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Yoosuf BT, Jain S, Kt MF, Bansal D. Safety Profile of Istradefylline in Parkinson's Disease: A Meta-Analysis of Randomized Controlled Trials and Disproportionality Analysis Using FAERS. J Geriatr Psychiatry Neurol 2025:8919887251343608. [PMID: 40396988 DOI: 10.1177/08919887251343608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
BackgroundIstradefylline, a selective adenosine A2A receptor antagonist, is used as an adjunct therapy to levodopa to improve motor symptoms in Parkinson's disease (PD) patients, particularly those experiencing wearing-off phenomena. This study integrates safety data on istradefylline for the treatment of PD from randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS).MethodsWe performed a systematic search of PubMed, EMBASE, Ovid, MEDLINE, and ClinicalTrials.gov for RCTs on istradefylline safety in PD patients up to September 2024. A random-effects meta-analysis estimated the Peto odds ratio (OR) with 95% confidence intervals (CIs). FAERS data were analyzed through disproportionality measures, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), with signal refinement to primary suspect cases.ResultsThe safety meta-analysis, encompassing data from 8 RCTs, reveals a significant association between istradefylline treatment and an increased risk of dyskinesia (odds ratio [OR] 1.77, 95% CI 1.32-2.36; P = 0.01), hallucinations (OR 2.08, 95% CI 1.11-3.90; P = 0.02), and nausea, when compared with placebo. In the FAERS database, 2597 patients were identified with adverse events (AEs) linked to istradefylline. Disproportionality analysis of istradefylline revealed 39 AEs strongly associated with its use, all of which were substantiated through signal refinement. The most commonly reported AEs were primarily associated with nervous system and psychiatric disorders.ConclusionThis study highlights distinct AE patterns for istradefylline in trials vs real-world data, underscoring the importance of post-marketing surveillance to detect underreported AEs and validate new safety signals effectively.
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Affiliation(s)
- Beema T Yoosuf
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar (Mohali), Punjab, India
| | - Suhani Jain
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar (Mohali), Punjab, India
| | - Muhammed Favas Kt
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar (Mohali), Punjab, India
| | - Dipika Bansal
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar (Mohali), Punjab, India
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de Bie RM, Katzenschlager R, Swinnen BE, Peball M, Lim S, Mestre TA, Perez Lloret S, Coelho M, Aquino C, Tan AH, Bruno V, Dijk JM, Heim B, Lin C, Kauppila LA, Litvan I, Spijker R, Seppi K, Costa J, Sampaio C, Fox SH, Silverdale MA. Update on Treatments for Parkinson's Disease Motor Fluctuations - An International Parkinson and Movement Disorder Society Evidence-Based Medicine Review. Mov Disord 2025; 40:776-794. [PMID: 40055961 PMCID: PMC12089898 DOI: 10.1002/mds.30162] [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: 10/30/2024] [Revised: 01/17/2025] [Accepted: 02/12/2025] [Indexed: 05/21/2025] Open
Abstract
OBJECTIVE To update evidence-based medicine recommendations for treating motor fluctuations of Parkinson's disease (PD). BACKGROUND The International Parkinson and Movement Disorder Society (MDS) Evidence Based Medicine in Movement Disorders Committee recommendations for the treatments of PD were first published in 2002 and regularly updated. The current review uses a new methodology, including the Cochrane Risk of Bias tool and a modified version of GRADE (Grading of Recommendations, Assessment, Development, and Evaluations). METHODS On January 1, 2023, a literature search was conducted without date limit in the MEDLINE, Embase, and Cochrane databases using the following search terms: Parkinson disease, levodopa and, for the Embase database, randomized controlled trial (RCT). The inclusion criteria for studies were: patients with PD, on oral levodopa therapy, experiencing motor fluctuations, investigating an intervention that was (commercially) available in at least one country, study design RCT, and with a follow-up duration of at least 3 months. RESULTS A total of 102 studies were included. Levodopa extended release, pramipexole immediate release and extended release, ropinirole immediate release, rotigotine, opicapone, safinamide, and bilateral subthalamic nucleus deep brain stimulation (DBS) were assessed as efficacious, and continuous intestinal levodopa infusion, continuous subcutaneous levodopa, continuous subcutaneous apomorphine, ropinirole prolonged release, ropinirole patch, entacapone, rasagiline, istradefylline, amantadine extended release, zonisamide, bilateral globus pallidus DBS, and pallidotomy were assessed as likely efficacious for the treatment of motor fluctuations in people with PD who are already being treated with levodopa. CONCLUSIONS There are several treatment options that can improve motor fluctuations in PD. These recommendations will assist physicians and patients in determining which intervention to use. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Rob M.A. de Bie
- Department of Neurology, Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Regina Katzenschlager
- Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative DisordersKlinik DonaustadtViennaAustria
| | | | - Marina Peball
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
| | - Shen‐Yang Lim
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
- The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Tiago A. Mestre
- Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Research Institute, Division of Neurology, Department of MedicineUniversity of Ottawa, The Ottawa Hospital OttawaOttawaOntarioCanada
| | - Santiago Perez Lloret
- Observatorio de Salud, Vicerrectorado de Investigación, Pontificia Universidad Católica ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (UCA‐CONICET)Buenos AiresArgentina
- Departamento de Fisiología, Facultad de MedicinaUniversidad de Buenos Aires (UBA)Buenos AiresArgentina
| | - Miguel Coelho
- Department of Neurosciences and Mental Health, Neurology Service, Hospital Santa Maria, Centro de Estudo Egas Moniz, Faculdade de MedicinaUniversidade de LisboaLisbonPortugal
| | - Camila Aquino
- Hotchkiss Brain Institute, Department of Clinical Neurosciences, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
| | - Ai Huey Tan
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
- The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Veronica Bruno
- Hotchkiss Brain Institute, Department of Clinical Neurosciences, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
| | - Joke M. Dijk
- Department of Neurology, Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Beatrice Heim
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
| | - Chin‐Hsien Lin
- Department of NeurologyNational Taiwan University HospitalTaipeiTaiwan
| | | | - Irene Litvan
- Parkinson and Other Movement Disorders Center, Department of NeurosciencesUniversity of CaliforniaLa JollaCaliforniaUSA
| | - René Spijker
- Amsterdam Public Health, Medical LibraryAmsterdam University Medical Center, University of AmsterdamAmsterdamThe Netherlands
| | - Klaus Seppi
- Department of NeurologyMedical University of InnsbruckInnsbruckAustria
- Department of Neurology, Hospital KufsteinKufsteinAustria
| | - João Costa
- Universidade de LisboaFaculdade de MedicinaLisbonPortugal
| | - Cristina Sampaio
- CHDI Management, Inc. (the company that manages the scientific activities of the CHDI Foundation)PrincetonNew JerseyUSA
- Laboratorio de Farmacologia Clinica, Faculdade de Medicina de Lisboa (FMUL)LisbonPortugal
| | - Susan H. Fox
- Edmond J. Safra Program in Parkinson DiseaseKrembil Brain Institute, Toronto Western Hospital, University of TorontoTorontoOntarioCanada
| | - Monty A. Silverdale
- Department of Neurology, Manchester Centre for Clinical Neurosciences, Manchester Academic Health Science CentreUniversity of ManchesterManchesterUnited Kingdom
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Shi Z, Wen K, Sammudin NH, LoRocco N, Zhuang X. Erasing "bad memories": reversing aberrant synaptic plasticity as therapy for neurological and psychiatric disorders. Mol Psychiatry 2025:10.1038/s41380-025-03013-0. [PMID: 40210977 DOI: 10.1038/s41380-025-03013-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 02/24/2025] [Accepted: 04/02/2025] [Indexed: 04/12/2025]
Abstract
Dopamine modulates corticostriatal plasticity in both the direct and indirect pathways of the cortico-striato-thalamo-cortical (CSTC) loops. These gradual changes in corticostriatal synaptic strengths produce long-lasting changes in behavioral responses. Under normal conditions, these mechanisms enable the selection of the most appropriate responses while inhibiting others. However, under dysregulated dopamine conditions, including a lack of dopamine release or dopamine signaling, these mechanisms could lead to the selection of maladaptive responses and/or the inhibition of appropriate responses in an experience-dependent and task-specific manner. In this review, we propose that preventing or reversing such maladaptive synaptic strengths and erasing such aberrant "memories" could be a disease-modifying therapeutic strategy for many neurological and psychiatric disorders. We review evidence from Parkinson's disease, drug-induced parkinsonism, L-DOPA-induced dyskinesia, obsessive-compulsive disorder, substance use disorders, and depression as well as research findings on animal disease models. Altogether, these studies allude to an emerging theme in translational neuroscience and promising new directions for therapy development. Specifically, we propose that combining pharmacotherapy with behavioral therapy or with deep brain stimulation (DBS) could potentially cause desired changes in specific neural circuits. If successful, one important advantage of correcting aberrant synaptic plasticity is long-lasting therapeutic effects even after treatment has ended. We will also discuss the potential molecular targets for these therapeutic approaches, including the cAMP pathway, proteins involved in synaptic plasticity as well as pathways involved in new protein synthesis. We place special emphasis on RNA binding proteins and epitranscriptomic mechanisms, as they represent a new frontier with the distinct advantage of rapidly and simultaneously altering the synthesis of many proteins locally.
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Affiliation(s)
- Zhuoyue Shi
- The Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, IL, 60637, USA
| | - Kailong Wen
- The Committee on Neurobiology, The University of Chicago, Chicago, IL, 60637, USA
| | - Nabilah H Sammudin
- The Committee on Neurobiology, The University of Chicago, Chicago, IL, 60637, USA
| | - Nicholas LoRocco
- The Interdisciplinary Scientist Training Program, The University of Chicago, Chicago, IL, 60637, USA
| | - Xiaoxi Zhuang
- The Department of Neurobiology, The University of Chicago, Chicago, IL, 60637, USA.
- The Neuroscience Institute, The University of Chicago, Chicago, IL, 60637, USA.
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Isaacson SH, Jenner P. Moving to a non-dopaminergic approach for the treatment of OFF fluctuations in Parkinson's disease. Clin Park Relat Disord 2025; 12:100303. [PMID: 39968317 PMCID: PMC11834069 DOI: 10.1016/j.prdoa.2025.100303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/09/2025] [Accepted: 01/22/2025] [Indexed: 02/20/2025] Open
Abstract
In levodopa treated patients with Parkinson's disease (PD), the standard approach to managing motor fluctuations is to adjust dopaminergic therapy. However, despite the availability of a wide armamentarium of dopaminergic medications, most patients treated with levodopa will still experience significant OFF time, and it is increasingly clear that motor fluctuations have a significant non-dopaminergic component. In this narrative review, we compare and contrast the therapeutic profiles of the only two non-dopaminergic medications approved in the US for the management of OFF time, namely amantadine and istradefylline. When compared against each other the two agents exemplify two different pharmacological approaches to treatment. Whereas amantadine has a multimodal pharmacology, istradefylline has highly specific actions at A2A receptors which are highly expressed in the indirect pathway of the basal ganglia. We discuss how both offer an important alternative approach to treatment, without increasing total dopaminergic load. Clinicians can also consider that amantadine and istradefylline each have overlapping indications with classic dopaminergic medications, but with distinct mechanisms of action that can complement each other to reduce motor complications in patients already being treated with other dopaminergic agents.
