme inhibitor, markedly attenuates the central sympathetic outflow during acute and prolonged dynamic exercise. ABSTRACT We tested the hypothesis that the signalling mechanisms associated with the dynamic exercise intensity related increases in muscle sympathetic nerve activity (MSNA) and arterial baroreflex resetting during exercise are located within the central nervous system. Participants performed three randomly ordered trials of 70° upright back-supported dynamic leg cycling after ingestion of placebo and two different lipid soluble angiotensin converting enzyme inhibitors (ACEi): perindopril (high lipid solubility), captopril (low lipid solubility). Repeated measurements of whole venous blood (n = 8), MSNA (n = 7) and arterial blood pressures (n = 14) were obtained at rest and during an acute (SS1) and prolonged (SS2) bout of steady state dynamic exercise. Arterial baroreflex function curves were modelled at rest and during exercise. Peripheral venous superoxide concentrations measured by electron spin resonance spectroscopy were elevated during exercise and were not altered by ACEi at rest (P ≥ 0.4) or during exercise (P ≥ 0.3). Baseline MSNA and mean arterial pressure were unchanged at rest (P ≥ 0.1; P ≥ 0.8, respectively). However, during both SS1 and SS2, the centrally acting ACEi perindopril attenuated MSNA compared to captopril and the placebo (P < 0.05). Arterial pressures at the operating point and threshold pressures were decreased with perindopril from baseline to SS1 with no further changes in the operating point pressure during SS2 under all three conditions. These data suggest that centrally acting ACEi is significantly more effective at attenuating the increase in the acute and prolonged exercise-induced increases in MSNA.
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Affiliation(s)
- Gilbert Moralez
- Institute for Cardiovascular and Metabolic DiseaseUniversity of North Texas Health Science CenterFort WorthTXUSA
- Institute for Exercise and Environmental MedicineTexas Health Presbyterian Hospital Dallas and The University of Texas Southwestern Medical CenterDallasTXUSA
| | - Noah P. Jouett
- Institute for Cardiovascular and Metabolic DiseaseUniversity of North Texas Health Science CenterFort WorthTXUSA
| | - Jun Tian
- Department of Cellular and Integrative PhysiologyUniversity of Nebraska Medical CenterOmahaNEUSA
| | - Matthew C. Zimmerman
- Department of Cellular and Integrative PhysiologyUniversity of Nebraska Medical CenterOmahaNEUSA
| | - Paul Bhella
- Department of Cardiac Imaging at the John Peter Smith Health NetworkFort WorthTXUSA
- Department of Internal MedicineTCU and UNTHSC School of MedicineFort WorthTXUSA
| | - Peter B. Raven
- Institute for Cardiovascular and Metabolic DiseaseUniversity of North Texas Health Science CenterFort WorthTXUSA
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33
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Kugaevskaya EV, Veselovsky AV, Indeykina MI, Solovyeva NI, Zharkova MS, Popov IA, Nikolaev EN, Mantsyzov AB, Makarov AA, Kozin SA. N-domain of angiotensin-converting enzyme hydrolyzes human and rat amyloid-β(1-16) peptides as arginine specific endopeptidase potentially enhancing risk of Alzheimer's disease. Sci Rep 2018; 8:298. [PMID: 29321566 PMCID: PMC5762728 DOI: 10.1038/s41598-017-18567-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 12/13/2017] [Indexed: 01/28/2023] Open
Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. Amyloid-β (Aβ) aggregation is likely to be the major cause of AD. In contrast to humans and other mammals, that share the same Aβ sequence, rats and mice are invulnerable to AD-like neurodegenerative pathologies, and Aβ of these rodents (ratAβ) has three amino acid substitutions in the metal-binding domain 1-16 (MBD). Angiotensin-converting enzyme (ACE) cleaves Aβ-derived peptide substrates, however, there are contradictions concerning the localization of the cleavage sites within Aβ and the roles of each of the two ACE catalytically active domains in the hydrolysis. In the current study by using mass spectrometry and molecular modelling we have tested a set of peptides corresponding to MBDs of Aβ and ratAβ to get insights on the interactions between ACE and these Aβ species. It has been shown that the N-domain of ACE (N-ACE) acts as an arginine specific endopeptidase on the Aβ and ratAβ MBDs with C-amidated termini, thus assuming that full-length Aβ and ratAβ can be hydrolyzed by N-ACE in the same endopeptidase mode. Taken together with the recent data on the molecular mechanism of zinc-dependent oligomerization of Aβ, our results suggest a modulating role of N-ACE in AD pathogenesis.
