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Zhou S, Li T, Zhang W, Wu J, Hong H, Quan W, Qiao X, Cui C, Qiao C, Zhao W, Shen Y. The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease. Neural Regen Res 2025; 20:2361-2372. [PMID: 39359093 PMCID: PMC11759022 DOI: 10.4103/nrr.nrr-d-23-01684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/05/2024] [Accepted: 02/06/2024] [Indexed: 10/04/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.
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Affiliation(s)
- Shengyang Zhou
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Ting Li
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Wei Zhang
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Jian Wu
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Hui Hong
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Wei Quan
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Xinyu Qiao
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Chun Cui
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Chenmeng Qiao
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Weijiang Zhao
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Yanqin Shen
- Laboratory of Neurodegenerative and Neuroinjury Diseases, Wuxi Medicine School, Jiangnan University, Wuxi, Jiangsu Province, China
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Lage L, Rodriguez-Perez AI, Labandeira-Garcia JL, Dominguez-Meijide A. Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms. Neurotherapeutics 2025; 22:e00544. [PMID: 39915220 DOI: 10.1016/j.neurot.2025.e00544] [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: 06/09/2024] [Revised: 01/27/2025] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.
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Affiliation(s)
- Lucia Lage
- Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana I Rodriguez-Perez
- Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain
| | - Jose Luis Labandeira-Garcia
- Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
| | - Antonio Dominguez-Meijide
- Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
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Xu TX, Jiang HY, Yang ZY. Renin-angiotensin system inhibitor use and risk of Parkinson's disease: a meta-analysis. Acta Neurol Belg 2025; 125:53-60. [PMID: 38669003 PMCID: PMC11876239 DOI: 10.1007/s13760-024-02560-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 04/07/2024] [Indexed: 03/05/2025]
Abstract
BACKGROUND Hypertension is a recognized risk factor for Parkinson's disease (PD). The renin-angiotensin system (RAS) inhibitors are widely used to treat hypertension. However, the association of RAS inhibitor use with PD has still been an area of controversy. METHODS Thus, we conducted a meta-analysis to investigate the relationship between RAS inhibitor use and PD. PUBMED and EMBASE databases were searched for articles published up to Oct 2023. All studies that examined the relationship between RAS inhibitor use and the incidence of PD were included. RESULTS Seven studies with total 3,495,218 individuals met our inclusion criteria for this meta-analysis. Overall, RAS inhibitor use was associated with a reduction in PD risk (OR = 0.88, 95%CI = 0.79-0.98) compared with the controls. When restricted the analysis to individuals with RAS inhibitor use indication, RAS inhibitor exposure was also associated with a decreased risk of PD (OR = 0.76, 95%CI = 0.62-0.92). Pooled results of cohort studies also did support a protective role of angiotensin converting enzyme inhibitors (ACEIs) (OR = 0.97, 95%CI = 0.89-1.07) users and angiotensin II receptor blockers (ARBs) (OR = 0.8, 95%CI = 0.63-1.02) in PD. CONCLUSION Overall, RAS inhibitor use as a class is associated with a reduction in PD risk. However, the findings of ACEIs and ARBs may be limited by small sample size. Future well-designed studies considering the classification by inhibitor type, duration, dose, or property of BBB penetration of RAS inhibitors are needed to clarify the contribution of these exposure parameters on the risk of PD.
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Affiliation(s)
- Tian-Xiang Xu
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Hai-Yin Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zeng-Yan Yang
- Guangxi University of Chinese Medicine, Nanning, Guangxi, China.
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Lage L, Rodríguez-Perez AI, Labandeira-Garcia JL, Dominguez-Meijide A. Angiotensin type-1 receptor autoantibodies promote alpha-synuclein aggregation in dopaminergic neurons. Front Immunol 2024; 15:1457459. [PMID: 39588364 PMCID: PMC11586346 DOI: 10.3389/fimmu.2024.1457459] [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: 06/30/2024] [Accepted: 10/21/2024] [Indexed: 11/27/2024] Open
Abstract
Angiotensin, through its type-1 receptor (AT1), is a major inducer of inflammation and oxidative stress, contributing to several diseases. Autoimmune processes have been involved in neurodegeneration, including Parkinson's disease (PD). AT1 autoantibodies (AT1-AA) enhance neurodegeneration and PD, which was related to increased neuronal oxidative stress and neuroinflammation. However, the effect of AT1-AA on α-synuclein aggregation, a major factor in PD progression, has not been studied. In cultures of dopaminergic neurons, we observed that AT1-AA promote aggregation of α-synuclein, as AT1-AA upregulated major mechanisms involved in the α-synuclein aggregation process such as NADPH-oxidase activation and intracellular calcium raising. The results further support the role of AT1 receptors in dopaminergic neuron degeneration, and several recent clinical studies observing the neuroprotective effects of AT1 receptor blockers.
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Affiliation(s)
- Lucia Lage
- Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana I. Rodríguez-Perez
- Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jose L. Labandeira-Garcia
- Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Antonio Dominguez-Meijide
- Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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Al‐Qahtani Z, Al‐kuraishy HM, Al‐Gareeb AI, Albuhadily AK, Ali NH, Alexiou A, Papadakis M, Saad HM, Batiha GE. The potential role of brain renin-angiotensin system in the neuropathology of Parkinson disease: Friend, foe or turncoat? J Cell Mol Med 2024; 28:e18495. [PMID: 38899551 PMCID: PMC11187740 DOI: 10.1111/jcmm.18495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/15/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD.
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Affiliation(s)
- Zainah Al‐Qahtani
- Neurology Section, Internal Medicine Department, College of MedicineKing khaled universityAbhaSaudi Arabia
| | - Hayder M. Al‐kuraishy
- Clinical pharmacology and medicine, college of medicineMustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Clinical pharmacology and medicine, college of medicineMustansiriyah UniversityBaghdadIraq
| | - Ali K. Albuhadily
- Clinical pharmacology and medicine, college of medicineMustansiriyah UniversityBaghdadIraq
| | - Naif H. Ali
- Department of Internal Medicine, Medical CollegeNajran UniversityNajranSaudi Arabia
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh UniversityMohaliIndia
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
- Department of Research & Development, FunogenAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
| | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐HerdeckeWuppertalGermany
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary MedicineMatrouh UniversityMatrouhEgypt
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourAlBeheiraEgypt
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Rodríguez-Pérez AI, Garrido-Gil P, García-Garrote M, Muñoz A, Parga JA, Labandeira-García JL, Rodríguez-Pallares J. Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models. Stem Cell Res Ther 2024; 15:138. [PMID: 38735991 PMCID: PMC11089721 DOI: 10.1186/s13287-024-03751-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 05/02/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
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Affiliation(s)
- Ana I Rodríguez-Pérez
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Pablo Garrido-Gil
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Maria García-Garrote
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ana Muñoz
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Juan A Parga
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jose Luis Labandeira-García
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
| | - Jannette Rodríguez-Pallares
- Research Center for Molecular Medicine and Chronic Diseases (CiMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
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Bej E, Cesare P, Volpe AR, d’Angelo M, Castelli V. Oxidative Stress and Neurodegeneration: Insights and Therapeutic Strategies for Parkinson's Disease. Neurol Int 2024; 16:502-517. [PMID: 38804477 PMCID: PMC11130796 DOI: 10.3390/neurolint16030037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/25/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative condition marked by the gradual deterioration of dopaminergic neurons in the substantia nigra. Oxidative stress has been identified as a key player in the development of PD in recent studies. In the first part, we discuss the sources of oxidative stress in PD, including mitochondrial dysfunction, dopamine metabolism, and neuroinflammation. This paper delves into the possibility of mitigating oxidative stress as a potential treatment approach for PD. In addition, we examine the hurdles and potential of antioxidant therapy, including the challenge of delivering antioxidants to the brain and the requirement for biomarkers to track oxidative stress in PD patients. However, even if antioxidant therapy holds promise, further investigation is needed to determine its efficacy and safety in PD treatment.
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Affiliation(s)
| | | | | | | | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.B.); (P.C.); (A.R.V.); (M.d.)
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Labandeira-Garcia JL, Labandeira CM, Guerra MJ, Rodriguez-Perez AI. The role of the brain renin-angiotensin system in Parkinson´s disease. Transl Neurodegener 2024; 13:22. [PMID: 38622720 PMCID: PMC11017622 DOI: 10.1186/s40035-024-00410-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/22/2024] [Indexed: 04/17/2024] Open
Abstract
The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
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Affiliation(s)
- Jose Luis Labandeira-Garcia
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
| | | | - Maria J Guerra
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ana I Rodriguez-Perez
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
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9
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Dong H, Zhang X, Duan Y, He Y, Zhao J, Wang Z, Wang J, Li Q, Fan G, Liu Z, Shen C, Zhang Y, Yu M, Fei J, Huang F. Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson's disease. J Neuroinflammation 2024; 21:80. [PMID: 38555419 PMCID: PMC10981320 DOI: 10.1186/s12974-024-03070-2] [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: 12/18/2023] [Accepted: 03/20/2024] [Indexed: 04/02/2024] Open
Abstract
Neuroinflammation is one of the core pathological features of Parkinson's disease (PD). Innate immune cells play a crucial role in the progression of PD. Microglia, the major innate immune cells in the brain, exhibit innate immune memory effects and are recognized as key regulators of neuroinflammatory responses. Persistent modifications of microglia provoked by the first stimuli are pivotal for innate immune memory, resulting in an enhanced or suppressed immune response to second stimuli, which is known as innate immune training and innate immune tolerance, respectively. In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific Hif-1α knockout mice were further employed to elucidate the regulatory role of HIF-1α in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1α in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1α is essential for microglial innate immune memory and can promote neuroinflammation associated with PD.