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Affiliation(s)
- Stuart H. Isaacson
- Parkinson’s Disease and Movement Disorders Center of Boca Raton Boca Raton FL USA
| | - Peter Jenner
- Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London London UK
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Torres-Yaghi Y, Qian J, Cummings H, Shimoda H, Ito S, Batson S, Mitchell S, Pagan F. Comparative Safety of Istradefylline Among Parkinson Disease Adjunctive Therapies: A Systematic Review and Meta-analysis of Randomized Controlled Studies. Clin Neuropharmacol 2025; 48:7-12. [PMID: 39805118 PMCID: PMC11913241 DOI: 10.1097/wnf.0000000000000620] [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] [Indexed: 01/16/2025]
Abstract
INTRODUCTION Adjunctive therapies to treat OFF episodes resulting from long-term levodopa treatment in Parkinson disease (PD) are hampered by safety and tolerability issues. Istradefylline offers an alternative mechanism (adenosine A2A receptor antagonist) and therefore potentially improved tolerability. METHODS A systematic review of PD adjuncts published in 2011 was updated to include randomized controlled trials published from January 1, 2010-April 15, 2019. Pairwise meta-analyses were updated, and Bucher indirect comparisons were used to generate estimates of relative safety, presented as odds ratio (OR) and 95% confidence interval (CI) for comparators versus istradefylline. RESULTS Fifty-seven randomized controlled trials involving 11,517 patients were included in the meta-analysis. Relative to istradefylline, dopamine agonists and catechol-O-methyl transferase (COMT) inhibitors had statistically significant higher odds of dyskinesia and somnolence. Monoamine oxidase-B inhibitors had significantly higher odds of hypotension. Amantadine extended-release (ER) had statistically significant higher odds of hallucination, orthostatic hypotension, insomnia, and withdrawals due to adverse events. All interventions combined had significantly higher odds of dyskinesia versus istradefylline 20 mg and somnolence versus istradefylline 40 mg. Considering overall incidence of adverse events, COMT inhibitors and amantadine ER had statistically significant higher odds versus both istradefylline doses (COMT versus istradefylline 40 mg, OR: 1.33; 95% CI: 1.03, 1.75; versus istradefylline 20 mg, OR: 1.32; 95% CI: 1.01, 1.72; amantadine ER versus istradefylline 40 mg, OR: 3.45; 95% CI: 1.85, 6.25; versus istradefylline 20 mg, OR: 3.33; 95% CI: 1.82, 6.25). CONCLUSION Istradefylline was associated with a generally favorable safety profile relative to other adjunct medications in this study.
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Affiliation(s)
| | | | | | | | - Satoru Ito
- Kyowa Kirin Co., Ltd., Tokyo, Japan
- Department of Pharmacovigilance Operation, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Sarah Batson
- Mtech Access, Bicester, Oxfordshire, United Kingdom
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Forde L, Gogoi D, Baird R, McCarthy C, Keane MP, Reeves EP, McGrath EE. Does Adenosine Triphosphate via Purinergic Receptor Signalling Fuel Pulmonary Fibrosis? J Innate Immun 2024; 17:44-55. [PMID: 39662078 PMCID: PMC11779128 DOI: 10.1159/000543083] [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: 10/15/2024] [Accepted: 12/09/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Interstitial lung diseases (ILD) are poorly understood disorders characterised by diffuse damage to the lung parenchyma, with inflammation and fibrosis. Some manifest a progressive fibrotic phenotype with high fatality and limited treatment options, such as idiopathic pulmonary fibrosis. SUMMARY The degree to which inflammation plays a role in fibrosis progression is unknown. However, wound healing and fibrosis are intricate processes influenced by various inflammatory factors. Extracellular nucleosides and nucleotides, including adenosine triphosphate, activate pro-inflammatory responses to innate immunity and are widely implicated in tissue fibrosis across different organs. The pro-inflammatory effects of extracellular nucleotides occur via P1 and P2 purinergic receptors, expressed across the lung and immune system, and have been implicated in various pulmonary diseases including pulmonary fibrosis. This review amalgamates available data on the complex role of P1 and P2 purinergic receptor signalling in pulmonary fibrosis and discusses perspectives for novel treatments. KEY MESSAGES Purinergic signalling plays a complex and pivotal role in pulmonary fibrosis, warranting further study. The intricate interplay between P1 and P2 receptor pathways necessitates a comprehensive approach to understand their collective impact. While evidence from preclinical models is promising, human studies are essential for further understanding of pulmonary fibrosis. Advances in receptor-specific agonists and antagonists provide novel avenues for research and may ultimately lead to new therapies for patients. BACKGROUND Interstitial lung diseases (ILD) are poorly understood disorders characterised by diffuse damage to the lung parenchyma, with inflammation and fibrosis. Some manifest a progressive fibrotic phenotype with high fatality and limited treatment options, such as idiopathic pulmonary fibrosis. SUMMARY The degree to which inflammation plays a role in fibrosis progression is unknown. However, wound healing and fibrosis are intricate processes influenced by various inflammatory factors. Extracellular nucleosides and nucleotides, including adenosine triphosphate, activate pro-inflammatory responses to innate immunity and are widely implicated in tissue fibrosis across different organs. The pro-inflammatory effects of extracellular nucleotides occur via P1 and P2 purinergic receptors, expressed across the lung and immune system, and have been implicated in various pulmonary diseases including pulmonary fibrosis. This review amalgamates available data on the complex role of P1 and P2 purinergic receptor signalling in pulmonary fibrosis and discusses perspectives for novel treatments. KEY MESSAGES Purinergic signalling plays a complex and pivotal role in pulmonary fibrosis, warranting further study. The intricate interplay between P1 and P2 receptor pathways necessitates a comprehensive approach to understand their collective impact. While evidence from preclinical models is promising, human studies are essential for further understanding of pulmonary fibrosis. Advances in receptor-specific agonists and antagonists provide novel avenues for research and may ultimately lead to new therapies for patients.
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Affiliation(s)
- Luke Forde
- Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland,
- Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland,
| | - Debananda Gogoi
- Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Rory Baird
- Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Cormac McCarthy
- Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Michael P Keane
- Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Emer P Reeves
- Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Emmet E McGrath
- Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
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Alotaibi S, Alfayez L, Alkhudhair M. Parkinson's Disease: Current Treatment Modalities and Emerging Therapies. Cureus 2024; 16:e75647. [PMID: 39803037 PMCID: PMC11725288 DOI: 10.7759/cureus.75647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
Herein, we review the literature on Parkinson's disease (PD) management and summarize the progress in medical, surgical, and assisted therapeutic modalities for motor and non-motor symptoms. A thorough search strategy was implemented to retrieve all relevant articles and identify the best evidence from different databases including Scopus, PubMed, Google Scholar, the Cochrane Database of Systematic Reviews, and Evidence-Based Medicine reviews from the International Parkinson and Movement Disorder Society. Multiple terms, such as Parkinson, tremor, predominant, Parkinson management, deep brain stimulation, LCIG, ablative surgery for PD, medical management of PD, and assistive devices for PD, were used for screening. A total of 160 articles were gathered; irrelevant papers and older articles were excluded. After initial exclusion, we had 140 articles to review from 1980 to 2022. Five articles were found to be duplicated, and another five articles were excluded as they did not have additional information on management that could be used in this research paper. We found that management options and assistive devices for PD are improving, with new therapeutic options emerging every year. Medical therapy is the most common therapy as it corrects dopamine deficiency which is the main factor implicated in PD; other surgical treatment options are available in cases of chronic progressive disease course. This article adds significant value to the literature as it includes the history and the role of most Parkinson's disease management options.
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Affiliation(s)
- Shabab Alotaibi
- Neurology, Movement Disorder and Neuromodulation, King Saud Medical City, Riyadh, SAU
| | - Lujain Alfayez
- Neurology, Neurology Center, Prince Sultan Military Medical City, Riyadh, SAU
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Yue Y, Zhang X, Lv W, Lai HY, Shen T. Interplay between the glymphatic system and neurotoxic proteins in Parkinson's disease and related disorders: current knowledge and future directions. Neural Regen Res 2024; 19:1973-1980. [PMID: 38227524 DOI: 10.4103/1673-5374.390970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/26/2023] [Indexed: 01/17/2024] Open
Abstract
Parkinson's disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins, including α-synuclein, amyloid-β, and tau, in addition to the impaired elimination of these neurotoxic protein. Atypical parkinsonism, which has the same clinical presentation and neuropathology as Parkinson's disease, expands the disease landscape within the continuum of Parkinson's disease and related disorders. The glymphatic system is a waste clearance system in the brain, which is responsible for eliminating the neurotoxic proteins from the interstitial fluid. Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease, as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage. Therefore, impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration. Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson's disease and related disorders; however, many unanswered questions remain. This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson's disease and related disorders. The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins, including loss of polarization of aquaporin-4 in astrocytic endfeet, sleep and circadian rhythms, neuroinflammation, astrogliosis, and gliosis. This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson's disease and related disorders, and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.
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Affiliation(s)
- Yumei Yue
- Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xiaodan Zhang
- Department of Emergency Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Wen Lv
- Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Hsin-Yi Lai
- Department of Neurology of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Interdisciplinary Institute of Neuroscience and Technology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang Province, China
- MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Ting Shen
- Department of Neurology of the Second Affiliated Hospital and School of Brain Science and Brain Medicine, Interdisciplinary Institute of Neuroscience and Technology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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Ullah I, Wang X, Li H. Novel and experimental therapeutics for the management of motor and non-motor Parkinsonian symptoms. Neurol Sci 2024; 45:2979-2995. [PMID: 38388896 DOI: 10.1007/s10072-023-07278-7] [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: 10/25/2023] [Accepted: 12/14/2023] [Indexed: 02/24/2024]
Abstract
BACKGROUND : Both motor and non-motor symptoms of Parkinson's disease (PD) have a substantial detrimental influence on the patient's quality of life. The most effective treatment remains oral levodopa. All currently known treatments just address the symptoms; they do not completely reverse the condition. METHODOLOGY In order to find literature on the creation of novel treatment agents and their efficacy for PD patients, we searched PubMed, Google Scholar, and other online libraries. RESULTS According to the most recent study on Parkinson's disease (PD), a great deal of work has been done in both the clinical and laboratory domains, and some current scientists have even been successful in developing novel therapies for PD patients. CONCLUSION The quality of life for PD patients has increased as a result of recent research, and numerous innovative medications are being developed for PD therapy. In the near future, we will see positive outcomes regarding PD treatment.
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Affiliation(s)
- Inam Ullah
- School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Xin Wang
- School of Pharmacy, Lanzhou University, Lanzhou, China.
| | - Hongyu Li
- School of Life Sciences, Lanzhou University, Lanzhou, China.
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Raïch I, Lillo J, Rivas-Santisteban R, Rebassa JB, Capó T, Santandreu M, Cubeles-Juberias E, Reyes-Resina I, Navarro G. Potential of CBD Acting on Cannabinoid Receptors CB 1 and CB 2 in Ischemic Stroke. Int J Mol Sci 2024; 25:6708. [PMID: 38928415 PMCID: PMC11204117 DOI: 10.3390/ijms25126708] [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: 04/03/2024] [Revised: 06/06/2024] [Accepted: 06/16/2024] [Indexed: 06/28/2024] Open
Abstract
Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia. Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential. These compounds bind cannabinoid receptors CB1 and CB2. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential. On the one hand, these compounds could selectively bind the CB2 receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer's, Parkinson's disease, or stroke. On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect. Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ9-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.
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Affiliation(s)
- Iu Raïch
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
| | - Jaume Lillo
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
- Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, 08028 Barcelona, Spain
| | - Rafael Rivas-Santisteban
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
- Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, 08028 Barcelona, Spain
| | - Joan Biel Rebassa
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
| | - Toni Capó
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
| | - Montserrat Santandreu
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
| | - Erik Cubeles-Juberias
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
| | - Irene Reyes-Resina
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
| | - Gemma Navarro
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; (I.R.); (J.B.R.); (T.C.); (M.S.); (E.C.-J.)