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Affiliation(s)
| | | | - Maria I Indeykina
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia.,Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia.,Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow Region, Russia
| | | | | | - Igor A Popov
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia.,Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia.,Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow Region, Russia
| | - Eugene N Nikolaev
- Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia.,Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow Region, Russia.,Skolkovo Institute of Science and technology, Moscow, Russia
| | - Alexey B Mantsyzov
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Alexander A Makarov
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Sergey A Kozin
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia.
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34
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Relationship Between Antihypertensive Medications and Cognitive Impairment: Part II. Review of Physiology and Animal Studies. Curr Hypertens Rep 2017; 18:66. [PMID: 27492369 PMCID: PMC4988998 DOI: 10.1007/s11906-016-0673-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
PURPOSE OF REVIEW There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer's disease; however, associations between antihypertensive medications (AHM) and dementia risk are less clear. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews provide comprehensive review. Our extensive review includes 24 mechanistic animal and human studies published over the last 5 years assessing relationship between AHM and cognitive function. RECENT FINDINGS All classes of AHM showed similar result patterns in animal studies. The mechanism by which AHM exert their effect was extensively studied by evaluating well-established pathways of AD disease process, including amyloid beta (Aβ), vascular, oxidative stress and inflammation pathways, but only few studies evaluated the blood pressure lowering effect on the AD disease process. Methodological limitations of the studies prevent comprehensive conclusions prior to further work evaluating AHM in animals and larger human observational studies, and selecting those with promising results for future RCTs.
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35
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Wiesmann M, Roelofs M, van der Lugt R, Heerschap A, Kiliaan AJ, Claassen JAHR. Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease. J Cereb Blood Flow Metab 2017; 37:2396-2413. [PMID: 27596834 PMCID: PMC5531339 DOI: 10.1177/0271678x16667364] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 07/26/2016] [Accepted: 08/08/2016] [Indexed: 12/11/2022]
Abstract
Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AβPPswe/PS1ΔE9 (AβPP/PS1/Alzheimer's disease) mice. AβPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aβ nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.
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Affiliation(s)
- Maximilian Wiesmann
- Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands
- Department of Geriatric Medicine, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Monica Roelofs
- Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Robert van der Lugt
- Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Arend Heerschap
- Department of Radiology & Nuclear Medicine, Radboud university medical center, Nijmegen, The Netherlands
| | - Amanda J Kiliaan
- Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Jurgen AHR Claassen
- Department of Geriatric Medicine, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands
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36
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Administration of bovine casein-derived peptide prevents cognitive decline in Alzheimer disease model mice. PLoS One 2017; 12:e0171515. [PMID: 28158298 PMCID: PMC5291428 DOI: 10.1371/journal.pone.0171515] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 01/03/2017] [Indexed: 01/07/2023] Open
Abstract
There is a growing interest in identifying natural food ingredients that may serve to prevent dementia such as that due to Alzheimer disease (AD). Peptides derived from food proteins have been demonstrated to have various physiological activities such as a hypotensive action. Recent findings have indicated possible associations of hypertension with AD progression, and suggest that angiotensin converting enzyme (ACE) inhibitors with potential to pass through the blood brain barrier (BBB) may reduce the risk of AD. In this study, we investigated the effect of milk peptide (CH-3) on cognitive function in AD model mice. CH-3 contains a tripeptide (methionine-lysine-proline, MKP) that has been found to have a strong ACE inhibitory effect and the potential to pass through the BBB. Adult male ddY mice were used in this study, and an animal model of AD was induced by intracerebroventricular (ICV) injection of Aβ1-42. CH-3 (250 mg/kg/day) or MKP (0.5 