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Karimi MA, Ghajari A, Khademi R, Etemadi MH, Firouz NS, Mohammadvand B, Janeshin K, Darvishi A, Asgarzadeh S, Sadat-Madani SF, Abbasalizadeh M, Shendi ZJ, Kohnehshahri AA, Deravi N, Mazhari SA, Aziz M, Bidares M, Belbasi M, Naziri M, Motlagh HA. Efficacy of preladenant in improving motor symptoms in Parkinson's disease: A systematic review and meta-analysis. IBRO Neurosci Rep 2024; 17:207-219. [PMID: 39262633 PMCID: PMC11387384 DOI: 10.1016/j.ibneur.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 07/20/2024] [Indexed: 09/13/2024] Open
Abstract
Background Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by dopamine depletion and severe motor impairments. Preladenant, an adenosine A2 receptor antagonist, is an investigational treatment for PD. This systematic review and meta-analysis aimed to critically evaluate the efficacy of Preladenant in improving motor symptoms in patients with PD. Methods A comprehensive literature search was conducted in PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to March 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized controlled trials (RCTs) comparing Preladenant with placebo in PD patients were included. The primary outcome was the change in daily ON time without troublesome dyskinesia. Secondary outcomes included the change in daily OFF time and adverse events. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results Four RCTs with a total of 2097 PD patients were included. Pooled analysis showed that Preladenant could generally increase daily ON time (pooled effect 0.15 and 95 % CI: -0.19-0.48) and reduce daily OFF time (pooled effect -0.04 and 95 % CI: -0.43-0.36) compared to placebo, however it was not significant. The included studies had moderate to high heterogeneity. No significant differences in adverse events were observed between Preladenant and placebo. Conclusion This meta-analysis suggests that Preladenant may improve motor fluctuations in PD patients by increasing ON time and reducing OFF time. However, the high heterogeneity among studies warrants further large-scale, high-quality RCTs to confirm these findings and establish the long-term safety and efficacy of Preladenant in PD management.
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Affiliation(s)
- Mohammad Amin Karimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Ghajari
- School of pharmacy Mashhad University of medical science, Mashhad, Iran
| | - Reza Khademi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Etemadi
- Students Research Committee, School of Medicine, Shahrekord University of Medical Science, Shahrekord, Iran
| | | | - Behnaz Mohammadvand
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kimia Janeshin
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Afra Darvishi
- School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shafagh Asgarzadeh
- Department of Neurology, Urumia Medical Science University, Urumia, Iran
| | | | | | | | - Ata Akhtari Kohnehshahri
- Student Research Committee, Faculty of Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mahsa Aziz
- Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Matin Bidares
- Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohaddeseh Belbasi
- Students research committee, School of pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mahdyieh Naziri
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Majumdar M, Badwaik H. Trends on Novel Targets and Nanotechnology-Based Drug Delivery System in the Treatment of Parkinson's disease: Recent Advancement in Drug Development. Curr Drug Targets 2024; 25:987-1011. [PMID: 39313872 DOI: 10.2174/0113894501312703240826070530] [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: 04/03/2024] [Revised: 05/29/2024] [Accepted: 07/24/2024] [Indexed: 09/25/2024]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder that impacts a significant portion of the population. Despite extensive research, an effective cure for PD remains elusive, and conventional pharmacological treatments often face limitations in efficacy and management of symptoms. There has been a lot of discussion about using nanotechnology to increase the bioavailability of small- molecule drugs to target cells in recent years. It is possible that PD treatment might become far more effective and have fewer side effects if medication delivery mechanisms were to be improved. Potential alternatives to pharmacological therapy for molecular imaging and treatment of PD may lie in abnormal proteins such as parkin, α-synuclein, leucine-rich repeat serine and threonine protein kinase 2. Published research has demonstrated encouraging outcomes when nanomedicine-based approaches are used to address the challenges of PD therapy. So, to address the present difficulties of antiparkinsonian treatment, this review outlines the key issues and limitations of antiparkinsonian medications, new therapeutic strategies, and the breadth of delivery based on nanomedicine. This review covers a wide range of subjects, including drug distribution in the brain, the efficacy of drug-loaded nano-carriers in crossing the blood-brain barrier, and their release profiles. In PD, the nano-carriers are also used. Novel techniques of pharmaceutical delivery are currently made possible by vesicular carriers, which eliminate the requirement to cross the blood-brain barrier (BBB).