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain; (J.L.); (R.R.-S.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Campus Mundet, Passeig de la Vall d’Hebron 171, 08035 Barcelona, Spain
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11
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Wang M, Guo W, Chen JF. Caffeine: a potential mechanism for anti-obesity. Purinergic Signal 2024:10.1007/s11302-024-10022-1. [PMID: 38802651 DOI: 10.1007/s11302-024-10022-1] [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: 03/05/2024] [Accepted: 05/13/2024] [Indexed: 05/29/2024] Open
Abstract
Obesity refers to the excessive accumulation of fat caused by a long-term imbalance between energy intake (EI) and energy expenditure (EE). Over recent years, obesity has become a major public health challenge. Caffeine is a natural product that has been demonstrated to exert anti-obesity effects; however, the mechanisms responsible for the effect of caffeine on weight loss have yet to be fully elucidated. Most obesity-related deaths are due to cardiovascular disease. Recent research has demonstrated that caffeine can reduce the risk of death from cardiovascular disease; thus, it can be hypothesized that caffeine may represent a new therapeutic agent for weight loss. In this review, we synthesize data arising from clinical and animal studies over the last decade and discuss the potential mechanisms by which caffeine may induce weight loss, focusing particularly on increasing energy consumption, suppressing appetite, altering lipid metabolism, and influencing the gut microbiota. Finally, we summarize the major challenges associated with caffeine and anti-obesity research and highlight possible directions for future research and development.
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Affiliation(s)
- Meng Wang
- International Joint Research Center on Purinergic Signaling, School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Wei Guo
- The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Jiang-Fan Chen
- The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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12
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Kee TR, Khan SA, Neidhart MB, Masters BM, Zhao VK, Kim YK, McGill Percy KC, Woo JAA. The multifaceted functions of β-arrestins and their therapeutic potential in neurodegenerative diseases. Exp Mol Med 2024; 56:129-141. [PMID: 38212557 PMCID: PMC10834518 DOI: 10.1038/s12276-023-01144-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 01/13/2024] Open
Abstract
Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, β-arrestin1, β-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of β-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that β-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). β-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, β-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, β-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the β2AR regulates SNCA gene expression. In this review, we aim to provide an overview of β-arrestin1 and β-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of β-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.
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Affiliation(s)
- Teresa R Kee
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA
- Department of Molecular Medicine, USF Health College of Medicine, Tampa, FL, 33613, USA
| | - Sophia A Khan
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA
| | - Maya B Neidhart
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA
| | - Brianna M Masters
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA
| | - Victoria K Zhao
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA
| | - Yenna K Kim
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA
| | | | - Jung-A A Woo
- Department of Pathology, CWRU School of Medicine, Cleveland, OH, 44106, USA.
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13
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Raïch I, Lillo J, Ferreiro-Vera C, Sánchez de Medina V, Navarro G, Franco R. Cannabidiol at Nanomolar Concentrations Negatively Affects Signaling through the Adenosine A 2A Receptor. Int J Mol Sci 2023; 24:17500. [PMID: 38139329 PMCID: PMC10744210 DOI: 10.3390/ijms242417500] [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: 10/28/2023] [Revised: 12/05/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Cannabidiol (CBD) is a phytocannabinoid with potential as a therapy for a variety of diseases. CBD may act via cannabinoid receptors but also via other G-protein-coupled receptors (GPCRs), including the adenosine A2A receptor. Homogenous binding and signaling assays in Chinese hamster ovary (CHO) cells expressing the human version of the A2A receptor were performed to address the effect of CBD on receptor functionality. CBD was not able to compete for the binding of a SCH 442416 derivative labeled with a red emitting fluorescent probe that is a selective antagonist that binds to the orthosteric site of the receptor. However, CBD reduced the effect of the selective A2A receptor agonist, CGS 21680, on Gs-coupling and on the activation of the mitogen activated kinase signaling pathway. It is suggested that CBD is a negative allosteric modulator of the A2A receptor.
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Affiliation(s)
- Iu Raïch
- Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, 08028 Barcelona, Spain; (I.R.); (G.N.)
- CiberNed, Network Center for Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28029 Madrid, Spain;
| | - Jaume Lillo
- CiberNed, Network Center for Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28029 Madrid, Spain;
- Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, 08028 Barcelona, Spain
| | | | | | - Gemma Navarro
- Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, 08028 Barcelona, Spain; (I.R.); (G.N.)
- CiberNed, Network Center for Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28029 Madrid, Spain;
- Institute of Neurosciences, Universitat de Barcelona, 08007 Barcelona, Spain
| | - Rafael Franco
- CiberNed, Network Center for Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28029 Madrid, Spain;
- Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, 08028 Barcelona, Spain
- School of Chemistry, Universitat de Barcelona, 08028 Barcelona, Spain
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14
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Koch J. Management of OFF condition in Parkinson disease. Ment Health Clin 2023; 13:289-297. [PMID: 38058599 PMCID: PMC10696172 DOI: 10.9740/mhc.2023.12.289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 08/31/2023] [Indexed: 12/08/2023] Open
Abstract
Parkinson disease (PD) impacts nearly 1 million individuals in the United States. Nearly every patient with PD will require therapy with dopamine in the form of levodopa as the disease progresses. In more advanced stages of the disease, patients will experience motor fluctuations and require adjustment to their medication regimens to maintain good control of their symptoms. During the last 10 years, several new therapeutic treatment options have come to the market to treat motor fluctuations and improve patient quality of life. Some of these agents represent additional options to previously available drug classes, such as the catechol-O-methyl transferase (COMT) inhibitor, opicapone, and monoamine-oxidase B-inhibitor (MAO-B inhibitor), safinamide, as well as new dosage forms for available therapeutics. One new agent, istradefylline, has a novel mechanism in the treatment of PD. The place in therapy for these newer therapeutic options will be explored through a series of patient cases. This article focuses on evidence-based recommendations for the use of these newer options in the management of patients experiencing OFF episodes.
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15
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Tang C, Liu D, Zhu Z. Research progress of microglial surface receptors in perioperative neurocognitive disorders. IBRAIN 2023; 10:450-461. [PMID: 39691417 PMCID: PMC11649389 DOI: 10.1002/ibra.12136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 09/23/2023] [Accepted: 09/26/2023] [Indexed: 12/19/2024]
Abstract
Perioperative neurocognitive disorder (PND) is a common complication in the perioperative period, which not only prolongs the hospitalization of patients, increases the cost of treatment, but even increases the postoperative mortality of patients, bringing a heavy burden to families and society. Mechanism exploration involves anesthesia and surgery that lead to microglial activation, promote the synthesis and secretion of inflammatory factors, cause an inflammatory cascade, aggravate nerve cell damage, and lead to cognitive dysfunction. It is believed that microglia-mediated neuroinflammatory responses play a vital role in the formation of PND. Microglia surface receptors are essential mediators for microglia to receive external stimuli, regulate microglial functional status, and carry out intercellular signal transmission. Various microglial surface receptors trigger neuroinflammation, damage neurons, and participate in the development and progression of PND by activating microglia. In this study, the roles of immunoglobulin receptors, chemokine receptors, purinergic receptors, and pattern recognition receptors in microglia surface receptors in PND were reviewed, to provide a reference for the mechanism research, prevention, and treatment of PND.
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Affiliation(s)
- Chun‐Chun Tang
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - De‐Xing Liu
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Zhao‐Qiong Zhu
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
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16
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Rivas-Santisteban R, Rico AJ, Muñoz A, Rodríguez-Pérez AI, Reyes-Resina I, Navarro G, Labandeira-García JL, Lanciego JL, Franco R. Boolean analysis shows a high proportion of dopamine D 2 receptors interacting with adenosine A 2A receptors in striatal medium spiny neurons of mouse and non-human primate models of Parkinson's disease. Neurobiol Dis 2023; 188:106341. [PMID: 37918757 DOI: 10.1016/j.nbd.2023.106341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/16/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023] Open
Abstract
The antagonistic effect of adenosine on dopaminergic transmission in the basal ganglia indirect motor control pathway is mediated by dopamine D2 (D2R) and adenosine A2A (A2AR) receptors co-expressed on medium spiny striatal neurons. The pathway is unbalanced in Parkinson's disease (PD) and an A2AR blocker has been approved for use with levodopa in the therapy of the disease. However, it is not known whether the therapy is acting on individually expressed receptors or in receptors forming A2A-D2 receptor heteromers, whose functionality is unique. For two proteins prone to interact, a very recently developed technique, MolBoolean, allows to determine the number of proteins that are either non-interacting or interacting. After checking the feasibility of the technique and reliability of data in transfected cells and in striatal primary neurons, the Boolean analysis of receptors in the striatum of rats and monkeys showed a high percentage of D2 receptors interacting with the adenosine receptor, while, on the contrary, a significant proportion of A2A receptors do not interact with dopamine receptors. The number of interacting receptors increased when rats and monkeys were lesioned to become a PD model. The use of a tracer of the indirect pathway in monkeys confirmed that the data was restricted to the population of striatal neurons projecting to the GPe. The results are not only relevant for being the first study quantifying individual versus interacting G protein-coupled receptors, but also for showing that the D2R in these specific neurons, in both control and PD animals, is under the control of the A2AR. The tight adenosine/dopamine receptor coupling suggest benefits of early antiparkinsonian treatment with adenosine receptor blockers.
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Affiliation(s)
- Rafael Rivas-Santisteban
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Campus Bellaterra, 08193 Barcelona. Spain; Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain.
| | - Alberto José Rico
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; CNS Gene Therapy Department, Center for Applied Medical Research (CIMA, IdiSNA), University of Navarra, Pamplona, Spain
| | - Ana Muñoz
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; 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 Rodríguez-Pérez
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; 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
| | - Irene Reyes-Resina
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Gemma Navarro
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, 08028 Barcelona, Spain; Institute of Neuroscience of the University of Barcelona, Universitat de Barcelona, 08028 Barcelona, Spain
| | - José Luis Labandeira-García
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; 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
| | - José Luis Lanciego
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; CNS Gene Therapy Department, Center for Applied Medical Research (CIMA, IdiSNA), University of Navarra, Pamplona, Spain
| | - Rafael Franco
- Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; Molecular Neurobiology laboratory, Dept. Biochemistry and Molecular Biomedicine, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; School of Chemistry, Universitat de Barcelona. Barcelona, Spain.
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17
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Sako W, Kogo Y, Koebis M, Kita Y, Yamakage H, Ishida T, Hattori N. Comparative efficacy and safety of adjunctive drugs to levodopa for fluctuating Parkinson's disease - network meta-analysis. NPJ Parkinsons Dis 2023; 9:143. [PMID: 37853009 PMCID: PMC10584871 DOI: 10.1038/s41531-023-00589-8] [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: 06/13/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023] Open
Abstract
It remains unclear which adjunctive drug for Parkinson's disease (PD) in combination with levodopa is more effective, tolerable, and safe. We aimed to compare the efficacy, tolerability, and safety among anti-PD drugs from several classes in patients with fluctuating PD who received levodopa through network meta-analysis (NMA). Twelve anti-PD drugs belonging to 4 different drug classes (dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, and an adenosine A2A receptor antagonist) were selected. We systematically searched PubMed, Embase, and the Cochrane Library for eligible randomized controlled trials (RCTs) comparing placebo with anti-PD drug or among anti-PD drugs in patients with PD who experienced motor fluctuations or wearing-off and received levodopa. We included 54 RCTs in the analysis. The NMA was performed under a frequentist framework using a random-effects model. The efficacy outcome was change in daily off-time, and the tolerability outcome was discontinuation due to all causes. Safety outcomes included discontinuation due to adverse events (AEs) and the incidence of AEs, dyskinesia, hallucination, and orthostatic hypotension. According to the surface under the cumulative ranking curve (SUCRA) in the NMA, ropinirole transdermal patch (SUCRA, 0.861) ranked the highest in efficacy, followed by pramipexole (0.762), ropinirole extended release (ER) (0.750), and safinamide (0.691). In terms of tolerability, ropinirole (0.954) ranked the highest, followed by pramipexole (0.857), safinamide (0.717), and ropinirole ER (0.708). Each anti-PD drug had different SUCRA ranking profiles for the safety outcomes. These findings suggest that ropinirole, pramipexole, and safinamide are well-balanced anti-PD drugs that satisfy both efficacy and tolerability outcomes.