mg/kg/day) was orally administered every day starting 2 days before ICV injection. At 3 weeks after ICV injection, cognitive function was evaluated by the Morris water maze test. Brain samples were obtained after behavioral testing, and expression of inflammatory cytokines and NADPH oxidase subunits was measured by real-time quantitative RT-PCR. ICV injection of Aβ1-42 significantly impaired cognitive function compared with that in PBS-injected mice. Daily administration of CH-3 markedly attenuated this Aβ1-42-induced cognitive decline. Aβ1-42 injection significantly enhanced the expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and p22phox in the mouse hippocampus compared with PBS injection, and showed a tendency to increase the expression of monocyte chemoattractant protein-1 (MCP-1), p47phox and gp91phox, whereas CH-3 treatment markedly reduced Aβ1-42-induced TNF-α, MCP-1, iNOS, p47phox and gp91phox expression. Finally, administration of MKP also attenuated Aβ1-42-induced cognitive impairment with an increase in cerebral blood flow. The present study demonstrated that repeated oral administration of CH-3 to AD model mice not only improved cognitive function but also suppressed the expression of inflammatory cytokines and production of oxidative stress, and suggests its therapeutic potential for preventing cognitive impairment in AD.
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Ongali B, Nicolakakis N, Tong XK, Aboulkassim T, Imboden H, Hamel E. Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis 2016; 51:1183-95. [PMID: 26923013 DOI: 10.3233/jad-150868] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.
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Affiliation(s)
- Brice Ongali
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada
| | - Nektaria Nicolakakis
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada
| | - Xing-Kang Tong
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada
| | - Tahar Aboulkassim
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada
| | - Hans Imboden
- Institute of Cell Biology, University of Bern, Switzerland
| | - Edith Hamel
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada
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Kehoe PG, Wong S, Al Mulhim N, Palmer LE, Miners JS. Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology. ALZHEIMERS RESEARCH & THERAPY 2016; 8:50. [PMID: 27884212 PMCID: PMC5123239 DOI: 10.1186/s13195-016-0217-7] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 10/20/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer's disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1-7 (Ang (1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity. METHODS We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. RESULTS ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = -0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = -0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = -0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1-7) (a proxy measure of ACE-2 activity indicating conversion of Ang II to Ang (1-7)) is reduced in AD. CONCLUSIONS Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD.
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Affiliation(s)
- Patrick Gavin Kehoe
- Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
| | - Steffenny Wong
- Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK
| | - Noura Al Mulhim
- Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK
| | - Laura Elyse Palmer
- Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK
| | - J Scott Miners
- Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
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Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer’s Disease. J Neuroimmune Pharmacol 2016; 11:774-785. [DOI: 10.1007/s11481-016-9703-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 08/17/2016] [Indexed: 10/21/2022]
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Renin-angiotensin system as a potential therapeutic target in stroke and retinopathy: experimental and clinical evidence. Clin Sci (Lond) 2016; 130:221-38. [PMID: 26769658 DOI: 10.1042/cs20150350] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
As our knowledge expands, it is now clear that the renin-angiotensin (Ang) system (RAS) mediates functions other than regulating blood pressure (BP). The RAS plays a central role in the pathophysiology of different neurovascular unit disorders including stroke and retinopathy. Moreover, the beneficial actions of RAS modulation in brain and retina have been documented in experimental research, but not yet exploited clinically. The RAS is a complex system with distinct yet interconnected components. Understanding the different RAS components and their functions under brain and retinal pathological conditions is crucial to reap their benefits. The aim of the present review is to provide an experimental and clinical update on the role of RAS in the pathophysiology and treatment of stroke and retinopathy. Combining the evidence from both these disorders allows a unique opportunity to move both fields forward.