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Affiliation(s)
- Hongtian Dong
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Xiaoshuang Zhang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Yufei Duan
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Yongtao He
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Jiayin Zhao
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Zishan Wang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Jinghui Wang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Qing Li
- School of Life Science and Technology, Tongji University, 1239 Shipping Road, Shanghai, 200092, China
| | - Guangchun Fan
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Zhaolin Liu
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Chenye Shen
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Yunhe Zhang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Mei Yu
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China.
| | - Jian Fei
- School of Life Science and Technology, Tongji University, 1239 Shipping Road, Shanghai, 200092, China.
- Shanghai Engineering Research Center for Model Organisms, Shanghai Model Organisms Center, INC., Shanghai, 201203, China.
| | - Fang Huang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China.
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10
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Jia F, Han J. COVID-19 related neurological manifestations in Parkinson's disease: has ferroptosis been a suspect? Cell Death Discov 2024; 10:146. [PMID: 38503730 PMCID: PMC10951317 DOI: 10.1038/s41420-024-01915-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 03/21/2024] Open
Abstract
A rising number of patient cases point to a probable link between SARS-CoV-2 infection and Parkinson's disease (PD), yet the mechanisms by which SARS-CoV-2 affects the brain and generates neuropsychiatric symptoms in COVID-19 patients remain unknown. Ferroptosis, a distinct iron-dependent non-apoptotic type of cell death characterized by lipid peroxidation and glutathione depletion, a key factor in neurological disorders. Ferroptosis may have a pathogenic role in COVID-19, according to recent findings, however its potential contributions to COVID-19-related PD have not yet been investigated. This review covers potential paths for SARS-CoV-2 infection of the brain. Among these putative processes, ferroptosis may contribute to the etiology of COVID-19-associated PD, potentially providing therapeutic methods.
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Affiliation(s)
- Fengju Jia
- School of Nursing, Qingdao University, No. 308 Ningxia Road, Qingdao, 266071, China.
| | - Jing Han
- School of Nursing, Qingdao University, No. 308 Ningxia Road, Qingdao, 266071, China
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11
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Lage L, Rodriguez-Perez AI, Villar-Cheda B, Labandeira-Garcia JL, Dominguez-Meijide A. Angiotensin type 1 receptor activation promotes neuronal and glial alpha-synuclein aggregation and transmission. NPJ Parkinsons Dis 2024; 10:37. [PMID: 38368444 PMCID: PMC10874459 DOI: 10.1038/s41531-024-00650-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 02/02/2024] [Indexed: 02/19/2024] Open
Abstract
The brain renin-angiotensin system (RAS) has been related to dopaminergic degeneration, and high expression of the angiotensin II (AngII) type 1 receptor (AT1) gene is a marker of the most vulnerable neurons in humans. However, it is unknown whether AngII/AT1 overactivation affects α-synuclein aggregation and transmission. In vitro, AngII/AT1 activation increased α-synuclein aggregation in dopaminergic neurons and microglial cells, which was related to AngII-induced NADPH-oxidase activation and intracellular calcium raising. In mice, AngII/AT1 activation was involved in MPTP-induced increase in α-synuclein expression and aggregation, as they significantly decreased in mice treated with the AT1 blocker telmisartan and AT1 knockout mice. Cell co-cultures (transwells) revealed strong transmission of α-synuclein from dopaminergic neurons to astrocytes and microglia. AngII induced a higher α-synuclein uptake by microglial cells and an increase in the transfer of α-synuclein among astroglial cells. However, AngII did not increase the release of α-synuclein by neurons. The results further support brain RAS dysregulation as a major mechanism for the progression of Parkinson's disease, and AT1 inhibition and RAS modulation as therapeutic targets.
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Affiliation(s)
- Lucia Lage
- Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana I Rodriguez-Perez
- Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Begoña Villar-Cheda
- Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jose L Labandeira-Garcia
- Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
| | - Antonio Dominguez-Meijide
- Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
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12
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AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability. Brain Behav Immun 2023; 108:255-268. [PMID: 36535607 DOI: 10.1016/j.bbi.2022.12.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 11/20/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson's disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson's disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs). In rats, metabolic syndrome induced the increase in circulating levels of LIGHT and other major pro-inflammatory cytokines, and 27-hydroxycholesterol. Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats. Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood-brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson's disease. Observations in the rat models, were analyzed in a cohort of parkinsonian and non-parkinsonian patients with or without metabolic syndrome. Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls. This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).
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13
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Liu H, Xue Y, Chen L. Angiotensin II increases the firing activity of pallidal neurons and participates in motor control in rats. Metab Brain Dis 2023; 38:573-587. [PMID: 36454502 DOI: 10.1007/s11011-022-01127-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
The globus pallidus has emerged as a crucial node in the basal ganglia motor control circuit under both healthy and parkinsonian states. Previous studies have shown that angiotensin II (Ang II) and angiotensin subtype 1 receptor (AT1R) are closely related to Parkinson's disease (PD). Recent morphological study revealed the expression of AT1R in the globus pallidus of mice. To investigate the functions of Ang II/AT1R on the globus pallidus neurons of both normal and parkinsonian rats, electrophysiological recordings and behavioral tests were performed in the present study. Electrophysiological recordings showed that exogenous and endogenous Ang II mainly excited the globus pallidus neurons through AT1R. Behavioral tests further demonstrated that unilateral microinjection of Ang II into the globus pallidus induced significantly contralateral-biased swing in elevated body swing test (EBST), and bilateral microinjection of Ang II into the globus pallidus alleviated catalepsy and akinesia caused by haloperidol. AT1R was involved in Ang II-induced behavioral effects. Immunostaining showed that AT1R was expressed in the globus pallidus of rats. On the basis of the present findings, we concluded that pallidal Ang II/AT1R alleviated parkinsonian motor deficits through activating globus pallidus neurons, which will provide a rationale for further investigations into the potential of Ang II in the treatment of motor disorders originating from the basal ganglia.
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Affiliation(s)
- Hongxia Liu
- Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Physiology, Binzhou Medical University, Yantai, China
| | - Yan Xue
- Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.
| | - Lei Chen
- Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.
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14
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Targeting G Protein-Coupled Receptors in the Treatment of Parkinson's Disease. J Mol Biol 2022:167927. [PMID: 36563742 DOI: 10.1016/j.jmb.2022.167927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 12/25/2022]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized in part by the deterioration of dopaminergic neurons which leads to motor impairment. Although there is no cure for PD, the motor symptoms can be treated using dopamine replacement therapies including the dopamine precursor L-DOPA, which has been in use since the 1960s. However, neurodegeneration in PD is not limited to dopaminergic neurons, and many patients experience non-motor symptoms including cognitive impairment or neuropsychiatric disturbances, for which there are limited treatment options. Moreover, there are currently no treatments able to alter the progression of neurodegeneration. There are many therapeutic strategies being investigated for PD, including alternatives to L-DOPA for the treatment of motor impairment, symptomatic treatments for non-motor symptoms, and neuroprotective or disease-modifying agents. G protein-coupled receptors (GPCRs), which include the dopamine receptors, are highly druggable cell surface proteins which can regulate numerous intracellular signaling pathways and thereby modulate the function of neuronal circuits affected by PD. This review will describe the treatment strategies being investigated for PD that target GPCRs and their downstream signaling mechanisms. First, we discuss new developments in dopaminergic agents for alleviating PD motor impairment, the role of dopamine receptors in L-DOPA induced dyskinesia, as well as agents targeting non-dopamine GPCRs which could augment or replace traditional dopaminergic treatments. We then discuss GPCRs as prospective treatments for neuropsychiatric and cognitive symptoms in PD. Finally, we discuss the evidence pertaining to ghrelin receptors, β-adrenergic receptors, angiotensin receptors and glucagon-like peptide 1 receptors, which have been proposed as disease modifying targets with potential neuroprotective effects in PD.
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15
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Garrido-Gil P, Pedrosa MA, Garcia-Garrote M, Pequeño-Valtierra A, Rodríguez-Castro J, García-Souto D, Rodríguez-Pérez AI, Labandeira-Garcia JL. Microglial angiotensin type 2 receptors mediate sex-specific expression of inflammatory cytokines independently of circulating estrogen. Glia 2022; 70:2348-2360. [PMID: 35943203 DOI: 10.1002/glia.24255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 01/07/2023]
Abstract
There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1β and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroids.
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Affiliation(s)
- Pablo Garrido-Gil
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Maria A Pedrosa
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Maria Garcia-Garrote
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Ana Pequeño-Valtierra
- Laboratory of Genomes and Disease, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Jorge Rodríguez-Castro
- Laboratory of Genomes and Disease, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Daniel García-Souto
- Laboratory of Genomes and Disease, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana I Rodríguez-Pérez
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Jose L Labandeira-Garcia
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
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16
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Bild W, Vasincu A, Rusu RN, Ababei DC, Stana AB, Stanciu GD, Savu B, Bild V. Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases. Biomolecules 2022; 12:1429. [PMID: 36291638 PMCID: PMC9599929 DOI: 10.3390/biom12101429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 11/17/2022] Open
Abstract
Brain neurodegenerative diseases (BND) are debilitating conditions that are especially characteristic of a certain period of life and considered major threats to human health. Current treatments are limited, meaning that there is a challenge in developing new options that can efficiently tackle the different components and pathophysiological processes of these conditions. The renin-angiotensin-aldosterone system (RAS) is an endocrine axis with important peripheral physiological functions such as blood pressure and cardiovascular homeostasis, as well as water and sodium balance and systemic vascular resistance-functions which are well-documented. However, recent work has highlighted the paracrine and autocrine functions of RAS in different tissues, including the central nervous system (CNS). It is known that RAS hyperactivation has pro-inflammatory and pro-oxidant effects, thus suggesting that its pharmacological modulation could be used in the management of these conditions. The present paper underlines the involvement of RAS and its components in the pathophysiology of BNDs such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), motor neuron disease (MND), and prion disease (PRD), as well as the identification of drugs and pharmacologically active substances that act upon RAS, which could alleviate their symptomatology or evolution, and thus, contribute to novel therapeutic approaches.