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Affiliation(s)
- Wataru Sako
- Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
| | - Yuki Kogo
- Medical Headquarters, Eisai Co., Ltd., Tokyo, Japan
| | | | - Yoshiaki Kita
- Publication Business, Medical Professional Relations Inc., Osaka, Japan
| | - Hajime Yamakage
- Department of Medical Statistics, Satista Co., Ltd., Kyoto, Japan
| | | | - Nobutaka Hattori
- Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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18
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Karati D, Mukherjee S, Roy S. Molecular and Structural Insight into Adenosine A 2A Receptor in Neurodegenerative Disorders: A Significant Target for Efficient Treatment Approach. Mol Neurobiol 2023; 60:5987-6000. [PMID: 37391647 DOI: 10.1007/s12035-023-03441-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 06/10/2023] [Indexed: 07/02/2023]
Abstract
All biological tissues and bodily fluids include the autacoid adenosine. The P1 class of purinergic receptors includes adenosine receptors. Four distinct G-protein-coupled receptors on the cellular membrane mediate the effects of adenosine, whose cytoplasmic content is regulated by producing/degrading enzymes and nucleoside transporters. A2A receptor has received a great deal of attention in recent years because it has a wide range of potential therapeutic uses. A2B and, more significantly, A2A receptors regulate numerous physiological mechanisms in the central nervous system (CNS). The inferior targetability of A2B receptors towards adenosine points that they might portray a promising medicinal target since they are triggered only under pharmacological circumstances (when adenosine levels rise up to micromolar concentrations). The accessibility of specific ligands for A2B receptors would permit the exploration of such a theory. A2A receptors mediate both potentially neurotoxic and neuroprotective actions. Hence, it is debatable to what extent they play a role in neurodegenerative illnesses. However, A2A receptor blockers have demonstrated clear antiparkinsonian consequences, and a significant attraction exists in the role of A2A receptors in other neurodegenerative disorders. Amyloid peptide extracellular accumulation and tau hyperphosphorylation are the pathogenic components of AD that lead to neuronal cell death, cognitive impairment, and memory loss. Interestingly, in vitro and in vivo research has shown that A2A adenosine receptor antagonists may block each of these clinical symptoms, offering a crucial new approach to combat a condition for which, regrettably, only symptomatic medications are currently available. At least two requirements must be met to determine whether such receptors are a target for diseases of the CNS: a complete understanding of the mechanisms governing A2A-dependent processes and the availability of ligands that can distinguish between the various receptor populations. This review concisely summarises the biological effects mediated by A2A adenosine receptors in neurodegenerative disorders and discusses the chemical characteristics of A2A adenosine receptor antagonists undergoing clinical trials. Selective A2A receptor blocker against neurodegenerative disorders.
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Affiliation(s)
- Dipanjan Karati
- Department of Pharmaceutical Technology, School of Pharmacy, Techno India University, Kolkata, 700091, India
| | - Swarupananda Mukherjee
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata, 124 B.L. Saha Road, Kolkata, West Bengal, 700053, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata, 124 B.L. Saha Road, Kolkata, West Bengal, 700053, India.
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19
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Ohno Y, Okita E, Kawai-Uchida M, Shoukei Y, Soshiroda K, Kanda T, Uchida S. The adenosine A 2A receptor antagonist/inverse agonist, KW-6356 enhances the anti-parkinsonian activity of L-DOPA with a low risk of dyskinesia in MPTP-treated common marmosets. J Pharmacol Sci 2023; 152:193-199. [PMID: 37257947 DOI: 10.1016/j.jphs.2023.05.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/27/2023] [Accepted: 05/08/2023] [Indexed: 06/02/2023] Open
Abstract
The adenosine A2A receptor antagonist/inverse agonist, KW-6356 has been shown to be effective in Parkinson's disease (PD) patients as monotherapy and as an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor. However, the effects of KW-6356 combined with L-DOPA on anti-parkinsonian activity and established dyskinesia has not been investigated in preclinical experiments. We examined the effects of combination of KW-6356 with L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. Oral administration of KW-6356 (1 mg/kg) enhanced the anti-parkinsonian activities of various doses of L-DOPA (2.5-10 mg/kg). In MPTP-treated common marmosets primed with L-DOPA to show dyskinesia, KW-6356 (1 mg/kg) also enhanced the anti-parkinsonian activities of various doses of L-DOPA (1.25-10 mg/kg) but not dyskinesia. Chronic co-administration of KW-6356 (1 mg/kg) with a low dose of L-DOPA (2.5 mg/kg) for 21 days increased the degree of dyskinesia induced by the low dose of L-DOPA, but the amplitude of dyskinesia induced by combined administration of KW-6356 (1 mg/kg) with L-DOPA (2.5 mg/kg) was lower than that induced by an optimal dose of L-DOPA (10 mg/kg). These results suggest that KW-6356 can be used to potentiate the effects of a wide range of L-DOPA doses with a low risk of dyskinesia for the treatment of PD.
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Affiliation(s)
- Yutaro Ohno
- Biomedical Science Research Laboratories 1, Research Unit, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
| | - Eri Okita
- Research Core Function Laboratories, Research Unit, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
| | - Mika Kawai-Uchida
- Research Core Function Laboratories, Research Unit, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
| | - Youji Shoukei
- Research Core Function Laboratories, Research Unit, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
| | - Kazuhiro Soshiroda
- Research Core Function Laboratories, Research Unit, R&D Division, Kyowa Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo, Japan
| | - Tomoyuki Kanda
- R&D Planning Department, R&D Division, Kyowa Kirin Co., Ltd., 1-9-2 Otemachi, Chiyoda-Ku, Tokyo, Japan
| | - Shinichi Uchida
- Biomedical Science Research Laboratories 1, Research Unit, R&D Division, Kyowa Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
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Richmond AM, Lyons KE, Pahwa R. Safety review of current pharmacotherapies for levodopa-treated patients with Parkinson's disease. Expert Opin Drug Saf 2023; 22:563-579. [PMID: 37401865 DOI: 10.1080/14740338.2023.2227096] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/15/2023] [Indexed: 07/05/2023]
Abstract
INTRODUCTION Levodopa remains the gold standard for treatment of Parkinson's disease (PD). Patients develop complications with disease progression, necessitating adjunctive therapy to control fluctuations in motor and non-motor symptoms and dyskinesia. Knowledge of medication safety and tolerability is critical to ascertain the benefit-risk ratio and select an adjunctive therapy that provides the highest chance for medication adherence. Posing a challenge are the sheer abundance of options, stemming from the development of several new drugs in recent years, as well as differences in commercial drug availability worldwide. AREAS COVERED This review evaluates the efficacy, safety, and tolerability of current US FDA-approved pharmacotherapies for levodopa-treated PD patients, including dopamine agonists, monoamine oxidase type-B inhibitors, catechol-O-methyltransferase inhibitors, the N-methyl-D-aspartate receptor antagonist amantadine, and the adenosine receptor antagonist istradefylline. Data were taken from pivotal phase III randomized controlled and post-surveillance studies, when available, that directly led to FDA-approval. EXPERT OPINION No strong evidence exists to support use of a specific adjunctive treatment for improving Off time. Only one medication has demonstrated improvement in dyskinesia in levodopa-treated PD patients; however, every patient cannot tolerate it and therefore adjunctive therapy should be tailored to an individual's symptoms and risk for specific adverse effects.
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Affiliation(s)
- Angela M Richmond
- Parkinson's and Movement Disorders Division, Department of Neurology, The University of Kansas Medical Center, Kansas, KS, United States of America
| | - Kelly E Lyons
- Research and Education, Parkinson's and Movement Disorders Division, Department of Neurology, The University of Kansas Medical Center, Kansas, KS, United States of America
| | - Rajesh Pahwa
- Laverne & Joyce Rider Professor of Neurology, Chief, Parkinson's and Movement Disorders Division Director, Parkinson's Foundation Center of Excellence, The University of Kansas Medical Center, Kansas, KS, United States of America
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di Biase L, Pecoraro PM, Carbone SP, Caminiti ML, Di Lazzaro V. Levodopa-Induced Dyskinesias in Parkinson's Disease: An Overview on Pathophysiology, Clinical Manifestations, Therapy Management Strategies and Future Directions. J Clin Med 2023; 12:4427. [PMID: 37445461 DOI: 10.3390/jcm12134427] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/18/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Since its first introduction, levodopa has become the cornerstone for the treatment of Parkinson's disease and remains the leading therapeutic choice for motor control therapy so far. Unfortunately, the subsequent appearance of abnormal involuntary movements, known as dyskinesias, is a frequent drawback. Despite the deep knowledge of this complication, in terms of clinical phenomenology and the temporal relationship during a levodopa regimen, less is clear about the pathophysiological mechanisms underpinning it. As the disease progresses, specific oscillatory activities of both motor cortical and basal ganglia neurons and variation in levodopa metabolism, in terms of the dopamine receptor stimulation pattern and turnover rate, underlie dyskinesia onset. This review aims to provide a global overview on levodopa-induced dyskinesias, focusing on pathophysiology, clinical manifestations, therapy management strategies and future directions.
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Affiliation(s)
- Lazzaro di Biase
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
- Brain Innovations Lab, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo, 21, 00128 Rome, Italy
| | - Pasquale Maria Pecoraro
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
- Unit of Neurology, Neurophysiology, Neurobiology and Psichiatry, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Simona Paola Carbone
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
- Unit of Neurology, Neurophysiology, Neurobiology and Psichiatry, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Maria Letizia Caminiti
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
- Unit of Neurology, Neurophysiology, Neurobiology and Psichiatry, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Vincenzo Di Lazzaro
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
- Unit of Neurology, Neurophysiology, Neurobiology and Psichiatry, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
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Lillo J, García-Pérez I, Lillo A, Serrano-Marín J, Martínez-Pinilla E, Navarro G, Franco R. The olfactory Olfr-78/51E2 receptor interacts with the adenosine A 2A receptor. Effect of menthol and 1,8-cineole on A 2A receptor-mediated signaling. Front Pharmacol 2023; 14:1108617. [PMID: 37266149 PMCID: PMC10229766 DOI: 10.3389/fphar.2023.1108617] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 04/27/2023] [Indexed: 06/03/2023] Open
Abstract
Heteromer formation is unknown for the olfactory family of G protein-coupled receptors (GPCRs). We here identified, in a heterologous system, heteromers formed by the adenosine A2A receptor (A2AR), which is a target for neuroprotection, and an olfactory receptor. A2AR interacts with the receptor family 51, subfamily E, member 2 (OR51E2), the human ortholog of the mouse Olfr-78, whose mRNA is differentially expressed in activated microglia treated with adenosine receptor ligands. Bioluminescence resonance energy transfer (BRET) assays were performed in HEK-293T cells expressing the human version of the receptors, OR51E2 and A2AR, fused, respectively, to Renilla luciferase (RLuc) and the yellow fluorescent protein (YFP). BRET data was consistent with a receptor-receptor interaction whose consequences at the functional level were measured by cAMP level determination in CHO cells. Results showed an olfactory receptor-mediated partial blockade of Gs coupling to the A2AR, i.e., the effect of the A2AR selective agonist on intracellular levels of cAMP was significantly reduced. Two odorants, menthol and 1,8-cineole, which failed to show Golf-mediated OR51E2 activation because they did not increase cytosolic cAMP levels, reduced the BRET readings in cells expressing A2AR-YFP and OR51E2-Rluc, most likely suggesting a conformational change of at least one receptor. These odorants led to an almost complete block of A2AR coupling to Gs.