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Ali MRAA, Abo-Youssef AMH, Messiha BAS, Khattab MM. Tempol and perindopril protect against lipopolysaccharide-induced cognition impairment and amyloidogenesis by modulating brain-derived neurotropic factor, neuroinflammation and oxido-nitrosative stress. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:637-56. [DOI: 10.1007/s00210-016-1234-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 03/21/2016] [Indexed: 01/01/2023]
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Goel R, Bhat SA, Hanif K, Nath C, Shukla R. Perindopril Attenuates Lipopolysaccharide-Induced Amyloidogenesis and Memory Impairment by Suppression of Oxidative Stress and RAGE Activation. ACS Chem Neurosci 2016; 7:206-17. [PMID: 26689453 DOI: 10.1021/acschemneuro.5b00274] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
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.
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Affiliation(s)
- Ruby Goel
- Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shahnawaz Ali Bhat
- Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Kashif Hanif
- Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Chandishwar Nath
- Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Rakesh Shukla
- Division of Pharmacology and ‡Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India
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Zhuang S, Li J, Wang X, Wang HF, Zhang WJ, Wang HY, Xing CM. Renin-angiotensin system-targeting antihypertensive drugs and risk of vascular cognitive impairment: A meta-analysis. Neurosci Lett 2016; 615:1-8. [PMID: 26797651 DOI: 10.1016/j.neulet.2016.01.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 09/25/2015] [Accepted: 01/08/2016] [Indexed: 11/19/2022]
Abstract
OBJECTIVES To evaluate the effects of renin-angiotensin system (RAS)-targeting antihypertensive drugs and its classes on the incidence of vascular cognitive impairment (VCI). METHODS Pubmed, Embase, and Cochrane Library database of selected articles, and previous systematic reviews through May 2015 were searched. Studies that evaluated the association between use of RAS-targeting drugs and VCI were included. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using fixed effects models or random effects models. RESULTS In all studies as a whole, the use of RAS-targeting drugs was significantly associated with a reduced risk of VCI (RR, 0.87; 95% CI, 0.75-0.98) and vascular dementia (VD) (RR, 0.78; 95% CI, 0.64-0.93), compared no use of RAS-targeting drugs. Subgroup analysis showed that subjects with Angiotensin-Converting Enzyme Inhibitors (ACEI) use significantly associated with a reduced incidence of VCI (RR, 0.81; 95% CI 0.70-0.91) and VD (RR, 0.75; 95% CI, 0.57-0.93); however, subjects with Angiotensin Receptor Blockers (ARB) use had not this effect on VCI (RR, 0.94; 95% CI 0.76-1.13) or VD (RR, 0.94; 95% CI, 0.45-1.44). In an analysis of subgroups, case-control studies found that the use of RAS-targeting drugs could effectively decrease the incidence of VCI (RR, 0.77; 95% CI 0.66-0.87) and VD (RR, 0.77; 95% CI, 0.66-0.88); however, the randomized trials alone showed no significant effect on the incidence of VCI (RR, 0.94; 95% CI 0.82-1.07) or VD (RR, 0.94; 95% CI, 0.35-1.53). Meanwhile, in an analysis of cognitive impairment of vascular origin (VaCI), no significant association was found between RAS-targeting drugs, ACEI, or ARB and the incidence of VaCI. CONCLUSION RAS-targeting drugs treatment may produce remarkable efficacy on reducing the incidence of VCI and VD. Meanwhile, ACEI use, rather than ARB use, significantly protects against VCI and VD incidence. However, among the classes of RAS-targeting drugs, neither ACEI nor ARB plays protective role in VaCI incidence. Further more RCTs are required to reliably establish whether RAS-targeting drugs use decreases the risk of VCI (VD and VaCI).