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Affiliation(s)
- Walther Bild
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Center of Biomedical Research of the Romanian Academy, 700506 Iasi, Romania
| | - Alexandru Vasincu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Răzvan-Nicolae Rusu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Daniela-Carmen Ababei
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Aurelian Bogdan Stana
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Gabriela Dumitrița Stanciu
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Bogdan Savu
- Department of Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Veronica Bild
- Center of Biomedical Research of the Romanian Academy, 700506 Iasi, Romania
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
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17
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Zhao W, Shen F, Yao J, Su S, Zhao Z. Angiotensin II receptor type 1 blocker candesartan improves morphine tolerance by reducing morphine‑induced inflammatory response and cellular activation of BV2 cells via the PPARγ/AMPK signaling pathway. Mol Med Rep 2022; 26:318. [PMID: 36004465 PMCID: PMC9437959 DOI: 10.3892/mmr.2022.12834] [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] [Received: 04/11/2022] [Accepted: 06/14/2022] [Indexed: 11/05/2022] Open
Abstract
Morphine is the most common drug of choice in clinical pain management; however, morphine tolerance presents a significant clinical challenge. The pathogenesis of morphine tolerance is known to be closely associated with angiotensin II receptor type 1 (AT1R) in microglia. As an AT1R antagonist, candesartan may serve an important role in regulating morphine tolerance. Therefore, the present study aimed to investigate the role of candesartan in morphine tolerance, and to explore the underlying mechanism. To meet this aim, BV2 microglial cells were treated with morphine or candesartan alone, or as a combination, and the expression levels of AT1R in BV2 cells were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. The levels of the inflammatory cytokines tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6 were subsequently detected by ELISA and western blotting. In addition, immunofluorescence analysis, western blotting and RT‑qPCR were used to detect the expression levels of the BV2 cell activation marker, ionized calcium‑binding adaptor molecule 1 (IBA‑1). Western blotting was also used to detect the expression levels of peroxisome proliferator‑activated receptor‑γ/AMP‑activated protein kinase (PPARγ/AMPK) signaling pathway‑associated proteins. Finally, the cells were treated with the PPARγ antagonist GW9662 and the AMPK inhibitor compound C to further explore the mechanism underlying the effects of candesartan on improving morphine tolerance. The expression levels of AT1R were revealed to be significantly increased following morphine induction; however, candesartan treatment inhibited the expression levels of AT1R, the levels of inflammatory cytokines and the protein expression levels of IBA‑1 in morphine‑induced BV2 cells in a dose‑dependent manner. These processes may be associated with activation of the PPARγ/AMPK signaling pathway. Taken together, the present study revealed that treatment with candesartan reduced morphine‑induced inflammatory response and cellular activation of BV2 cells via PPARγ/AMPK signaling.
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Affiliation(s)
- Wenxin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Feiyan Shen
- Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Jixiang Yao
- Department of Pain Management, Affiliated Hospital 5 of Nantong University (Taizhou People's Hospital), Taizhou, Jiangsu 225300, P.R. China
| | - Shanshan Su
- Department of Pain Management, Affiliated Hospital 5 of Nantong University (Taizhou People's Hospital), Taizhou, Jiangsu 225300, P.R. China
| | - Zhongmin Zhao
- Department of Pain Management, Affiliated Hospital 5 of Nantong University (Taizhou People's Hospital), Taizhou, Jiangsu 225300, P.R. China
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18
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Guo L, Li Y, Li W, Qiu J, Du J, Wang L, Zhang T. Shikonin ameliorates oxidative stress and neuroinflammation via the Akt/
ERK
/
JNK
/
NF‐κB
signaling pathways in model of Parkinson’s disease. Clin Exp Pharmacol Physiol 2022; 49:1221-1231. [DOI: 10.1111/1440-1681.13709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Lei Guo
- Department of Neurology Yantai City Yantaishan Hospital Yantai Shandong China
| | - Yuanyuan Li
- Department of Health Care Dongying People's Hospital Dongying Shandong China
| | - Wenna Li
- Department of Neurology Yantai City Yantaishan Hospital Yantai Shandong China
| | - Jiaoxue Qiu
- Department of Neurology Yantai City Yantaishan Hospital Yantai Shandong China
| | - Juan Du
- Department of Neurology Yantai City Yantaishan Hospital Yantai Shandong China
| | - Lingling Wang
- Department of Neurology Yantai City Yantaishan Hospital Yantai Shandong China
| | - Ting Zhang
- Department of Health Care Dongying People's Hospital Dongying Shandong China
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19
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Association of Angiotensin Receptor Blockers with Incident Parkinson Disease in Patients with Hypertension: A Retrospective Cohort Study. Am J Med 2022; 135:1001-1007. [PMID: 35580718 DOI: 10.1016/j.amjmed.2022.04.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 04/18/2022] [Accepted: 04/27/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Angiotensin receptor blockers (ARBs), which are commonly used antihypertensives, have been proposed to lower the risk of Parkinson disease by reducing oxidative stress based on animal and in vitro studies. Thus, this study aimed to test this association in patients with newly diagnosed hypertension. METHODS This retrospective cohort study enrolled 107,207 patients with newly diagnosed hypertension between 2001 and 2013. The hazard ratios for Parkinson disease were calculated for ARB treatment compared with those who never used ARBs and among the 5 subgroups receiving different cumulative ARB dosages. RESULTS We identified 527 (1.1%) Parkinson disease cases among patients with ARB treatment in a median observation period of 8.4 years compared to the 1,255 (2.2%) Parkinson disease cases among those without ARB treatment in a median observation period of 6.8 years. Overall, risk for developing Parkinson disease was statistically lower in the ARB-treated group with a hazard ratio of 0.56 (95% confidence interval: 0.51-0.63) than those without ARB. CONCLUSIONS ARB treatment was associated with a statistically important reduction of Parkinson disease risk in patients with newly diagnosed hypertension. Therefore, ARB may constitute an effective neuroprotective strategy to lower Parkinson disease risk in such patients.
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20
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Grotemeyer A, McFleder RL, Wu J, Wischhusen J, Ip CW. Neuroinflammation in Parkinson's Disease - Putative Pathomechanisms and Targets for Disease-Modification. Front Immunol 2022; 13:878771. [PMID: 35663989 PMCID: PMC9158130 DOI: 10.3389/fimmu.2022.878771] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022] Open
Abstract
Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD.
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Affiliation(s)
| | | | - Jingjing Wu
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Jörg Wischhusen
- Section for Experimental Tumor Immunology, Department of Obstetrics and Gynecology, University Hospital of Würzburg, Würzburg, Germany
| | - Chi Wang Ip
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
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21
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Szczepanska-Sadowska E, Wsol A, Cudnoch-Jedrzejewska A, Czarzasta K, Żera T. Multiple Aspects of Inappropriate Action of Renin-Angiotensin, Vasopressin, and Oxytocin Systems in Neuropsychiatric and Neurodegenerative Diseases. J Clin Med 2022; 11:908. [PMID: 35207180 PMCID: PMC8877782 DOI: 10.3390/jcm11040908] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 02/04/2023] Open
Abstract
The cardiovascular system and the central nervous system (CNS) closely cooperate in the regulation of primary vital functions. The autonomic nervous system and several compounds known as cardiovascular factors, especially those targeting the renin-angiotensin system (RAS), the vasopressin system (VPS), and the oxytocin system (OTS), are also efficient modulators of several other processes in the CNS. The components of the RAS, VPS, and OTS, regulating pain, emotions, learning, memory, and other cognitive processes, are present in the neurons, glial cells, and blood vessels of the CNS. Increasing evidence shows that the combined function of the RAS, VPS, and OTS is altered in neuropsychiatric/neurodegenerative diseases, and in particular in patients with depression, Alzheimer's disease, Parkinson's disease, autism, and schizophrenia. The altered function of the RAS may also contribute to CNS disorders in COVID-19. In this review, we present evidence that there are multiple causes for altered combined function of the RAS, VPS, and OTS in psychiatric and neurodegenerative disorders, such as genetic predispositions and the engagement of the RAS, VAS, and OTS in the processes underlying emotions, memory, and cognition. The neuroactive pharmaceuticals interfering with the synthesis or the action of angiotensins, vasopressin, and oxytocin can improve or worsen the effectiveness of treatment for neuropsychiatric/neurodegenerative diseases. Better knowledge of the multiple actions of the RAS, VPS, and OTS may facilitate programming the most efficient treatment for patients suffering from the comorbidity of neuropsychiatric/neurodegenerative and cardiovascular diseases.
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Affiliation(s)
- Ewa Szczepanska-Sadowska
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.W.); (A.C.-J.); (K.C.); (T.Ż.)