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Affiliation(s)
- Jaume Lillo
- Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain
- CiberNed, Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, Spain
| | - Irene García-Pérez
- Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Alejandro Lillo
- Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain
- CiberNed, Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, Spain
| | - Joan Serrano-Marín
- Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Eva Martínez-Pinilla
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Asturias, Spain
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), Asturias, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain
| | - Gemma Navarro
- Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain
- CiberNed, Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, Spain
- Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain
| | - Rafael Franco
- CiberNed, Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, Spain
- Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
- School of Chemistry, Universitat de Barcelona, Barcelona, Spain
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Fabbri M, Barbosa R, Rascol O. Off-time Treatment Options for Parkinson's Disease. Neurol Ther 2023; 12:391-424. [PMID: 36633762 PMCID: PMC10043092 DOI: 10.1007/s40120-022-00435-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/20/2022] [Indexed: 01/13/2023] Open
Abstract
Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.
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Affiliation(s)
- Margherita Fabbri
- Department of Clinical Pharmacology and Neurosciences, Toulouse Parkinson Expert Centre, Toulouse NeuroToul Center of Excellence in Neurodegeneration (COEN), French NS-Park/F-CRIN Network, University of Toulouse 3, CHU of Toulouse, INSERM, Toulouse, France.
| | - Raquel Barbosa
- Department of Clinical Pharmacology and Neurosciences, Toulouse Parkinson Expert Centre, Toulouse NeuroToul Center of Excellence in Neurodegeneration (COEN), French NS-Park/F-CRIN Network, University of Toulouse 3, CHU of Toulouse, INSERM, Toulouse, France.,Department of Neurology, Hospital de Egas Moniz Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.,NOVA Medical School, Faculdade de Ciências Médicas Universidade Nova de Lisboa, Lisbon, Portugal
| | - Olivier Rascol
- Department of Clinical Pharmacology and Neurosciences, Toulouse Parkinson Expert Centre, Toulouse NeuroToul Center of Excellence in Neurodegeneration (COEN), French NS-Park/F-CRIN Network, University of Toulouse 3, CHU of Toulouse, INSERM, Toulouse, France
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Jing XZ, Yuan XZ, Luo X, Zhang SY, Wang XP. An Update on Nondopaminergic Treatments for Motor and Non-motor Symptoms of Parkinson's Disease. Curr Neuropharmacol 2023; 21:1806-1826. [PMID: 35193486 PMCID: PMC10514518 DOI: 10.2174/1570159x20666220222150811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/19/2022] [Accepted: 02/19/2022] [Indexed: 11/22/2022] Open
Abstract
Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.
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Affiliation(s)
- Xiao-Zhong Jing
- Department of Neurology, TongRen Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiang-Zhen Yuan
- Department of Neurology, Weifang People's Hospital, Weifang, Shandong, China
| | - Xingguang Luo
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Shu-Yun Zhang
- Department of Neurology, Weifang People's Hospital, Weifang, Shandong, China
| | - Xiao-Ping Wang
- Department of Neurology, TongRen Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Tibashailwa N, Stephano F, Shadrack DM, Munissi JJE, Nyandoro SS. Neuroprotective potential of cinnamoyl derivatives against Parkinson's disease indicators in Drosophila melanogaster and in silico models. Neurotoxicology 2023; 94:147-157. [PMID: 36410467 DOI: 10.1016/j.neuro.2022.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 09/23/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022]
Abstract
Parkinson's disease (PD) is a movement disorder resulting from the loss of dopaminergic neurons over time. While there is no cure for PD, available conventional therapies aid to manage the motor symptoms. Natural products (NPs) derived from plants are among the most potent alternative therapies for PD. This study explored the neuroprotective potential of selected cinnamoyl derivatives namely toussaintine A (1), E-toussaintine E (2), asperphenamate (3) and julocrotine (4) against PD indicators using rotenone-challenged Drosophila melanogaster and in silico models. The compounds were first assessed for their toxicity preceding treatment experiments. Adult flies (aged 1-4 days) were exposed to varying concentrations of the compounds for 7 days. During the experiment, the mortality of flies was observed, and the lethal concentration (LC50) of each tested compound was determined. The LC50 values were found to be 50.1, 55.6, 513.5, and 101.0 µM for compounds 1, 2, 3, and 4, respectively. For seven days, we exposed flies to 500 µM of rotenone and co-fed with a chosen dose of 40 µM of each test compound in the diet. Using a negative geotaxis test, rotenone-challenged flies exhibited compromised climbing ability in comparison to control flies, the condition that was reversed by the action of studied compounds. Rotenone exposure also elevated malondialdehyde levels in the brain tissues, as measured by lipid peroxidation, when compared to control flies. In flies exposed to rotenone and co-fed with the compounds, this effect was lessened. In flies exposed to rotenone, mRNA levels of antioxidant enzymes such as superoxide dismutase and catalase were raised but were normalized in flies treated with the investigated compounds. Moreover, in-silico studies examined the inhibitory ability of compounds 1-4 against selected PD molecular targets, revealing the strong power of toussaintine A (1) against Adenosine receptor 2 (A2AR) and monoamine oxidase B. Thus, our findings suggest that cinnamoyl derivatives have neuroprotective potential via reducing the oxidative burden and improving locomotor ability after toxin invectives. In particular, compound 1 at lower doses can simultaneously be a potential inhibitor of A2AR and an anti-oxidative mediator in the development of anti-PD agents.
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Affiliation(s)
- Nelson Tibashailwa
- Chemistry Department, College of Natural and Applied Sciences, University of Dar es Salaam, P.O Box 35061, Dar es Salaam, Tanzania; Department of Zoology and Wildlife Conservation, College of Natural and Applied Sciences, University of Dar es Salaam, P.O Box 35064, Dar es Salaam, Tanzania
| | - Flora Stephano
- Department of Zoology and Wildlife Conservation, College of Natural and Applied Sciences, University of Dar es Salaam, P.O Box 35064, Dar es Salaam, Tanzania.
| | - Daniel M Shadrack
- Department of Chemistry, Faculty of Natural and Applied Sciences, St. John's University of Tanzania, Dodoma, P.O Box 47, Dodoma, Tanzania
| | - Joan J E Munissi
- Chemistry Department, College of Natural and Applied Sciences, University of Dar es Salaam, P.O Box 35061, Dar es Salaam, Tanzania
| | - Stephen S Nyandoro
- Chemistry Department, College of Natural and Applied Sciences, University of Dar es Salaam, P.O Box 35061, Dar es Salaam, Tanzania
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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: 6] [Impact Index Per Article: 2.0] [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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Safety and effectiveness of istradefylline as add-on therapy to levodopa in patients with Parkinson's disease: Final report of a post-marketing surveillance study in Japan. J Neurol Sci 2022; 443:120479. [PMID: 36395674 DOI: 10.1016/j.jns.2022.120479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/21/2022] [Accepted: 10/23/2022] [Indexed: 11/11/2022]
Abstract
INTRODUCTION Istradefylline is approved in Japan and the US for treatment of Parkinson's disease (PD) in adult patients who experience the wearing-off phenomenon while receiving levodopa; however, safety and efficacy data for real-world clinical use are lacking. METHODS We report the final results of a prospective, long-term, post-marketing surveillance study of istradefylline adjunct to levodopa for adults with PD experiencing the wearing-off phenomenon. Patients across 214 study sites initiating treatment with oral istradefylline once-daily 20- or 40-mg were followed-up for 1 year. We collected demographic data, disease and treatment histories, and recorded adverse events and adverse drug reactions (ADRs). The priority survey item was the occurrence of psychiatric ADRs. Effectiveness was evaluated by the physician's global and motor function assessments. RESULTS Case report forms were collected for 1320 patients, and the safety and effectiveness analysis sets included 1318 and 1284 patients, respectively. The mean age was 71.5 years and 56.2% of patients were women. A total of 274 patients (20.8%) experienced an ADR, 39 patients had a serious ADR, and 7 patients had a fatal ADR that was considered not related to istradefylline. Common ADRs included dyskinesia, hallucination, and visual hallucination. Sixty-five patients (4.9%) experienced a psychiatric ADR. Istradefylline was effective (physician-rated) in 59.8% of patients, and most patients had reduced or unchanged off-time duration, improved or unchanged off-time symptoms, and improved or unchanged motor symptoms. CONCLUSION Istradefylline safely and effectively improves motor symptoms in PD patients experiencing the wearing-off phenomenon with levodopa therapy in the real-world setting.
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Rose R, Mitchell E, Van Der Graaf P, Takaichi D, Hosogi J, Geerts H. A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson’s disease: application to preladenant. J Pharmacokinet Pharmacodyn 2022; 49:593-606. [DOI: 10.1007/s10928-022-09825-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022]
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Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF Episodes in Parkinson’s Disease: A US Perspective of Common Clinical Scenarios. Degener Neurol Neuromuscul Dis 2022; 12:97-109. [PMID: 35910426 PMCID: PMC9329678 DOI: 10.2147/dnnd.s245197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022] Open
Abstract
The effective management of OFF episodes remains an important unmet need for patients with Parkinson’s disease (PD) who develop motor complications with long-term levodopa therapy. Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with PD experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Originally approved in Japan, istradefylline was recently approved in the USA. In this article, we provide a specific review of the four clinical studies that the FDA included in the approval of istradefylline in the USA, and discuss common clinical scenarios, based on our experience, where treatment with istradefylline may benefit patients experiencing motor fluctuations.
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Affiliation(s)
- Stuart H Isaacson
- Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA
- Correspondence: Stuart H Isaacson, Parkinson’s Disease and Movement Disorders Center of Boca Raton, 951 NW 13th Street, Bldg. 5-E, Boca Raton, FL, 33486, USA, Tel +1 561-392-1818, Fax +1 561-392-8989, Email
| | - Sagari Betté
- Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA
| | - Rajesh Pahwa
- University of Kansas Medical Center, Kansas City, KS, USA
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Pathophysiological Role and Medicinal Chemistry of A 2A Adenosine Receptor Antagonists in Alzheimer's Disease. Molecules 2022; 27:molecules27092680. [PMID: 35566035 PMCID: PMC9102440 DOI: 10.3390/molecules27092680] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 12/20/2022] Open
Abstract
The A2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A2A adenosine receptors in AD animal and human studies and reports the state of the art of A2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.
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Bandopadhyay R, Mishra N, Rana R, Kaur G, Ghoneim MM, Alshehri S, Mustafa G, Ahmad J, Alhakamy NA, Mishra A. Molecular Mechanisms and Therapeutic Strategies for Levodopa-Induced Dyskinesia in Parkinson's Disease: A Perspective Through Preclinical and Clinical Evidence. Front Pharmacol 2022; 13:805388. [PMID: 35462934 PMCID: PMC9021725 DOI: 10.3389/fphar.2022.805388] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/21/2022] [Indexed: 12/20/2022] Open
Abstract
Parkinson's disease (PD) is the second leading neurodegenerative disease that is characterized by severe locomotor abnormalities. Levodopa (L-DOPA) treatment has been considered a mainstay for the management of PD; however, its prolonged treatment is often associated with abnormal involuntary movements and results in L-DOPA-induced dyskinesia (LID). Although LID is encountered after chronic administration of L-DOPA, the appearance of dyskinesia after weeks or months of the L-DOPA treatment has complicated our understanding of its pathogenesis. Pathophysiology of LID is mainly associated with alteration of direct and indirect pathways of the cortico-basal ganglia-thalamic loop, which regulates normal fine motor movements. Hypersensitivity of dopamine receptors has been involved in the development of LID; moreover, these symptoms are worsened by concurrent non-dopaminergic innervations including glutamatergic, serotonergic, and peptidergic neurotransmission. The present study is focused on discussing the recent updates in molecular mechanisms and therapeutic approaches for the effective management of LID in PD patients.