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Affiliation(s)
- Shan Zhuang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Jun Li
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Xin Wang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Hai-feng Wang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Wei-jie Zhang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Hong-yan Wang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Cheng-ming Xing
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.
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Gadelha A, Vendramini AM, Yonamine CM, Nering M, Berberian A, Suiama MA, Oliveira V, Lima-Landman MT, Breen G, Bressan RA, Abílio V, Hayashi MAF. Convergent evidences from human and animal studies implicate angiotensin I-converting enzyme activity in cognitive performance in schizophrenia. Transl Psychiatry 2015; 5:e691. [PMID: 26645626 PMCID: PMC5068582 DOI: 10.1038/tp.2015.181] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 08/31/2015] [Accepted: 09/19/2015] [Indexed: 01/25/2023] Open
Abstract
In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations.
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Affiliation(s)
- A Gadelha
- Integrated Laboratory of Clinical Neurosciences and Schizophrenia Program, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil
| | - A M Vendramini
- Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - C M Yonamine
- Integrated Laboratory of Clinical Neurosciences and Schizophrenia Program, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil,Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - M Nering
- Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - A Berberian
- Integrated Laboratory of Clinical Neurosciences and Schizophrenia Program, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil
| | - M A Suiama
- Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - V Oliveira
- Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brazil
| | - M T Lima-Landman
- Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - G Breen
- Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK
| | - R A Bressan
- Integrated Laboratory of Clinical Neurosciences and Schizophrenia Program, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil
| | - V Abílio
- Integrated Laboratory of Clinical Neurosciences and Schizophrenia Program, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil,Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - M A F Hayashi
- Integrated Laboratory of Clinical Neurosciences and Schizophrenia Program, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil,Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil,Departamento de Farmacologia, Universidade Federal de São Paulo, Rua 3 de maio 100, Ed. INFAR, 3rd floor, CEP 04044-020, São Paulo, Brazil. E-mail: or
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Kaur P, Muthuraman A, Kaur M. The implications of angiotensin-converting enzymes and their modulators in neurodegenerative disorders: current and future perspectives. ACS Chem Neurosci 2015; 6:508-21. [PMID: 25680080 DOI: 10.1021/cn500363g] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Angiotensin converting enzyme (ACE) is a dipeptidyl peptidase transmembrane bound enzyme. Generally, ACE inhibitors are used for the cardiovascular disorders. ACE inhibitors are primary agents for the management of hypertension, so these cannot be avoided for further use. The present Review focuses on the implications of angiotensin converting enzyme inhibitors in neurodegenerative disorders such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and diabetic neuropathy. ACE inhibitors such as ramipril, captopril, perindopril, quinapril, lisinopril, enalapril, and trandolapril have been documented to ameliorate the above neurodegenerative disorders. Neurodegeneration occurs not only by angiotensin II, but also by other endogenous factors, such as the formation of free radicals, amyloid beta, immune reactions, and activation of calcium dependent enzymes. ACE inhibitors interact with the above cellular mechanisms. Thus, these may act as a promising factor for future medicine for neurological disorders beyond the cardiovascular actions. Central acting ACE inhibitors can be useful in the future for the management of neuropathic pain due to following actions: (i) ACE-2 converts angiotensinogen to angiotensin(1-7) (hepatapeptide) which produces neuroprotective action; (ii) ACE inhibitors downregulate kinin B1 receptors in the peripheral nervous system which is responsible for neuropathic pain. However, more extensive research is required in the field of neuropathic pain for the utilization of ACE inhibitors in human.