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22
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Azzam AY, Ghozy S, Azab MA. Vitamin D and its' role in Parkinson's disease patients with SARS-CoV-2 infection. A review article. INTERDISCIPLINARY NEUROSURGERY : ADVANCED TECHNIQUES AND CASE MANAGEMENT 2021; 27:101441. [PMID: 34868885 PMCID: PMC8627384 DOI: 10.1016/j.inat.2021.101441] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/05/2021] [Accepted: 11/21/2021] [Indexed: 12/12/2022]
Abstract
A novel coronavirus reportedly called 2019-nCoV started to spread around the world at the end of 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was later renamed after links with SARS were observed. Multiple studies have reported possible connections between the COVID-19 virus and neurodegenerative diseases, including Parkinson's disease. Theories support that vitamin D deficiency plays a part in the pathogenicity of Parkinson's disease or the credibility of the associated dopamine system. Administration of vitamin D3 was shown to significantly enhance the motor and non-motor manifestations of Parkinson's disease and enhance the quality of life. Also, multiple recent reviews have shown specific ways in which vitamin D reduces the risk of pathogenic infections. Recent studies supported the potential role of vitamin D in reducing the risk of COVID-19 infections and mortality. On the immunological level, immune response regulation remains one of the well-recognized actions of vitamin D. Vitamin D deficiency has been linked to complications in patients with SARS-CoV-2 infection and Parkinson's disease. Whereas more studies are required, Vitamin D supplementation with a moderate and well-calculated dosage of vitamin D3 in patients with Parkinson's disease can help minimize the risk and burden of COVID-19 complications.
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Affiliation(s)
- Ahmed Y Azzam
- October 6 University Faculty of Medicine, Giza, Egypt
| | - Sherief Ghozy
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Mohammed A Azab
- Department of Biomolecular Sciences, Boise State University, Boise, ID, USA
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23
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Danilenko V, Devyatkin A, Marsova M, Shibilova M, Ilyasov R, Shmyrev V. Common Inflammatory Mechanisms in COVID-19 and Parkinson's Diseases: The Role of Microbiome, Pharmabiotics and Postbiotics in Their Prevention. J Inflamm Res 2021; 14:6349-6381. [PMID: 34876830 PMCID: PMC8643201 DOI: 10.2147/jir.s333887] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/29/2021] [Indexed: 12/14/2022] Open
Abstract
In the last decade, metagenomic studies have shown the key role of the gut microbiome in maintaining immune and neuroendocrine systems. Malfunction of the gut microbiome can induce inflammatory processes, oxidative stress, and cytokine storm. Dysfunction of the gut microbiome can be caused by short-term (virus infection and other infectious diseases) or long-term (environment, nutrition, and stress) factors. Here, we reviewed the inflammation and oxidative stress in neurodegenerative diseases and coronavirus infection (COVID-19). Here, we reviewed the renin-angiotensin-aldosterone system (RAAS) involved in the processes of formation of oxidative stress and inflammation in viral and neurodegenerative diseases. Moreover, the coronavirus uses ACE2 receptors of the RAAS to penetrate human cells. The coronavirus infection can be the trigger for neurodegenerative diseases by dysfunction of the RAAS. Pharmabiotics, postbiotics, and next-generation probiotics, are considered as a means to prevent oxidative stress, inflammatory processes, neurodegenerative and viral diseases through gut microbiome regulation.
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Affiliation(s)
- Valery Danilenko
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
| | - Andrey Devyatkin
- Central Clinical Hospital with a Polyclinic CMP RF, Moscow, Russia
| | - Mariya Marsova
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
| | | | - Rustem Ilyasov
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
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24
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Sunanda T, Ray B, Mahalakshmi AM, Bhat A, Rashan L, Rungratanawanich W, Song BJ, Essa MM, Sakharkar MK, Chidambaram SB. Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson's Disease: The Role of Brain Renin Angiotensin System Components. Biomolecules 2021; 11:1669. [PMID: 34827667 PMCID: PMC8615717 DOI: 10.3390/biom11111669] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/29/2021] [Accepted: 11/04/2021] [Indexed: 12/12/2022] Open
Abstract
The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). In PD, alterations in mitochondria, endoplasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin-angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson's disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD.
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Affiliation(s)
- Tuladhar Sunanda
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (T.S.); (B.R.); (A.M.M.); (A.B.)
- Centre for Experimental Pharmacology and Toxicology, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Bipul Ray
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (T.S.); (B.R.); (A.M.M.); (A.B.)
- Centre for Experimental Pharmacology and Toxicology, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Arehally M. Mahalakshmi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (T.S.); (B.R.); (A.M.M.); (A.B.)
| | - Abid Bhat
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (T.S.); (B.R.); (A.M.M.); (A.B.)
- Centre for Experimental Pharmacology and Toxicology, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Luay Rashan
- Biodiversity Research Centre, Dohfar University, Salalah 2059, Oman;
| | - Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA; (W.R.); (B.-J.S.)
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA; (W.R.); (B.-J.S.)
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat 123, Oman;
- Ageing and Dementia Research Group, Sultan Qaboos University, Muscat 123, Oman
| | - Meena Kishore Sakharkar
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada
| | - Saravana Babu Chidambaram
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (T.S.); (B.R.); (A.M.M.); (A.B.)
- Centre for Experimental Pharmacology and Toxicology, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
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25
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Parga JA, Rodriguez-Perez AI, Garcia-Garrote M, Rodriguez-Pallares J, Labandeira-Garcia JL. NRF2 Activation and Downstream Effects: Focus on Parkinson's Disease and Brain Angiotensin. Antioxidants (Basel) 2021; 10:antiox10111649. [PMID: 34829520 PMCID: PMC8614768 DOI: 10.3390/antiox10111649] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 12/18/2022] Open
Abstract
Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson's disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson's disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches.
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Affiliation(s)
- Juan A. Parga
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (A.I.R.-P.); (M.G.-G.); (J.R.-P.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain
- Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, CIMUS, Department of Morphological Sciences, University of Santiago de Compostela, R/ San Francisco s/n, 15782 Santiago de Compostela, Spain
- Correspondence: (J.A.P.); (J.L.L.-G.)
| | - Ana I. Rodriguez-Perez
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (A.I.R.-P.); (M.G.-G.); (J.R.-P.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain
- Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, CIMUS, Department of Morphological Sciences, University of Santiago de Compostela, R/ San Francisco s/n, 15782 Santiago de Compostela, Spain
| | - Maria Garcia-Garrote
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (A.I.R.-P.); (M.G.-G.); (J.R.-P.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain
- Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, CIMUS, Department of Morphological Sciences, University of Santiago de Compostela, R/ San Francisco s/n, 15782 Santiago de Compostela, Spain
| | - Jannette Rodriguez-Pallares
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (A.I.R.-P.); (M.G.-G.); (J.R.-P.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain
- Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, CIMUS, Department of Morphological Sciences, University of Santiago de Compostela, R/ San Francisco s/n, 15782 Santiago de Compostela, Spain
| | - Jose L. Labandeira-Garcia
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (A.I.R.-P.); (M.G.-G.); (J.R.-P.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain
- Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, CIMUS, Department of Morphological Sciences, University of Santiago de Compostela, R/ San Francisco s/n, 15782 Santiago de Compostela, Spain
- Correspondence: (J.A.P.); (J.L.L.-G.)
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26
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Li J, Shui X, Sun R, Wan L, Zhang B, Xiao B, Luo Z. Microglial Phenotypic Transition: Signaling Pathways and Influencing Modulators Involved in Regulation in Central Nervous System Diseases. Front Cell Neurosci 2021; 15:736310. [PMID: 34594188 PMCID: PMC8476879 DOI: 10.3389/fncel.2021.736310] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/18/2021] [Indexed: 12/12/2022] Open
Abstract
Microglia are macrophages that reside in the central nervous system (CNS) and belong to the innate immune system. Moreover, they are crucially involved in CNS development, maturation, and aging; further, they are closely associated with neurons. In normal conditions, microglia remain in a static state. Upon trauma or lesion occurrence, microglia can be activated and subsequently polarized into the pro-inflammatory or anti-inflammatory phenotype. The phenotypic transition is regulated by numerous modulators. This review focus on the literature regarding the modulators and signaling pathways involved in regulating the microglial phenotypic transition, which are rarely mentioned in other reviews. Hence, this review provides molecular insights into the microglial phenotypic transition, which could be a potential therapeutic target for neuroinflammation.
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Affiliation(s)
- Jiaxin Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Xinyu Shui
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruizheng Sun
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Lily Wan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Boxin Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaohui Luo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
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27
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Christmann A, Gries M, Scholz P, Stahr PL, Law JKY, Schulte S, Martin M, Lilischkis R, Ingebrandt S, Keck CM, Schäfer KH. The antioxidant Rutin counteracts the pathological impact of α-synuclein on the enteric nervous system in vitro. Biol Chem 2021; 403:103-122. [PMID: 34582634 DOI: 10.1515/hsz-2021-0259] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/15/2021] [Indexed: 11/15/2022]
Abstract
Motoric disturbances in Parkinson's disease (PD) derive from the loss of dopaminergic neurons in the substantia nigra. Intestinal dysfunctions often appear long before manifestation of neuronal symptoms, suggesting a strong correlation between gut and brain in PD. Oxidative stress is a key player in neurodegeneration causing neuronal cell death. Using natural antioxidative flavonoids like Rutin, might provide intervening strategies to improve PD pathogenesis. To explore the potential effects of micro (mRutin) compared to nano Rutin (nRutin) upon the brain and the gut during PD, its neuroprotective effects were assessed using an in vitro PD model. Our results demonstrated that Rutin inhibited the neurotoxicity induced by A53T α-synuclein (Syn) administration by decreasing oxidized lipids and increasing cell viability in both, mesencephalic and enteric cells. For enteric cells, neurite outgrowth, number of synaptic vesicles, and tyrosine hydroxylase positive cells were significantly reduced when treated with Syn. This could be reversed by the addition of Rutin. nRutin revealed a more pronounced result in all experiments. In conclusion, our study shows that Rutin, especially the nanocrystals, are promising natural compounds to protect neurons from cell death and oxidative stress during PD. Early intake of Rutin may provide a realizable option to prevent or slow PD pathogenesis.