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Affiliation(s)
- Ritam Bandopadhyay
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Nainshi Mishra
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Ruhi Rana
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Gagandeep Kaur
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, Saudi Arabia
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Gulam Mustafa
- College of Pharmacy (Boys), Al-Dawadmi Campus, Shaqra University, Riyadh, Saudi Arabia
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Nabil. A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Guwahati, Guwahati, India
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Hatano T, Kano O, Sengoku R, Yoritaka A, Suzuki K, Nishikawa N, Mukai Y, Nomura K, Yoshida N, Seki M, Matsukawa MK, Terashi H, Kimura K, Tashiro J, Hirano S, Murakami H, Joki H, Uchiyama T, Shimura H, Ogaki K, Fukae J, Tsuboi Y, Takahashi K, Yamamoto T, Yanagisawa N, Nagayama H. Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study. BMC Neurol 2022; 22:71. [PMID: 35241003 PMCID: PMC8892732 DOI: 10.1186/s12883-022-02600-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/23/2022] [Indexed: 12/02/2022] Open
Abstract
Background Levodopa remains the most effective symptomatic treatment for Parkinson’s disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. Methods This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30–84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300–400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. Discussion This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. Trial registration Japan Registry of Clinical Trials, jRCTs031180248; registered 12 March 2019.
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Affiliation(s)
- Taku Hatano
- Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan.
| | - Osamu Kano
- Department of Neurology, Faculty of Medicine, Toho University, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Renpei Sengoku
- Department of Neurology, Jikei University Daisan Hospital, 4-11-1 Izumihoncho, Komae, Tokyo, 201-0003, Japan
| | - Asako Yoritaka
- Department of Neurology, Juntendo University Koshigaya Hospital, 560 Fukuroyama, Koshigaya-shi, Saitama, 343-0032, Japan
| | - Keisuke Suzuki
- Department of Neurology, Dokkyo Medical University Hospital, 880 Oaza Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan
| | - Noriko Nishikawa
- Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan.,Department of Neurology, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira-shi, Tokyo, 187-8551, Japan
| | - Yohei Mukai
- Department of Neurology, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira-shi, Tokyo, 187-8551, Japan
| | - Kyoichi Nomura
- Department of Neurology, Saitama Medical Center, Kawagoe-shi, Saitama, 350-8550, Japan
| | - Norihito Yoshida
- Department of Neurology, Saitama Medical Center, Kawagoe-shi, Saitama, 350-8550, Japan
| | - Morinobu Seki
- Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Miho Kawabe Matsukawa
- Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Hiroo Terashi
- Department of Neurology, Tokyo Medical University Hospital, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Katsuo Kimura
- Department of Neurology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama-shi, Kanagawa, 232-0024, Japan
| | - Jun Tashiro
- Sapporo Parkinson MS Neurological Clinic, Dai 27 Big Sapporo-kita Sky Building 12F, 7-6 Kita-7 jo Nishi-5 chome, Kita-ku, Sapporo-shi, Hokkaido, 060-0807, Japan
| | - Shigeki Hirano
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan
| | - Hidetomo Murakami
- Department of Neurology, The Jikei University Hospital, 3-19-18 Nishishinbashi, Minato-ku, Tokyo, 105-8471, Japan
| | - Hideto Joki
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Tsuyoshi Uchiyama
- Department of Neurology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Naka-ku, Hamamatsu-shi, Shizuoka, 430-8558, Japan
| | - Hideki Shimura
- Department of Neurology, Juntendo Tokyo Koto Geriatric Medical Center, 3-3-20 Shinsuna, Koto-ku, Tokyo, 136-0075, Japan
| | - Kotaro Ogaki
- Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Jiro Fukae
- Department of Neurology, Juntendo University Nerima Hospital, 3-1-10 Takano-dai, Nerima-ku, Tokyo, 177-8521, Japan
| | - Yoshio Tsuboi
- Department of Neurology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Johnan-ku, Fukuoka, 814-0180, Japan
| | - Kazushi Takahashi
- Department of Neurology, Tokyo Metropolitan Neurological Hospital, Musashidai 2-6-1, Fuchu-shi, Tokyo, 183-0042, Japan
| | - Toshimasa Yamamoto
- Department of Neurology, Saitama Medical University Hospital, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Naotake Yanagisawa
- Medical Technology Innovation Center, Juntendo University and Juntendo Clinical Research and Trial Center, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hiroshi Nagayama
- Department of Neurology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan
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Angela Cenci M, Skovgård K, Odin P. Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease. Neuropharmacology 2022; 210:109027. [DOI: 10.1016/j.neuropharm.2022.109027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/06/2022] [Accepted: 03/09/2022] [Indexed: 12/21/2022]
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Jost WH, Tönges L. [Adenosine A2A Receptor Antagonists as a Treatment Option for Parkinson's Disease?]. FORTSCHRITTE DER NEUROLOGIE-PSYCHIATRIE 2022; 90:565-570. [PMID: 35226930 DOI: 10.1055/a-1771-6225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In Parkinson's disease, the focus has long been on motor symptoms and therapy with dopaminergic substances. In recent years, the importance of non-motor symptoms has been increasingly recognized, as they occur early in the course of the disease and restrict considerably the quality of life. However, this also made the need for treatment of non-dopaminergic deficits obvious. Adenosine A2A receptor antagonists were identified as an additional therapy, since the adenosine A2A receptors are non-dopaminergic and selectively localized in the basal ganglia. This means that the striato-thalamo-cortical loops can be modulated. An adenosine A2A receptor antagonist was already approved in Japan in 2013 and in the USA in 2019 as an add-on to L-DOPA. Approval for this drug in Europe is expected in the near future. In this overview, we present the theoretical basis and current data on its efficacy and therapeutic use.
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Affiliation(s)
| | - Lars Tönges
- Klinik für Neurologie, Ruhr-Universität Bochum, St. Josef-Hospital, Bochum, Germany
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35
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nnEfficacy and safety of istradefylline for Parkinson's disease: A systematic review and meta-analysis. Neurosci Lett 2022; 774:136515. [PMID: 35149201 DOI: 10.1016/j.neulet.2022.136515] [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: 12/13/2021] [Revised: 01/21/2022] [Accepted: 02/05/2022] [Indexed: 11/23/2022]
Abstract
As an adenosine receptor A2A antagonist, istradefylline is used as an adjunctive agent of levodopa to improve motor symptoms in advanced Parkinson's disease (PD) patients. In this study, we re-evaluated the effects of istradefylline on treating the motor symptoms of PD patients. We performed a literature search up to November 2021 from electronic databases. Eligible studies were synthesized for efficacy, tolerability, OFF time, Unified Parkinson's Disease Rating Scale part III score, ON state with dyskinesia, and the incidence of treatment-emergent adverse events. As a result, nine clinical studies with 2727 subjects on istradefylline treatment for PD patients were included. Our results showed that compared to placebo, istradefylline exhibited a statically significant difference in efficacy (1.39 [1.15 to 1.69]; p = 0.001), decreasing OFF time (-0.58 [-1.01 to -0.16]; p = 0.007), and improving ON state with dyskinesia (0.69 [0.02 to 1.37]; p = 0.043). For tolerability, UPDRS III, and adverse effects, there was no significant difference between istradefylline and placebo. In conclusion, the results suggest that istradefylline exhibits an efficient and well-tolerated role in treating PD patients. Randomized controlled trials and long-term studies are still required to investigate the effects of istradefylline on motor and non-motor symptoms of PD in future research.
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Cummins L, Cates ME. Istradefylline: A novel agent in the treatment of “off” episodes associated with levodopa/carbidopa use in Parkinson disease. Ment Health Clin 2022; 12:32-36. [PMID: 35116210 PMCID: PMC8788305 DOI: 10.9740/mhc.2022.01.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 11/04/2021] [Indexed: 11/13/2022] Open
Abstract
Abstract
The current gold standard for treatment of Parkinson disease (PD) is levodopa/carbidopa (L/C), but long-term treatment frequently results in motor complications, such as wearing-off and motor fluctuations (eg, dyskinesia, “on-off” phenomenon). Istradefylline is a new drug with a unique pharmacologic profile that was approved by the FDA for use as adjunctive treatment to L/C in adult patients with PD experiencing “off” episodes. The drug was shown to reduce “off” time in 4 randomized, double-blind, placebo-controlled studies. The most common adverse effects are dyskinesia, dizziness, constipation, nausea, hallucinations, and insomnia. Unlike many drugs that treat PD, istradefylline is a nondopaminergic drug that exerts its effects via adenosine A2A receptor antagonism. The major drug interactions involve inhibitors or inducers of CYP3A4 as well as tobacco smoking via induction of CYP1A1. Istradefylline is taken once daily as a 20- or 40-mg dose, except in cases involving drug interactions or hepatic impairment. The cost of the drug is relatively expensive, which has implications for Medicare and private insurance coverage. Istradefylline is an alternative option to dopaminergic drugs such as dopamine agonists, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors as an adjunct to L/C in patients with motor fluctuations, but clinical use will further define its role in treatment of PD.
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Affiliation(s)
- Lauren Cummins
- PharmD Candidate 2022, Samford University McWhorter School of Pharmacy, Birmingham, Alabama
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Expression of the Adenosine A2A-A3 Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APPSw,Ind Alzheimer’s Disease Model. Biomedicines 2022; 10:biomedicines10020214. [PMID: 35203424 PMCID: PMC8869194 DOI: 10.3390/biomedicines10020214] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Adenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A1 Ado receptor interacting with the A2A Ado receptor, there has been more recent data on the possibility that every Ado receptor type, A1, A2A, A2B, and A3, may interact with each other. The aim of this paper was to look for the expression and function of the A2A/A3 receptor heteromer (A2AA3Het) in neurons and microglia. In situ proximity ligation assays (PLA), performed in primary cells, showed that A2AA3Het expression was markedly higher in striatal than in cortical and hippocampal neurons, whereas it was similar in resting and activated microglia. Signaling assays demonstrated that the effect of the A2AR agonist, PSB 777, was reduced in the presence of the A3R agonist, 2-Cl-IB-MECA, whereas the effect of the A3R agonist was potentiated by the A2AR antagonist, SCH 58261. Interestingly, the expression of the heteromer was markedly enhanced in microglia from the APPSw,Ind model of Alzheimer’s disease. The functionality of the heteromer in primary microglia from APPSw,Ind mice was more similar to that found in resting microglia from control mice.