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Affiliation(s)
- Parneet Kaur
- Department of Pharmacology and Toxicology, Neurodegenerative Research Division, Akal College of Pharmacy & Technical Education, Mastuana Sahib, Sangrur-148001, Punjab, India
| | - Arunachalam Muthuraman
- Department of Pharmacology and Toxicology, Neurodegenerative Research Division, Akal College of Pharmacy & Technical Education, Mastuana Sahib, Sangrur-148001, Punjab, India
| | - Manjinder Kaur
- Department of Pharmacology and Toxicology, Neurodegenerative Research Division, Akal College of Pharmacy & Technical Education, Mastuana Sahib, Sangrur-148001, Punjab, India
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Ano Y, Ozawa M, Kutsukake T, Sugiyama S, Uchida K, Yoshida A, Nakayama H. Preventive effects of a fermented dairy product against Alzheimer's disease and identification of a novel oleamide with enhanced microglial phagocytosis and anti-inflammatory activity. PLoS One 2015; 10:e0118512. [PMID: 25760987 PMCID: PMC4356537 DOI: 10.1371/journal.pone.0118512] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 01/19/2015] [Indexed: 11/24/2022] Open
Abstract
Despite the ever-increasing number of patients with dementia worldwide, fundamental therapeutic approaches to this condition have not been established. Epidemiological studies suggest that intake of fermented dairy products prevents cognitive decline in the elderly. However, the active compounds responsible for the effect remain to be elucidated. The present study aims to elucidate the preventive effects of dairy products on Alzheimer’s disease and to identify the responsible component. Here, in a mouse model of Alzheimer’s disease (5xFAD), intake of a dairy product fermented with Penicillium candidum had preventive effects on the disease by reducing the accumulation of amyloid β (Aβ) and hippocampal inflammation (TNF-α and MIP-1α production), and enhancing hippocampal neurotrophic factors (BDNF and GDNF). A search for preventive substances in the fermented dairy product identified oleamide as a novel dual-active component that enhanced microglial Aβ phagocytosis and anti-inflammatory activity towards LPS stimulation in vitro and in vivo. During the fermentation, oleamide was synthesized from oleic acid, which is an abundant component of general dairy products owing to lipase enzymatic amidation. The present study has demonstrated the preventive effect of dairy products on Alzheimer’s disease, which was previously reported only epidemiologically. Moreover, oleamide has been identified as an active component of dairy products that is considered to reduce Aβ accumulation via enhanced microglial phagocytosis, and to suppress microglial inflammation after Aβ deposition. Because fermented dairy products such as camembert cheese are easy to ingest safely as a daily meal, their consumption might represent a preventive strategy for dementia.
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Affiliation(s)
- Yasuhisa Ano
- Central Laboratories for Key Technologies, Kirin Company Ltd., 1–13–5 Fukuura Kanazawa-ku, Yokohama-shi, Kanagawa, 236–0004, Japan
- * E-mail:
| | - Makiko Ozawa
- Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1–1–1 Yayoi, Bunkyo-ku, Tokyo, 113–8657, Japan
| | - Toshiko Kutsukake
- Central Laboratories for Key Technologies, Kirin Company Ltd., 1–13–5 Fukuura Kanazawa-ku, Yokohama-shi, Kanagawa, 236–0004, Japan
| | - Shinya Sugiyama
- Koiwai Dairy Products Co., Ltd., 36–1 Maruyachi, Shizukuishi-cho, Iwate, 020–0507, Japan
| | - Kazuyuki Uchida
- Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1–1–1 Yayoi, Bunkyo-ku, Tokyo, 113–8657, Japan
| | - Aruto Yoshida
- Central Laboratories for Key Technologies, Kirin Company Ltd., 1–13–5 Fukuura Kanazawa-ku, Yokohama-shi, Kanagawa, 236–0004, Japan
| | - Hiroyuki Nakayama
- Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1–1–1 Yayoi, Bunkyo-ku, Tokyo, 113–8657, Japan
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Mora L, Hayes M. Cardioprotective cryptides derived from fish and other food sources: generation, application, and future markets. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:1319-1331. [PMID: 25597264 DOI: 10.1021/jf505019z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
The primary function of dietary protein is to provide amino acids for protein synthesis. However, protein is also a source of latent bioactive peptides or cryptides with potential health benefits including the control and regulation of blood pressure. Hypertension or high blood pressure is one of the major, controllable risk factors in the development of cardiovascular disease (CVD), and it is also implicated in the development of myocardial infarction, heart failure, and end-stage diabetes. Cryptides can act on various systems of the body including the circulatory, gastrointestinal (GI), nervous, skeletal, and respiratory systems. A number of studies carried out to date have examined the health benefits of food protein isolates and hydrolysates. This review provides an overview of existing blood pressure regulating peptides and products derived from fish and other protein sources and hydrolysates. It discusses the methods used currently to generate and identify cryptides from these sources and their application in food and pharmaceutical products. It also looks at the current market for protein-derived peptides and peptide-containing products, legislation governing their use, and the future development of research in this area.