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Affiliation(s)
- Anne Christmann
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany
| | - Manuela Gries
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany
| | - Patrik Scholz
- Formulation Development, BAYER AG, R&D, D-51373Leverkusen, Germany
| | - Pascal L Stahr
- Department of Pharmaceutics and Biopharmaceutics, Philipps-Universität Marburg, D-35037Marburg, Germany
| | - Jessica Ka Yan Law
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany
| | - Steven Schulte
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany
| | - Monika Martin
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany
| | - Rainer Lilischkis
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany
| | - Sven Ingebrandt
- Institute of Materials in Electrical Engineering, RWTH Aachen University, D-52074Aachen, Germany
| | - Cornelia M Keck
- Department of Pharmaceutics and Biopharmaceutics, Philipps-Universität Marburg, D-35037Marburg, Germany
| | - Karl-Herbert Schäfer
- Department of Informatics and Microsystems and Technology, University of Applied Science Kaiserslautern, Working Group Enteric Nervous System, D-66482Zweibrücken, Germany.,Department of Pediatric Surgery, Medical Faculty Mannheim, University of Heidelberg, D-68167Mannheim, Germany
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28
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Sinha S, Mittal S, Roy R. Parkinson's Disease and the COVID-19 Pandemic: A Review Article on the Association between SARS-CoV-2 and α-Synucleinopathy. J Mov Disord 2021; 14:184-192. [PMID: 34315206 PMCID: PMC8490193 DOI: 10.14802/jmd.21046] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/13/2021] [Accepted: 05/26/2021] [Indexed: 11/24/2022] Open
Abstract
There is an extensive debate on the neurological consequences of 2019 novel coronavirus disease (COVID-19) and its impact on Parkinson's disease (PD) patients, which seems to puzzle neurologists. Links between viral infections and PD have long been suspected and studied, but the exact relationship remains elusive. Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the brain through multiple routes and has a direct impact on the brain, cumulative damage occurs due to the activation of proinflammatory cytokines and chemokines. SARS-CoV-2 seems to aggravate PD due to its effects on α-synuclein, mitochondrial dysfunction, and dopamine depletion. A few studies have even highlighted the higher vulnerability of PD patients to COVID-19. The sudden dramatic change in lifestyle caused by the pandemic and the widespread lockdowns that were implemented have added to the hidden sorrows of PD patients, as they already have a compromised mechanism for coping with stress. This review summarizes insights from basic science and the clinical effect of SARS-CoV-2 infection on the human brain, with a specific focus on PD.
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Affiliation(s)
- Smriti Sinha
- Department of Physiology, Andhra Medical College, Visakhapatnam, India
| | - Swati Mittal
- Department of Physiology, All India Institute of Medical Sciences, Deoghar, India
| | - Rupali Roy
- Ministry of Health and Family Welfare, New Delhi, India
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29
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NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death. Antioxidants (Basel) 2021; 10:antiox10091340. [PMID: 34572972 PMCID: PMC8472832 DOI: 10.3390/antiox10091340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 11/16/2022] Open
Abstract
Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renin-treated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process.
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30
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El‐Qushayri AE, Ghozy S, Reda A, Kamel AMA, Abbas AS, Dmytriw AA. The impact of Parkinson's disease on manifestations and outcomes of Covid-19 patients: A systematic review and meta-analysis. Rev Med Virol 2021; 32:e2278. [PMID: 34260773 PMCID: PMC8420424 DOI: 10.1002/rmv.2278] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Parkinson's disease (PD) patients who contracted Coronavirus disease 2019 (Covid‐19) had a decline in motor functions; nevertheless, there is limited evidence on whether PD patients have a higher risk for contracting Covid‐19 or have worse outcomes. This is the first systematic review and meta‐analysis to review the impact of PD on the prognosis of Covid‐19 patients. We performed a systematic search through seven electronic databases under the recommendations of the Preferred Reporting Items for Systematic Review and Meta‐analyses statement (PRISMA) guidelines. The R software version 4.0.2 was used to calculate pooled sample sizes and their associated confidence intervals (95%CI). Finally, we included 13 papers in this study. The pooled prevalence rate of Covid‐19 was 2.12% (95%CI: 0.75–5.98). Fever, cough, fatigue and anorexia were the most common symptoms with a rate of 72.72% (95% CI: 57.3 ‐ 92.29), 66.99% (95% CI: 49.08–91.42), 61.58% (95% CI: 46.69–81.21) and 52.55% (95% CI: 35.09–78.68), respectively. The pooled rates were 39.89% (95% CI: 27.09–58.73) for hospitalisation, 4.7% (95% CI: 1.56–14.16) for ICU admission and 25.1% (95%CI: 16.37–38.49) for mortality. On further comparison of hospitalisation and mortality rates among Covid‐19 patients with and without PD, there were no significant differences. In conclusion, the prevalence and prognosis of Covid‐19 patients seem comparable in patients with PD and those without it. The increased hospitalisation and mortality may be attributed to old age and co‐morbidities.
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Affiliation(s)
| | | | | | | | | | - Adam A. Dmytriw
- Neuroradiology and Neurointervention ServiceBrigham and Women's HospitalBostonMassachusettsUSA
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31
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Ghosh R, Biswas U, Roy D, Pandit A, Lahiri D, Ray BK, Benito‐León J. De Novo Movement Disorders and COVID-19: Exploring the Interface. Mov Disord Clin Pract 2021; 8:669-680. [PMID: 34230886 PMCID: PMC8250792 DOI: 10.1002/mdc3.13224] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/17/2021] [Accepted: 04/05/2021] [Indexed: 12/14/2022] Open
Abstract
Background Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being widely documented. However, movement disorders in the setting of 2019 coronavirus infectious disease (COVID-19) have been a strikingly less discussed topic. Objectives To summarize available pieces of evidence documenting de novo movement disorders in COVID-19. Methods We used the existing PRISMA consensus statement. Data were collected from PubMed, EMBASE, Web of Science, and Scopus databases up to the 29th January, 2021, using pre-specified searching strategies. Results Twenty-two articles were selected for the qualitative synthesis. Among these, a total of 52 patients with de novo movement disorders were reported. Most of these had myoclonus, ataxia, tremor or a combination of these, while three had parkinsonism and one a functional disorder. In general, they were managed successfully by intravenous immunoglobulin or steroids. Some cases, primarily with myoclonus, could be ascribed to medication exposures, metabolic disturbances or severe hypoxia, meanwhile others to a post-or para-infectious immune-mediated mechanism. SARS-CoV-2 could also invade the central nervous system, through vascular or retrograde axonal pathways, and cause movement disorders by two primary mechanisms. Firstly, through the downregulation of angiotensin-converting enzyme 2 receptors, resulting in the imbalance of dopamine and norepinephrine; and secondly, the virus could cause cellular vacuolation, demyelination and gliosis, leading to encephalitis and associated movement disorders. Conclusion De novo movement disorders are scantly reported in COVID-19. The links between SARS-CoV-2 and movement disorders are not yet established. However, we should closely monitor COVID-19 survivors for the possibility of post-COVID movement disorders.
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Affiliation(s)
- Ritwik Ghosh
- Department of General MedicineBurdwan Medical College & HospitalBurdwanIndia
| | - Uttam Biswas
- Department of General MedicineBurdwan Medical College & HospitalBurdwanIndia
| | - Dipayan Roy
- Department of BiochemistryAll India Institute of Medical Sciences (AIIMS)JodhpurIndia
- Indian Institute of Technology (IIT)MadrasIndia
| | - Alak Pandit
- Department of NeuromedicineBangur Institute of NeurosciencesKolkataIndia
| | - Durjoy Lahiri
- Department of NeuromedicineBangur Institute of NeurosciencesKolkataIndia
| | - Biman Kanti Ray
- Department of NeuromedicineBangur Institute of NeurosciencesKolkataIndia
| | - Julián Benito‐León
- Department of NeurologyUniversity Hospital “12 de Octubre”MadridSpain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
- Department of MedicineComplutense UniversityMadridSpain
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32
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Fearon C, Fasano A. Parkinson's Disease and the COVID-19 Pandemic. JOURNAL OF PARKINSONS DISEASE 2021; 11:431-444. [PMID: 33492244 PMCID: PMC8150477 DOI: 10.3233/jpd-202320] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Studies focusing on the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and Parkinson’s disease (PD) have provided conflicting results. We review the literature to investigate: 1) Are PD patients at higher risk for contracting COVID-19 and are there specific contributing factors to that risk? 2) How does COVID-19 affect PD symptoms? 3) How does COVID-19 present in PD patients? 4) What are the outcomes in PD patients who contract COVID-19? 5) What is the impact of COVID-19 on PD care? 6) Does COVID-19 increase the risk of developing PD? A literature search was performed from 1979 to 2020 using the terms: ‘Parkinson’s disease’ and ‘parkinsonism’ combined with: ‘COVID-19’; ‘SARS-CoV-2’ and ‘coronavirus’. It does not appear that PD is a specific risk factor for COVID-19. There is evidence for direct/indirect effects of SARS-CoV-2 on motor/non-motor symptoms of PD. Although many PD patients present with typical COVID-19 symptoms, some present atypically with isolated worsening of parkinsonian symptoms, requiring increased anti-PD therapy and having worse outcomes. Mortality data on PD patients with COVID-19 is inconclusive (ranging from 5.2%to 100%). Patients with advanced PD appear to be particularly vulnerable. Single cases of acute hypokinetic-rigid syndrome have been described but no other convincing data has been reported. The rapidity with which COVID-19 has swept across the globe has favored the proliferation of studies which lack scientific rigor and the PD literature has not been immune. A coordinated effort is required to assimilate data and answer these questions in larger PD cohorts.