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Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K. Adenosine A 2A Receptor Occupancy by Caffeine After Coffee Intake in Parkinson's Disease. Mov Disord 2022; 37:853-857. [PMID: 35001424 PMCID: PMC9306703 DOI: 10.1002/mds.28897] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 11/26/2022] Open
Abstract
Background Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2AR) antagonist action. Objective We aimed to calculate occupancy rates of striatal A2ARs by caffeine after coffee intake in PD. Methods Five patients with PD underwent 11C‐preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129.5 mg (n = 3) or 259 mg (n = 2) of caffeine. Concurrently, serum caffeine levels were measured. Results The mean serum caffeine level (μg/mL) was 0.374 at baseline and increased to 4.48 and 8.92 by 129.5 and 259 mg of caffeine, respectively. The mean occupancy rates of striatal A2ARs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively. Conclusions A sufficient A2AR occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Kenji Ishibashi
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.,Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Yoshiharu Miura
- Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Kei Wagatsuma
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.,School of Allied Health Science, Kitasato University, Sagamihara, Japan
| | - Jun Toyohara
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Kiichi Ishiwata
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.,Institute of Cyclotron and Drug Discovery Research, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan.,Department of Biofunctional Imaging, Fukushima Medical University, Fukushima, Japan
| | - Kenji Ishii
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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Siddique Y. Neurodegenerative Disorders and the Current State, Pathophysiology, and Management of Parkinson's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2022; 21:574-595. [PMID: 34477534 DOI: 10.2174/1871527320666210903101841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 12/14/2020] [Accepted: 02/13/2021] [Indexed: 06/13/2023]
Abstract
In the last few decades, major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson's Disease (PD). Based on neurotoxicological studies and postmortem investigations, there is a general concept of how environmental toxicants (neurotoxins, pesticides, insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of the midbrain and modulate cellular processes leading to the pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils, is associated with cellular dysfunction and neuronal death, thus possibly contributing to PD propagation. With advances made in identifying loci that contribute to PD, molecular pathways involved in disease pathogenesis are now clear, and introducing therapeutic strategy at the right time may delay the progression. Biomarkers for PD have helped monitor PD progression; therefore, personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, independent validation of biomarkers is required.
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Affiliation(s)
- Yasir Siddique
- Drosophila Transgenic Laboratory, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India
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40
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Merighi S, Borea PA, Varani K, Vincenzi F, Jacobson KA, Gessi S. A 2A Adenosine Receptor Antagonists in Neurodegenerative Diseases. Curr Med Chem 2022; 29:4138-4151. [PMID: 34844537 PMCID: PMC9148371 DOI: 10.2174/0929867328666211129122550] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/01/2021] [Accepted: 10/07/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million cases reported in America in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A2A receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. OBJECTIVE In this review, recent advances covering A2A adenosine receptor antagonists will be extensively reviewed, providing a basis for the rational design of future A2A inhibitors. METHODS Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation, as well as the effects of A2A antagonism in animal models of AD and in humans, are reviewed. Furthermore, current chemical and structure-based strategies are presented. RESULTS Caffeine, the most widely consumed natural product stimulant and an A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD. CONCLUSION This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.
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Affiliation(s)
- Stefania Merighi
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy;,Address correspondence to these authors at the Department Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy; ; ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States;
| | | | - Katia Varani
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy
| | - Fabrizio Vincenzi
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy
| | - Kenneth A. Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States,Address correspondence to these authors at the Department Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy; ; ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States;
| | - Stefania Gessi
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy;,Address correspondence to these authors at the Department Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy; ; ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States;
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Sivanandy P, Leey TC, Xiang TC, Ling TC, Wey Han SA, Semilan SLA, Hong PK. Systematic Review on Parkinson's Disease Medications, Emphasizing on Three Recently Approved Drugs to Control Parkinson's Symptoms. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 19:364. [PMID: 35010624 PMCID: PMC8744877 DOI: 10.3390/ijerph19010364] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022]
Abstract
Parkinson's Disease (PD) is a disease that involves neurodegeneration and is characterised by the motor symptoms which include muscle rigidity, tremor, and bradykinesia. Other non-motor symptoms include pain, depression, anxiety, and psychosis. This disease affects up to ten million people worldwide. The pathophysiology behind PD is due to the neurodegeneration of the nigrostriatal pathway. There are many conventional drugs used in the treatment of PD. However, there are limitations associated with conventional drugs. For instance, levodopa is associated with the on-off phenomenon, and it may induce wearing off as time progresses. Therefore, this review aimed to analyze the newly approved drugs by the United States-Food and Drug Administration (US-FDA) from 2016-2019 as the adjuvant therapy for the treatment of PD symptoms in terms of efficacy and safety. The new drugs include safinamide, istradefylline and pimavanserin. From this review, safinamide is considered to be more efficacious and safer as the adjunct therapy to levodopa as compared to istradefylline in controlling the motor symptoms. In Study 016, both safinamide 50 mg (p = 0.0138) and 100 mg (p = 0.0006) have improved the Unified Parkinson's Disease Rating Scale (UPDRS) part III score as compared to placebo. Improvement in Clinical Global Impression-Change (CGI-C), Clinical Global Impression-Severity of Illness (CGI-S) and off time were also seen in both groups of patients following the morning levodopa dose. Pimavanserin also showed favorable effects in ameliorating the symptoms of Parkinson's Disease Psychosis (PDP). A combination of conventional therapy and non-pharmacological treatment is warranted to enhance the well-being of PD patients.
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Affiliation(s)
- Palanisamy Sivanandy
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
- School of Postgraduate Studies, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Tan Choo Leey
- Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (T.C.L.); (T.C.X.); (T.C.L.); (S.A.W.H.); (S.L.A.S.); (P.K.H.)
| | - Tan Chi Xiang
- Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (T.C.L.); (T.C.X.); (T.C.L.); (S.A.W.H.); (S.L.A.S.); (P.K.H.)
| | - Tan Chi Ling
- Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (T.C.L.); (T.C.X.); (T.C.L.); (S.A.W.H.); (S.L.A.S.); (P.K.H.)
| | - Sean Ang Wey Han
- Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (T.C.L.); (T.C.X.); (T.C.L.); (S.A.W.H.); (S.L.A.S.); (P.K.H.)
| | - Samantha Lia Anak Semilan
- Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (T.C.L.); (T.C.X.); (T.C.L.); (S.A.W.H.); (S.L.A.S.); (P.K.H.)
| | - Phoon Kok Hong
- Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (T.C.L.); (T.C.X.); (T.C.L.); (S.A.W.H.); (S.L.A.S.); (P.K.H.)
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Borgus JR, Wang Y, DiScenza DJ, Venton BJ. Spontaneous Adenosine and Dopamine Cotransmission in the Caudate-Putamen Is Regulated by Adenosine Receptors. ACS Chem Neurosci 2021; 12:4371-4379. [PMID: 34783243 DOI: 10.1021/acschemneuro.1c00175] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Transient changes in adenosine and dopamine have been measured in vivo, but no studies have examined if these transient changes occur simultaneously. In this study, we characterized spontaneous adenosine and dopamine transients in anesthetized mice, examining coincident release in the caudate-putamen for the first time. We found that in C57B mice, most of the dopamine transients (77%) were coincident with adenosine, but fewer adenosine transients (12%) were coincident with a dopamine transient. On average, the dopamine transient started 200 ms before its coincident adenosine transient, so they occurred concurrently. There was a positive correlation (r = 0.7292) of adenosine and dopamine concentrations during coincident release. ATP is quickly broken down to adenosine in the extracellular space, and the coincident events may be due to corelease, where dopaminergic vesicles are packaged with ATP, or cotransmission, where ATP is packaged in different vesicles released simultaneously with dopamine. The high frequency of adenosine transients compared to that of dopamine transients suggests that adenosine is also released from nondopaminergic vesicles. We investigated how A1 and A2A adenosine receptors regulate adenosine and dopamine transients using A1 and A2AKO mice. In A1KO mice, the frequency of adenosine and dopamine transients increased, while in A2AKO mice, the frequency of adenosine alone increased. Adenosine receptors modulate coincident transients and could be drug targets to modulate both dopamine and adenosine release. Many spontaneous dopamine transients have coincident adenosine release, and regulating adenosine and dopamine cotransmission could be important for designing treatments for dopamine diseases, such as Parkinson's or addiction.
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Affiliation(s)
- Jason R. Borgus
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, United States
| | - Ying Wang
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, United States
| | - Dana J. DiScenza
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, United States
| | - B. Jill Venton
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, United States
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Singh A, Gupta D, Dhaneria S, Sheth PG. Istradefylline Versus Opicapone for "Off" Episodes in Parkinson's Disease: A Systematic Review and Meta-Analysis. Ann Neurosci 2021; 28:65-73. [PMID: 34733056 PMCID: PMC8558978 DOI: 10.1177/09727531211046362] [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: 01/19/2021] [Accepted: 08/03/2021] [Indexed: 01/21/2023] Open
Abstract
Background: In recent times, the US-FDA approved istradefylline and opicapone as an adjunct to
levodopa/carbidopa for managing the "off" episodes in Parkinson’s disease. Purpose: Current meta-analysis was performed to determine the safety and efficacy of these drugs
in the management of “off” episodes and to recognize which among them would provide
therapeutic benefits clinically. Methods: A thorough literature search was performed through the Cochrane Library, PubMed, and
clinicaltrials.gov for a period from January 2003 to October 2020, with the following
keywords: Istradefylline, KW-6002, opicapone, BIA 9-1067, and Parkinson’s disease. Those
randomized, double-blind placebo/active comparator-controlled trials that analyzed the
efficacy and safety of istradefylline and opicapone and that were published in the
English language were included. In this analysis, the outcomes focused on the least
square mean change in “off” time and Unified Parkinson’s Disability Rating Scale (UPDRS)
III score from baseline to the end of the study, and the incidence of treatment-emergent
adverse events (TEAEs) and dyskinesia. Results: Both drugs have shown significant reduction in “off” time duration (mean difference
[MD] = –0.70; 95% CI [–1.11, –0.30]; P < 0.001 for istradefylline
and MD = –0.85; 95% CI [–1.09, –0.61]; P < .001 for opicapone).
Istradefylline showed significant improvement in UPDRS III (MD = –1.56; 95% CI [–2.71,
–0.40]; P < .008), but the same was not observed with opicapone (MD
= –0.63; 95% CI [–1.42, –0.15]; P < .12). The incidence of TEAEs and
dyskinesia reportedly were higher in the intervention group rather than with the
placebo, (risk ratio RR =1.11, 95% CI [1.02,1.20] for istradefylline and RR =1.12, 95%
CI [1.00,1.25] for opicapone, and for dyskinesia particularly, the incidence was higher
with opicapone as compared to istradefylline (RR = 3.47, 95% CI [2.17, 5.57], and RR =
1.77, 95% CI [1.29, 2.44], respectively). Conclusions: Both drugs were comparable in efficacy; however, istradefylline seemed to be better in
reducing the UPDRS III score. Although the incidence of TEAEs and dyskinesia were higher
with both the drugs, the incidence of dyskinesia was more in the opicapone group.
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Affiliation(s)
- Alok Singh
- Department of Pharmacology, All India Institute of Medical Sciences,
Raipur, Chhattisgarh, India
- Alok Singh, Department of Pharmacology, All India
Institute of Medical Sciences, Raipur, Chhattisgarh 492099, India. E-mail:
| | - Dhyuti Gupta
- Department of Pharmacology, All India Institute of Medical Sciences,
Raipur, Chhattisgarh, India
| | - Suryaprakash Dhaneria
- Department of Pharmacology, All India Institute of Medical Sciences,
Raipur, Chhattisgarh, India
| | - Pranav G. Sheth
- Department of Pharmacology, All India Institute of Medical Sciences,
Raipur, Chhattisgarh, India
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Franco R, Rivas-Santisteban R, Navarro G, Reyes-Resina I. Adenosine Receptor Antagonists to Combat Cancer and to Boost Anti-Cancer Chemotherapy and Immunotherapy. Cells 2021; 10:cells10112831. [PMID: 34831054 PMCID: PMC8616521 DOI: 10.3390/cells10112831] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/15/2021] [Accepted: 10/16/2021] [Indexed: 12/22/2022] Open
Abstract
Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A1, A2A, A2B and A3, belong to the class A family of G protein-coupled receptors (GPCRs) and all four have been involved in one way or another in regulating tumor progression. Prompted by the successful anti-cancer immunotherapy, the focus was placed on the ARs more involved in regulation of immune cell differentiation and activation and that are able to establish molecular and functional interactions. This review focuses on the potential of A2A and A2B receptor antagonists in cancer control and in boosting anti-cancer chemotherapy and immunotherapy. The article also overviews the ongoing clinical trials in which A2AR and A2BR ligands are being tested in anti-cancer therapy.