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Affiliation(s)
- Leticia Mora
- Instituto de Agroquı́mica y Tecnologı́a de Alimentos (CSIC), Avenida Agustín Escardino 7, 46980 Paterna, Valencia, Spain
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Marcelo A, Bix G. The potential role of perlecan domain V as novel therapy in vascular dementia. Metab Brain Dis 2015; 30:1-5. [PMID: 24964971 DOI: 10.1007/s11011-014-9576-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 06/13/2014] [Indexed: 10/25/2022]
Abstract
Vascular dementia (VaD) is the second most common cause of dementia and leads to a decline in cognitive thinking via conditions that lead to blockage or reduced blood flow to the brain. It is a poorly understood disease, and the changes that occur are often linked to other types of dementia such as Alzheimer's disease. To date, there are no approved therapies or drugs to treat the symptoms of VaD, even though there is some evidence of drugs approved for Alzheimer's that might have some benefit in patients diagnosed with VaD. The altered blood flow that precedes VaD may result in compensatory mechanisms, such as angiogenesis, to increase blood flow in the brain. Angiogenesis, the process of new blood vessel formations from pre-existing ones, involves several pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and is regulated by a variety of growth factors from neurons, astrocytes, and pericytes in the brain as well the extracellular matrix (ECM). The ECM highly regulates angiogenesis and other processes in the brain. One such ECM component is the heparan sulfate proteoglycan perlecan and its bioactive region, Domain V (DV). Here we discuss the potential role of DV as a novel therapy to treat VaD.
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Affiliation(s)
- Aileen Marcelo
- Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology and Department of Neurology, University of Kentucky, 430 Sanders Brown Building, 800 S. Limestone Street, Lexington, KY, 40536-0230, USA
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Kim TW. Drug repositioning approaches for the discovery of new therapeutics for Alzheimer's disease. Neurotherapeutics 2015; 12:132-42. [PMID: 25549849 PMCID: PMC4322062 DOI: 10.1007/s13311-014-0325-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.
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Affiliation(s)
- Tae-Wan Kim
- Department of Pathology and Cell Biology, and Taub Institute of Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, 10032, USA,
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Zhang XZ, Quan Y, Tang GY. Medical genetics-based drug repurposing for Alzheimer's disease. Brain Res Bull 2014; 110:26-9. [PMID: 25446738 DOI: 10.1016/j.brainresbull.2014.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 11/12/2014] [Accepted: 11/13/2014] [Indexed: 12/31/2022]
Abstract
Alzheimer's disease (AD) is a disease that threatens the elderly. No efficient therapeutic method is currently available to combat AD. Drug repurposing has provided a new route for AD drug discovery, and medical genetics has shown potential in target-based drug repurposing. We compared AD-associated genes with approved drug targets and found that three are targeted by 23 approved drugs. Thus, these drugs may be used to treat AD according to the medical genetic information of the targets. In vitro and in vivo experiments revealed that four drugs, all of which are angiotensin-converting enzyme (ACE) inhibitors, had potential to treat AD.
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Affiliation(s)
- Xiu-Zhen Zhang
- School of Life Sciences, Shandong University of Technology, Zibo 255049, PR China.
| | - Yuan Quan
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, PR China.
| | - Guang-Yan Tang
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, PR China.
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