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Affiliation(s)
- Conor Fearon
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital - UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada
| | - Alfonso Fasano
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital - UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.,Krembil Research Institute, Toronto, Ontario, Canada.,Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada
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Kobiec T, Otero-Losada M, Chevalier G, Udovin L, Bordet S, Menéndez-Maissonave C, Capani F, Pérez-Lloret S. The Renin-Angiotensin System Modulates Dopaminergic Neurotransmission: A New Player on the Scene. Front Synaptic Neurosci 2021; 13:638519. [PMID: 33967734 PMCID: PMC8100578 DOI: 10.3389/fnsyn.2021.638519] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/11/2021] [Indexed: 11/13/2022] Open
Abstract
Parkinson's disease (PD) is an extrapyramidal disorder characterized by neuronal degeneration in several regions of the peripheral and central nervous systems. It is the second most frequent neurodegenerative disease after Alzheimer's. It has become a major health problem, affecting 1% of the world population over 60 years old and 3% of people beyond 80 years. The main histological findings are intracellular Lewy bodies composed of misfolded α-synuclein protein aggregates and loss of dopaminergic neurons in the central nervous system. Neuroinflammation, apoptosis, mitochondrial dysfunction, altered calcium homeostasis, abnormal protein degradation, and synaptic pathobiology have been put forward as mechanisms leading to cell death, α-synuclein deposition, or both. A progressive loss of dopaminergic neurons in the substantia nigra late in the neurodegeneration leads to developing motor symptoms like bradykinesia, tremor, and rigidity. The renin-angiotensin system (RAS), which is involved in regulating blood pressure and body fluid balance, also plays other important functions in the brain. The RAS is involved in the autocrine and paracrine regulation of the nigrostriatal dopaminergic synapses. Dopamine depletion, as in PD, increases angiotensin II expression, which stimulates or inhibits dopamine synthesis and is released via AT1 or AT2 receptors. Furthermore, angiotensin II AT1 receptors inhibit D1 receptor activation allosterically. Therefore, the RAS may have an important modulating role in the flow of information from the brain cortex to the basal ganglia. High angiotensin II levels might even aggravate neurodegeneration, activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which leads to increased reactive oxygen species production.
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Affiliation(s)
- Tamara Kobiec
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Centro de Investigaciones en Psicología y Psicopedagogía, Facultad de Psicología y Psicopedagogía, Universidad Católica Argentina, Buenos Aires, Argentina
| | - Matilde Otero-Losada
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Guenson Chevalier
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Lucas Udovin
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Sofía Bordet
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Centro de Investigaciones en Psicología y Psicopedagogía, Facultad de Psicología y Psicopedagogía, Universidad Católica Argentina, Buenos Aires, Argentina
| | - Camila Menéndez-Maissonave
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Centro de Investigaciones en Psicología y Psicopedagogía, Facultad de Psicología y Psicopedagogía, Universidad Católica Argentina, Buenos Aires, Argentina
| | - Francisco Capani
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Centro de Investigaciones en Psicología y Psicopedagogía, Facultad de Psicología y Psicopedagogía, Universidad Católica Argentina, Buenos Aires, Argentina
- Facultad de Psicología y Psicopedagogía, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
- Departamento de Biología, Universidad Argentina John F. Kennedy, Buenos Aires, Argentina
- Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago de Chile, Chile
| | - Santiago Pérez-Lloret
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Facultad de Medicina, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
- Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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Meléndez-Flores JD, Estrada-Bellmann I. Linking chronic kidney disease and Parkinson's disease: a literature review. Metab Brain Dis 2021; 36:1-12. [PMID: 32990929 DOI: 10.1007/s11011-020-00623-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/22/2020] [Indexed: 10/23/2022]
Abstract
Chronic kidney disease (CKD) has been typically implicated in cardiovascular risk, considering the function the kidney has related to blood pressure, vitamin D, red blood cell metabolism, and electrolyte and acid-base regulation. However, neurological consequences are also attributed to this disease. Among these, recent large epidemiological studies have demonstrated an increased risk for Parkinson's disease (PD) in patients with CKD. Multiple studies have evaluated individually the association of blood pressure, vitamin D, and red blood cell dysmetabolism with PD, however, no study has reviewed the potential mechanisms related to these components in context of CKD and PD. In this review, we explored the association of CKD and PD and linked the components of the former to propose potential pathways explaining a future increased risk for PD, where renin-angiotensin system, oxidative stress, and inflammation have a main role. Potential preventive and therapeutic interventions based on these associations are also explored. More preclinical studies are needed to confirm the potential link of CKD conditions and future PD risk, whereas more interventional studies targeting this association are warranted to confirm their potential benefit in PD.
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Affiliation(s)
- Jesús D Meléndez-Flores
- Neurology Division, Internal Medicine Department, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, 64700, Monterrey, NL, Mexico
- Faculty of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Ingrid Estrada-Bellmann
- Neurology Division, Internal Medicine Department, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, 64700, Monterrey, NL, Mexico.
- Movement Disorders Clinic, Neurology Division, Internal Medicine Department, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Mexico.
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Visanji NP, Madan P, Lacoste AMB, Buleje I, Han Y, Spangler S, Kalia LV, Hensley Alford S, Marras C. Using artificial intelligence to identify anti-hypertensives as possible disease modifying agents in Parkinson's disease. Pharmacoepidemiol Drug Saf 2020; 30:201-209. [PMID: 33219601 DOI: 10.1002/pds.5176] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 08/25/2020] [Accepted: 10/21/2020] [Indexed: 11/10/2022]
Abstract
PURPOSE Drug repurposing is an effective means of increasing treatment options for diseases, however identifying candidate molecules for the indication of interest from the thousands of approved drugs is challenging. We have performed a computational analysis of published literature to rank existing drugs according to predicted ability to reduce alpha synuclein (aSyn) oligomerization and analyzed real-world data to investigate the association between exposure to highly ranked drugs and PD. METHODS Using IBM Watson for Drug Discoveryâ (WDD) we identified several antihypertensive drugs that may reduce aSyn oligomerization. Using IBM MarketScanâ Research Databases we constructed a cohort of individuals with incident hypertension. We conducted univariate and multivariate Cox proportional hazard analyses (HR) with exposure as a time-dependent covariate. Diuretics were used as the referent group. Age at hypertension diagnosis, sex, and several comorbidities were included in multivariate analyses. RESULTS Multivariate results revealed inverse associations for time to PD diagnosis with exposure to the combination of the combination of angiotensin receptor II blockers (ARBs) and dihydropyridine calcium channel blockers (DHP-CCB) (HR = 0.55, p < 0.01) and angiotensin converting enzyme inhibitors (ACEi) and diuretics (HR = 0.60, p-value <0.01). Increased risk was observed with exposure to alpha-blockers alone (HR = 1.81, p < 0.001) and the combination of alpha-blockers and CCB (HR = 3.17, p < 0.05). CONCLUSIONS We present evidence that a computational approach can efficiently identify leads for disease-modifying drugs. We have identified the combination of ARBs and DHP-CCBs as of particular interest in PD.
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Affiliation(s)
- Naomi P Visanji
- Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
| | | | | | - Italo Buleje
- Foundational Innovation, Health Care and Life Sciences, IBM Cambridge Research Center, Cambridge, Massachusetts, USA
| | - Yanyan Han
- IBM Almaden Research Center, San Jose, California, USA
| | | | - Lorraine V Kalia
- Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
| | | | - Connie Marras
- Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
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Chrissobolis S, Luu AN, Waldschmidt RA, Yoakum ME, D'Souza MS. Targeting the renin angiotensin system for the treatment of anxiety and depression. Pharmacol Biochem Behav 2020; 199:173063. [PMID: 33115635 DOI: 10.1016/j.pbb.2020.173063] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/13/2020] [Accepted: 10/22/2020] [Indexed: 12/27/2022]
Abstract
Emotional disorders like anxiety and depression are responsible for considerable morbidity and mortality all over the world. Several antidepressant and anxiolytic medications are available for the treatment of anxiety and depression. However, a significant number of patients either do not respond to these medications or respond inadequately. Hence, there is a need to identify novel targets for the treatment of anxiety and depression. In this review we focus on the renin angiotensin system (RAS) as a potential target for the treatment of these disorders. We review work that has evaluated the effects of various compounds targeting the RAS on anxiety- and depression-like behaviors. Further, we suggest future work that must be carried out to fully exploit the RAS for the treatment of anxiety and depression. The RAS provides an attractive target for both the identification of novel anxiolytic and antidepressant medications and/or for enhancing the efficacy of currently available medications used for the treatment of anxiety and depression.
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Affiliation(s)
- Sophocles Chrissobolis
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States of America
| | - Anh N Luu
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States of America
| | - Ryan A Waldschmidt
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States of America
| | - Madison E Yoakum
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States of America
| | - Manoranjan S D'Souza
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States of America.
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Labandeira-Garcia JL, Valenzuela R, Costa-Besada MA, Villar-Cheda B, Rodriguez-Perez AI. The intracellular renin-angiotensin system: Friend or foe. Some light from the dopaminergic neurons. Prog Neurobiol 2020; 199:101919. [PMID: 33039415 PMCID: PMC7543790 DOI: 10.1016/j.pneurobio.2020.101919] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 08/20/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022]
Abstract
The renin-angiotensin system (RAS) is one of the oldest hormone systems in vertebrate phylogeny. RAS was initially related to regulation of blood pressure and sodium and water homeostasis. However, local or paracrine RAS were later identified in many tissues, including brain, and play a major role in their physiology and pathophysiology. In addition, a major component, ACE2, is the entry receptor for SARS-CoV-2. Overactivation of tissue RAS leads several oxidative stress and inflammatory processes involved in aging-related degenerative changes. In addition, a third level of RAS, the intracellular or intracrine RAS (iRAS), with still unclear functions, has been observed. The possible interaction between the intracellular and extracellular RAS, and particularly the possible deleterious or beneficial effects of the iRAS activation are controversial. The dopaminergic system is particularly interesting to investigate the RAS as important functional interactions between dopamine and RAS have been observed in the brain and several peripheral tissues. Our recent observations in mitochondria and nucleus of dopaminergic neurons may clarify the role of the iRAS. This may be important for the developing of new therapeutic strategies, since the effects on both extracellular and intracellular RAS must be taken into account, and perhaps better understanding of COVID-19 cell mechanisms.