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Affiliation(s)
- Rafael Franco
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain; (R.R.-S.); (G.N.); (I.R.-R.)
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
- Correspondence: or
| | - Rafael Rivas-Santisteban
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain; (R.R.-S.); (G.N.); (I.R.-R.)
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Gemma Navarro
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain; (R.R.-S.); (G.N.); (I.R.-R.)
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain
| | - Irene Reyes-Resina
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain; (R.R.-S.); (G.N.); (I.R.-R.)
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
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Shang P, Baker M, Banks S, Hong SI, Choi DS. Emerging Nondopaminergic Medications for Parkinson's Disease: Focusing on A2A Receptor Antagonists and GLP1 Receptor Agonists. J Mov Disord 2021; 14:193-203. [PMID: 34399565 PMCID: PMC8490190 DOI: 10.14802/jmd.21035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/21/2021] [Accepted: 06/10/2021] [Indexed: 12/16/2022] Open
Abstract
Parkinson's disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A2A receptors (A2AR) and dopamine D2 receptors (D2R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A2AR antagonists and GLP1R agonists in clinical practice.
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Affiliation(s)
- Pei Shang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Matthew Baker
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Samantha Banks
- Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Sa-Ik Hong
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
| | - Doo-Sup Choi
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
- Department of Psychiatry and Psychology, Mayo Clinic, College of Medicine, Rochester, MN, USA
- Department of Neuroscience Program, Mayo Clinic, College of Medicine, Rochester, MN, USA
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Nemade D, Subramanian T, Shivkumar V. An Update on Medical and Surgical Treatments of Parkinson's Disease. Aging Dis 2021; 12:1021-1035. [PMID: 34221546 PMCID: PMC8219497 DOI: 10.14336/ad.2020.1225] [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: 11/30/2020] [Accepted: 12/25/2020] [Indexed: 12/11/2022] Open
Abstract
Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta and other neuronal populations. The worldwide prevalence of PD is over 7 million and has been increasing more rapidly than many other neurodegenerative disorders. PD symptoms can be broadly divided into motor (slowness, stiffness, tremor) and non-motor symptoms (such as depression, dementia, psychosis, orthostatic hypotension). Patients can also have prodromal symptoms of rapid eye movement sleep behavior disorder, hyposmia, and constipation. The diagnosis of PD is mainly clinical, but dopamine transporter single-photon emission computed tomography can improve the accuracy of the diagnosis. Dopamine based therapies are used for the treatment of motor symptoms. Non-motor symptoms are treated with other medications such as selective serotonin reuptake inhibitors (depression/anxiety), acetylcholinesterase inhibitors (dementia), and atypical antipsychotics (psychosis). Patients with motor fluctuations or uncontrolled tremor, benefit from deep brain stimulation. Levodopa-carbidopa intestinal gel is an alternative to deep brain stimulation for uncontrolled motor fluctuations. Rehabilitative therapies such as physical, occupational, and speech therapy are important during all stages of the disease. Management of PD is complex but there have been significant advancements in the treatment of motor and non-motor symptoms over the past few years. This review discusses the updates in the medical and surgical management of PD.
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Affiliation(s)
- Dipali Nemade
- 1Department of Neurology, Marshall University School of Medicine, Huntington, WV 25701, USA
| | - Thyagarajan Subramanian
- 2Department of Neurology and Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - Vikram Shivkumar
- 1Department of Neurology, Marshall University School of Medicine, Huntington, WV 25701, USA
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Franco R, Lillo A, Rivas-Santisteban R, Reyes-Resina I, Navarro G. Microglial Adenosine Receptors: From Preconditioning to Modulating the M1/M2 Balance in Activated Cells. Cells 2021; 10:1124. [PMID: 34066933 PMCID: PMC8148598 DOI: 10.3390/cells10051124] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/19/2021] [Accepted: 05/01/2021] [Indexed: 12/14/2022] Open
Abstract
Neuronal survival depends on the glia, that is, on the astroglial and microglial support. Neurons die and microglia are activated not only in neurodegenerative diseases but also in physiological aging. Activated microglia, once considered harmful, express two main phenotypes: the pro-inflammatory or M1, and the neuroprotective or M2. When neuroinflammation, i.e., microglial activation occurs, it is important to achieve a good M1/M2 balance, i.e., at some point M1 microglia must be skewed into M2 cells to impede chronic inflammation and to afford neuronal survival. G protein-coupled receptors in general and adenosine receptors in particular are potential targets for increasing the number of M2 cells. This article describes the mechanisms underlying microglial activation and analyzes whether these cells exposed to a first damaging event may be ready to be preconditioned to better react to exposure to more damaging events. Adenosine receptors are relevant due to their participation in preconditioning. They can also be overexpressed in activated microglial cells. The potential of adenosine receptors and complexes formed by adenosine receptors and cannabinoids as therapeutic targets to provide microglia-mediated neuroprotection is here discussed.
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Affiliation(s)
- Rafael Franco
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain;
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Alejandro Lillo
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain;
| | - Rafael Rivas-Santisteban
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain;
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Irene Reyes-Resina
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain;
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Gemma Navarro
- CiberNed, Network Research Center, Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28034 Madrid, Spain;
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain;
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Franco R, Rivas-Santisteban R, Lillo J, Camps J, Navarro G, Reyes-Resina I. 5-Hydroxytryptamine, Glutamate, and ATP: Much More Than Neurotransmitters. Front Cell Dev Biol 2021; 9:667815. [PMID: 33937270 PMCID: PMC8083958 DOI: 10.3389/fcell.2021.667815] [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: 02/14/2021] [Accepted: 03/17/2021] [Indexed: 01/08/2023] Open
Abstract
5-hydroxytryptamine (5-HT) is derived from the essential amino acid L-tryptophan. Although the compound has been studied extensively for its neuronal handling and synaptic actions, serotonin 5-HT receptors can be found extra-synaptically and not only in neurons but in many types of mammalian cells, inside and outside the central nervous system (CNS). In sharp contrast, glutamate (Glu) and ATP are better known as metabolism-related molecules, but they also are neurotransmitters, and their receptors are expressed on almost any type of cell inside and outside the nervous system. Whereas 5-hydroxytryptamine and Glu are key regulators of the immune system, ATP actions are more general. 5-hydroxytryptamine, ATP and Glu act through both G protein-coupled receptors (GPCRs), and ionotropic receptors, i.e., ligand gated ion channels. These are the three examples of neurotransmitters whose actions as holistic regulatory molecules are briefly put into perspective here.
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Affiliation(s)
- Rafael Franco
- Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIberNed), Instituto de Salud Carlos III, Madrid, Spain,*Correspondence: Rafael Franco, ;
| | - Rafael Rivas-Santisteban
- Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIberNed), Instituto de Salud Carlos III, Madrid, Spain
| | - Jaume Lillo
- Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIberNed), Instituto de Salud Carlos III, Madrid, Spain
| | - Jordi Camps
- Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, 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, University of Barcelona, Barcelona, Spain
| | - Irene Reyes-Resina
- Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, Spain,Irene Reyes-Resina,
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WANG Y, LÜ X, XU H, MENG Z, LI J, XU Z, XUE M. [Separation and identification of impurities from intermediates of istradefylline]. Se Pu 2021; 39:430-436. [PMID: 34227764 PMCID: PMC9404203 DOI: 10.3724/sp.j.1123.2020.10013] [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: 10/28/2020] [Indexed: 11/25/2022] Open
Abstract
Istradefylline is a novel selective adenosine A2A receptor antagonist that is used to treat Parkinson's disease and improve motor dysfunction in the early stage of this disease. During the synthesis of intermediate A1 (6-amino-1,3-diethyl-2,4-(1H,3H)-pyrimidinedione), at least two by-products were formed under alkaline or high-temperature conditions. In a previous study, one of the by-products in the synthesis of the intermediate was studied, and its structure was identified as (E)-N-ethyl-2-cyano-3-ethylamino-2-butene amide. In this study, we used high performance liquid chromatography (HPLC) to analyze another impurity formed during the synthesis of A1, and the following steps were executed: 0.4 g of intermediate was weighed and added to a 50 mL beaker, followed by the sequential addition of 8 mL water and 8 mL acetonitrile, and then, ultrasonic dissolution was performed. Finally, the solution was filtered through a 0.45-μm organic membrane and the test sample solution was obtained. We used the Agilent zorbax C18 chromatography column, with acetonitrile (A)/water(B) as the mobile phase under gradient elution ((tmin/A∶B)=t0/20∶80, t15/60∶40, t20-t50/90∶10). The detector wavelength is 268 nm. In order to separate the impurity from A1, we used a Ceres B preparative column, with acetonitrile-water (30/70, v/v) as the mobile phase. The flow rate was set at 30 mL/min, and the detection wavelength was 268 nm. The structure of the impurity was confirmed by high-resolution mass spectrometry (HRMS), one-dimensional nuclear magnetic resonance (NMR), and two-dimensional nuclear magnetic resonance (2D NMR), and characterized by single-crystal X-ray diffraction (XRD). In MS experiments, an electrospray ionization (ESI) source was used with positive ion scanning. In the NMR experiments, we used tetramethylsilane (TMS) as the internal standard and deuterated dimethyl sulfoxide (DMSO-d6) as the solvent to obtain the spectra. The results of preparative high performance liquid chromatography (Prep-HPLC) showed that good separation effect could be achieved by isocratic elution, and the impurity was perfectly separated. The1H-NMR spectral data are as follows:1H-NMR (600 MHz, DMSO): δ 1.01 (q, J=6.9 Hz, 3H), 1.02 (q, J=6.9 Hz, 3H), 1.07 (t, J=6.9 Hz, 3H), 3.04 (p, J=6.8 Hz, 2H), 3.74 (q, J=7.0 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 5.85 (s, 1H). The 13C-NMR spectral data are summarized as follows: 13C-NMR (150 MHz, DMSO): δ13.9, 14.1, 15.9, 34.6, 34.9, 36.9, 81.9, 152.2, 153.3, 159.3, 162.0. The impurity was characterized by single-crystal XRD, and its spatial structure was further verified and determined as 1-(1,3-diethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-3-ethylurea. Based on the chemical structure of the impurity, we propose the following mechanism for the impurity: when A1 is synthesized under alkaline conditions or at high temperature, excessive diethylurea continues to undergo amidation with A1 to obtain this by-product. Although the formation mechanism of the impurity studied in this paper is different from that of the intermediate A1 impurity (E)-N-ethyl-2-cyano-3-ethylamino-2-butene amide, both the impurities are formed at high temperatures. Both will be accompanied by A1 in the subsequent reaction of istradefylline synthesis. The relationship between drug impurities and drug safety is a complex relationship that is affected by many factors. Generally, most impurities in drugs have potential biological activities, and some even interact with the drugs, thus affecting their efficacy and safety and inducing toxic effects. Therefore, to ensure the quality of istradefylline, it is necessary to control the impurity content during the production. The findings of this paper may provide guidelines for controlling the impurity content in istradefylline.
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50
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Liu J, Ting JP, Al-Azzam S, Ding Y, Afshar S. Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int J Mol Sci 2021; 22:ijms22062805. [PMID: 33802091 PMCID: PMC8001105 DOI: 10.3390/ijms22062805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/06/2021] [Indexed: 02/08/2023] Open
Abstract
Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.
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Affiliation(s)
- Jinsha Liu
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Joey Paolo Ting
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Shams Al-Azzam
- Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, PA 17605, USA;
| | - Yun Ding
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Sepideh Afshar
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
- Correspondence:
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