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Affiliation(s)
- Jose L Labandeira-Garcia
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain.
| | - Rita Valenzuela
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Maria A Costa-Besada
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Begoña Villar-Cheda
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
| | - Ana I Rodriguez-Perez
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CiberNed), Madrid, Spain
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Nicotianamine-rich foods for improving the learning and memory functions and as an effective preventing agent of hypertension. FOOD BIOSCI 2020. [DOI: 10.1016/j.fbio.2020.100729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Cosarderelioglu C, Nidadavolu LS, George CJ, Oh ES, Bennett DA, Walston JD, Abadir PM. Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty. Front Neurosci 2020; 14:586314. [PMID: 33117127 PMCID: PMC7561440 DOI: 10.3389/fnins.2020.586314] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 08/25/2020] [Indexed: 12/15/2022] Open
Abstract
The renin–angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT1R, AT2R, MasR, and AT4R. These receptors have opposing effects; AT1R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT2R and MasR counteract the effects of AT1R. AT4R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer’s disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.
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Affiliation(s)
- Caglar Cosarderelioglu
- Division of Geriatrics, Department of Internal Medicine, Ankara University School of Medicine, Ankara, Turkey.,Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lolita S Nidadavolu
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Claudene J George
- Division of Geriatrics, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States
| | - Esther S Oh
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States
| | - Jeremy D Walston
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Peter M Abadir
- Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Campos J, Pacheco R. Involvement of dopaminergic signaling in the cross talk between the renin-angiotensin system and inflammation. Semin Immunopathol 2020; 42:681-696. [PMID: 32997225 PMCID: PMC7526080 DOI: 10.1007/s00281-020-00819-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 09/25/2020] [Indexed: 12/11/2022]
Abstract
The renin-angiotensin system (RAS) is a fundamental regulator of blood pressure and has emerged as an important player in the control of inflammatory processes. Accordingly, imbalance on RAS components either systemically or locally might trigger the development of inflammatory disorders by affecting immune cells. At the same time, alterations in the dopaminergic system have been consistently involved in the physiopathology of inflammatory disorders. Accordingly, the interaction between the RAS and the dopaminergic system has been studied in the context of inflammation of the central nervous system (CNS), kidney, and intestine, where they exert antagonistic actions in the regulation of the immune system. In this review, we summarized, integrated, and discussed the cross talk of the dopaminergic system and the RAS in the regulation of inflammatory pathologies, including neurodegenerative disorders, such as Parkinson’s disease. We analyzed the molecular mechanisms underlying the interaction between both systems in the CNS and in systemic pathologies. Moreover, we also analyzed the impact of the commensal microbiota in the regulation of RAS and dopaminergic system and how it is involved in inflammatory disorders. Furthermore, we summarized the therapeutic approaches that have yielded positive results in preclinical or clinical studies regarding the use of drugs targeting the RAS and dopaminergic system for the treatment of inflammatory conditions. Further understanding of the molecular and cellular regulation of the RAS-dopaminergic cross talk should allow the formulation of new therapies consisting of novel drugs and/or repurposing already existing drugs, alone or in combination, for the treatment of inflammatory disorders.
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Affiliation(s)
- Javier Campos
- Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Av. Zañartu 1482, 7780272 Ñuñoa, Santiago, Chile
| | - Rodrigo Pacheco
- Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Av. Zañartu 1482, 7780272 Ñuñoa, Santiago, Chile. .,Universidad San Sebastián, 7510156 Providencia, Santiago, Chile.
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Del Prete E, Francesconi A, Palermo G, Mazzucchi S, Frosini D, Morganti R, Coleschi P, Raglione LM, Vanni P, Ramat S, Novelli A, Napolitano A, Battisti C, Giuntini M, Rossi C, Menichetti C, Ulivelli M, De Franco V, Rossi S, Bonuccelli U, Ceravolo R. Prevalence and impact of COVID-19 in Parkinson's disease: evidence from a multi-center survey in Tuscany region. J Neurol 2020; 268:1179-1187. [PMID: 32880722 PMCID: PMC7471534 DOI: 10.1007/s00415-020-10002-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 12/17/2022]
Abstract
Background If Parkinson’s Disease (PD) may represent a risk factor for Coronavirus disease 2019 (COVID-19) is debated and there are few data on the direct and indirect effects of this pandemic in PD patients. Objective In the current study we evaluated the prevalence, mortality and case-fatality of COVID-19 in a PD cohort, also exploring possible risk factors. We also aimed to investigate the effect of lockdown on motor/non-motor symptoms in PD patients as well as their acceptability/accessibility to telemedicine. Method A case-controlled survey about COVID-19 and other clinical features in PD patients living in Tuscany was conducted. In non-COVID-19 PD patients motor/non-motor symptoms subjective worsening during the lockdown as well as feasibility of telemedicine were explored. Results Out of 740 PD patients interviewed, 7 (0.9%) were affected by COVID-19, with 0.13% mortality and 14% case-fatality. COVID-19 PD patients presented a higher presence of hypertension (p < 0.001) and diabetes (p = 0.049) compared to non-COVID-19. In non-COVID-19 PD population (n = 733) about 70% did not experience a subjective worsening of motor symptoms or mood, anxiety or insomnia. In our population 75.2% of patients was favorable to use technology to perform scheduled visits, however facilities for telemedicine were available only for 51.2% of cases. Conclusion A higher prevalence of COVID-19 respect to prevalence in Tuscany and Italy was found in the PD population. Hypertension and diabetes, as for general population, were identified as risk factors for COVID-19 in PD. PD patients did not experience a subjective worsening of symptoms during lockdown period and they were also favorable to telemedicine, albeit we reported a reduced availability to perform it.
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Affiliation(s)
- Eleonora Del Prete
- Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy
| | - Alessio Francesconi
- Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy
| | - Giovanni Palermo
- Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy
| | - Sonia Mazzucchi
- Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy
| | - Daniela Frosini
- Department of Medical Specialties, Neurology Unit, AOUP, Pisa, Italy
| | | | - Piero Coleschi
- Unit of Neurology, Ospedale San Donato Arezzo, Arezzo, Italy
| | - Laura Maria Raglione
- Unit of Neurology of Florence, Central Tuscany Local Health Authority, San Giovanni Di Dio Hospital, Firenze, Italy
| | - Paola Vanni
- Ospedale S. Maria Annunziata, ASL Centro, Firenze, Italy
| | - Silvia Ramat
- Parkinson Unit, Department of NeuroMuscular- Skeletal and Sensorial Organs, AO Careggi-Firenze, Firenze, Italy
| | - Alessio Novelli
- Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Firenze, Italy
| | | | - Carla Battisti
- Department of Medical-Surgical Science and Neuroscience, University of Siena, Siena, Italy
| | - Martina Giuntini
- Unit of Neurology, S. Stefano Prato Hospital, Azienda Toscana Centro, Pisa, Italy
| | - Carlo Rossi
- Unit of Neurology, Pontedera Hospital, Azienda Toscana nord-ovest, Pisa, Italy
| | | | - Monica Ulivelli
- Department of Medicine, Surgery and Neuroscience, Unit of Neurology and Clinical Neurophysiology, University of Siena, Siena, Italy
| | - Valentino De Franco
- Department of Medicine, Surgery and Neuroscience, Unit of Neurology and Clinical Neurophysiology, University of Siena, Siena, Italy
| | - Simone Rossi
- Department of Medicine, Surgery and Neuroscience, Unit of Neurology and Clinical Neurophysiology, University of Siena, Siena, Italy
| | - Ubaldo Bonuccelli
- Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy
| | - Roberto Ceravolo
- Clinical and Experimental Medicine Department, Neurology Unit, University of Pisa, Via Roma 67, Pisa, Italy.
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Sulzer D, Antonini A, Leta V, Nordvig A, Smeyne RJ, Goldman JE, Al-Dalahmah O, Zecca L, Sette A, Bubacco L, Meucci O, Moro E, Harms AS, Xu Y, Fahn S, Ray Chaudhuri K. COVID-19 and possible links with Parkinson's disease and parkinsonism: from bench to bedside. NPJ Parkinsons Dis 2020; 6:18. [PMID: 32885037 PMCID: PMC7441399 DOI: 10.1038/s41531-020-00123-0] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/20/2020] [Indexed: 02/08/2023] Open
Abstract
This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus on Parkinson's disease. Major points include that neuropathology studies have not answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia, and the brain vascular cell types that express virus have not yet been identified. Currently, there is no clear evidence for human neuronal or astrocyte expression of angiotensin-converting enzyme 2 (ACE2), the major receptor for viral entry, but ACE2 expression may be activated by inflammation, and a comparison of healthy and infected brains is important. In contrast to the 1918 influenza pandemic and avian flu, reports of encephalopathy in COVID-19 have been slow to emerge, and there are so far no documented reports of parkinsonism apart from a single case report. We recommend consensus guidelines for the clinical treatment of Parkinson's patients with COVID-19. While a role for the virus in causing or exacerbating Parkinson's disease appears unlikely at this time, aggravation of specific motor and non-motor symptoms has been reported, and it will be important to monitor subjects after recovery, particularly for those with persisting hyposmia.
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Affiliation(s)
- David Sulzer
- Departments of Psychiatry, Neurology, Pharmacology, Columbia University Medical Center, New York State Psychiatric Institute, New York, NY 10032 USA
| | - Angelo Antonini
- Department of Neuroscience, Parkinson and Movement Disorders Unit, University of Padua, Padua, Italy
| | - Valentina Leta
- King’s College London, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, SE5 8AF UK
- Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London, SE5 9RS UK
| | - Anna Nordvig
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY 10032 USA
| | - Richard J. Smeyne
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - James E. Goldman
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY 10032 USA
| | - Osama Al-Dalahmah
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY 10032 USA
| | - Luigi Zecca
- Institute of Biomedical Technologies, National Research Council of Italy, Segrate, Milan, Italy
| | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92093 USA
- Department of Medicine, University of California, San Diego, CA 92093 USA
| | - Luigi Bubacco
- Department of Biology, University of Padova, Padova, Italy
| | - Olimpia Meucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102 USA
- Center of Neuroimmunology and CNS Therapeutics, Institute of Molecular Medicine and Infectious Diseases, Drexel University College of Medicine, Philadelphia, PA 19102 USA
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102 USA
| | - Elena Moro
- Department of Neurology, Grenoble Alpes University Hospital, Grenoble, France
- Grenoble Institute of Neurosciences GIN-INSERM U1216/CEA/UGA, Grenoble, France
- Grenoble Alpes University, Grenoble, France
| | - Ashley S. Harms
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
| | - Yaqian Xu
- Department of Psychiatry, Columbia University Irving Medical Center, New York, NY 10032 USA
| | - Stanley Fahn
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY 10032 USA
| | - K. Ray Chaudhuri
- King’s College London, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, SE5 8AF UK
- Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London, SE5 9RS UK
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Rivas-Santisteban R, Rodriguez-Perez AI, Muñoz A, Reyes-Resina I, Labandeira-García JL, Navarro G, Franco R. Angiotensin AT 1 and AT 2 receptor heteromer expression in the hemilesioned rat model of Parkinson's disease that increases with levodopa-induced dyskinesia. J Neuroinflammation 2020; 17:243. [PMID: 32807174 PMCID: PMC7430099 DOI: 10.1186/s12974-020-01908-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS The renin-angiotensin system (RAS) is altered in Parkinson's disease (PD), a disease due to substantia nigra neurodegeneration and whose dopamine-replacement therapy, using the precursor levodopa, leads to dyskinesias as the main side effect. Angiotensin AT1 and AT2 receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (AT1/2Hets), are present in the central nervous system. We assessed the functionality and expression of AT1/2Hets in Parkinson disease (PD). METHODS Immunocytochemistry was used to analyze the colocalization between angiotensin receptors; bioluminescence resonance energy transfer was used to detect AT1/2Hets. Calcium and cAMP determination, MAPK activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify receptor expression in mouse primary cultures and in rat striatal sections. RESULTS We confirmed that AT1 and AT2 receptors form AT1/2Hets that are expressed in cells of the central nervous system. AT1/2Hets are novel functional units with particular signaling properties. Importantly, the coactivation of the two receptors in the heteromer reduces the signaling output of angiotensin. Remarkably, AT1/2Hets that are expressed in both striatal neurons and microglia make possible that candesartan, the antagonist of AT1, increases the effect of AT2 receptor agonists. In addition, the level of striatal expression increased in the unilateral 6-OH-dopamine lesioned rat PD model and was markedly higher in parkinsonian-like animals that did not become dyskinetic upon levodopa chronic administration if compared with expression in those that became dyskinetic. CONCLUSION The results indicate that boosting the action of neuroprotective AT2 receptors using an AT1 receptor antagonist constitutes a promising therapeutic strategy in PD.
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Affiliation(s)
- Rafael Rivas-Santisteban
- Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain
| | - Ana I Rodriguez-Perez
- Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain.,Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana Muñoz
- Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain.,Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Irene Reyes-Resina
- Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain.,Current adress: RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany
| | - José Luis Labandeira-García
- Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain.,Laboratory of Cellular and Molecular Neurobiology of Parkinson's disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Gemma Navarro
- Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain. .,Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.
| | - Rafael Franco
- Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain. .,School of Chemistry, Universitat de Barcelona, Barcelona, Spain.
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Geyer HL, Kaufman DM, Parihar RK, Mehler MF. Movement Disorders in COVID-19: Whither Art Thou? Tremor Other Hyperkinet Mov (N Y) 2020; 10:25. [PMID: 32864184 PMCID: PMC7427659 DOI: 10.5334/tohm.553] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022] Open
Affiliation(s)
- Howard L. Geyer
- Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, US
| | - David M. Kaufman
- Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, US
| | - Raminder K. Parihar
- Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, US
| | - Mark F. Mehler
- Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, US
- Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Institute for Brain Disorders and Neural Regeneration, Departments of Neuroscience, Psychiatry and Behavioral Sciences, Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, US
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Franco R, Rivas-Santisteban R, Serrano-Marín J, Rodríguez-Pérez AI, Labandeira-García JL, Navarro G. SARS-CoV-2 as a Factor to Disbalance the Renin–Angiotensin System: A Suspect in the Case of Exacerbated IL-6 Production. THE JOURNAL OF IMMUNOLOGY 2020; 205:1198-1206. [DOI: 10.4049/jimmunol.2000642] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
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Antonini A, Leta V, Teo J, Chaudhuri KR. Outcome of Parkinson's Disease Patients Affected by COVID-19. Mov Disord 2020; 35:905-908. [PMID: 32347572 PMCID: PMC7267273 DOI: 10.1002/mds.28104] [Citation(s) in RCA: 172] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 01/15/2023] Open
Affiliation(s)
- Angelo Antonini
- Parkinson and Movement Disorders Unit, University of Padua, Padua, Italy
| | - Valentina Leta
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom.,Parkinson's Foundation Centre of Excellence, King's College Hospital, London, United Kingdom
| | - James Teo
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom.,King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - K Ray Chaudhuri
- King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom.,Parkinson's Foundation Centre of Excellence, King's College Hospital, London, United Kingdom
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Synthesis and Evaluation of [ 18F]FEtLos and [ 18F]AMBF 3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors. Molecules 2020; 25:molecules25081872. [PMID: 32325695 PMCID: PMC7221519 DOI: 10.3390/molecules25081872] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/18/2020] [Accepted: 01/23/2020] [Indexed: 01/13/2023] Open
Abstract
Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.
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Donertas Ayaz B, Zubcevic J. Gut microbiota and neuroinflammation in pathogenesis of hypertension: A potential role for hydrogen sulfide. Pharmacol Res 2020; 153:104677. [PMID: 32023431 PMCID: PMC7056572 DOI: 10.1016/j.phrs.2020.104677] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/27/2019] [Accepted: 01/27/2020] [Indexed: 02/06/2023]
Abstract
Inflammation and gut dysbiosis are hallmarks of hypertension (HTN). Hydrogen sulfide (H2S) is an important freely diffusing molecule that modulates the function of neural, cardiovascular and immune systems, and circulating levels of H2S are reduced in animals and humans with HTN. While most research to date has focused on H₂S produced endogenously by the host, H2S is also produced by the gut bacteria and may affect the host homeostasis. Here, we review an association between neuroinflammation and gut dysbiosis in HTN, with special emphasis on a potential role of H2S in this interplay.
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Affiliation(s)
- Basak Donertas Ayaz
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States; Department of Pharmacology, College of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Jasenka Zubcevic
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
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Role of brain renin angiotensin system in neurodegeneration: An update. Saudi J Biol Sci 2020; 27:905-912. [PMID: 32127770 PMCID: PMC7042626 DOI: 10.1016/j.sjbs.2020.01.026] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 01/12/2023] Open
Abstract
Renin angiotensin system (RAS) is an endocrine system widely known for its physiological roles in electrolyte homeostasis, body fluid volume regulation and cardiovascular control in peripheral circulation. However, brain RAS is an independent form of RAS expressed locally in the brain, which is known to be involved in brain functions and disorders. There is strong evidence for a major involvement of excessive brain angiotensin converting enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin type-1 receptor (AT-1R) axis in increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration in several brain disorders. Numerous studies have demonstrated strong neuroprotective effects by blocking AT1R in these brain disorders. Additionally, the angiotensin converting enzyme 2 (ACE2)/Angiotensin (1–7)/Mas receptor (MASR), is another axis of brain RAS which counteracts the damaging effects of ACE/Ang II/AT1R axis on neurons in the brain. Thus, angiotensin II receptor blockers (ARBs) and activation of ACE2/Angiotensin (1–7)/MASR axis may serve as an exciting and novel method for neuroprotection in several neurodegenerative diseases. Here in this review article, we discuss the expression of RAS in the brain and highlight how altered RAS level may cause neurodegeneration. Understanding the pathophysiology of RAS and their links to neurodegeneration has enormous potential to identify potentially effective pharmacological tools to treat neurodegenerative diseases in the brain.
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Abstract
Hypertension is an important risk factor for cardiovascular morbidity and mortality and for events such as myocardial infarction, stroke, heart failure and chronic kidney disease and is a major determinant of disability-adjusted life-years. Despite the importance of hypertension, the pathogenesis of essential hypertension, which involves the complex interaction of several mechanisms, is still poorly understood. Evidence suggests that interplay between bone marrow, microglia and immune mediators underlies the development of arterial hypertension, in particular through mechanisms involving cytokines and peptides, such as neuropeptide Y, substance P, angiotensin II and angiotensin-(1-7). Chronic psychological stress also seems to have a role in increasing the risk of hypertension, probably through the activation of neuroimmune pathways. In this Review, we summarize the available data on the possible role of neuroimmune crosstalk in the origin and maintenance of arterial hypertension and discuss the implications of this crosstalk for recovery and rehabilitation after cardiac and cerebral injuries.
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