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Affiliation(s)
- Manisha Majumdar
- Department of Pharmacy, Shri Shankaracharya Professional University, Bhilai, Chhattisgarh, India
| | - Hemant Badwaik
- Department of Pharmacy, Shri Shankaracharya Professional University, Bhilai, Chhattisgarh, India
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Qi C, Feng Y, Jiang Y, Chen W, Vakal S, Chen JF, Zheng W. A 2AR antagonist treatment for multiple sclerosis: Current progress and future prospects. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 170:185-223. [PMID: 37741692 DOI: 10.1016/bs.irn.2023.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2023]
Abstract
Emerging evidence suggests that both selective and non-selective Adenosine A2A receptor (A2AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes, along with its proven clinical safety, has prompted us to explore the potential of A2AR antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of A2AR signaling in EAE pathology has raised concerns about the feasibility of using A2AR antagonists as a therapeutic approach for MS. This review addresses the potential effect of A2AR antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, A2AR antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood-brain barrier. Consequently, A2AR signaling remains an essential immunomodulator in EAE/MS, suggesting that A2AR antagonists hold promise as a drug class for treating MS.
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Affiliation(s)
- Chenxing Qi
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China
| | - Yijia Feng
- Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Yiwei Jiang
- Alberta Institute, Wenzhou Medical University, Wenzhou, P.R. China
| | - Wangchao Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China
| | - Serhii Vakal
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
| | - Jiang-Fan Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China
| | - Wu Zheng
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China.
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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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Jakova E, Moutaoufik MT, Lee JS, Babu M, Cayabyab FS. Adenosine A1 receptor ligands bind to α-synuclein: implications for α-synuclein misfolding and α-synucleinopathy in Parkinson's disease. Transl Neurodegener 2022; 11:9. [PMID: 35139916 PMCID: PMC8830172 DOI: 10.1186/s40035-022-00284-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/21/2022] [Indexed: 12/20/2022] Open
Abstract
Background Accumulating α-synuclein (α-syn) aggregates in neurons and glial cells are the staples of many synucleinopathy disorders, such as Parkinson’s disease (PD). Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor (A1R) stimulation leads to neurodegeneration, we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promote α-syn aggregation (e.g., the amphetamine analogue 2-aminoindan) or inhibit α-syn aggregation (e.g., Rasagiline metabolite 1-aminoindan). In the present study, we determined whether adenosine, A1R receptor agonist N6-Cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) could directly interact with α-syn to modulate α-syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra (SN). Methods Nanopore analysis and molecular docking were used to test the binding properties of CPA and DPCPX with α-syn in vitro. Sprague–Dawley rats were administered with 7-day intraperitoneal injections of the A1R ligands and 1- and 2-aminoindan, and levels of α-syn aggregation and neurodegeneration were examined in the SN pars compacta and hippocampal regions using confocal imaging and Western blotting. Results Using nanopore analysis, we showed that the A1R agonists (CPA and adenosine) interacted with the N-terminus of α-syn, similar to 2-aminoindan, which is expected to promote a “knot” conformation and α-syn misfolding. In contrast, the A1R antagonist DPCPX interacted with the N- and C-termini of α-syn, similar to 1-aminoindan, which is expected to promote a “loop” conformation that prevents α-syn misfolding. Molecular docking studies revealed that adenosine, CPA and 2-aminoindan interacted with the hydrophobic core of α-syn N-terminus, whereas DPCPX and 1-aminoindan showed direct binding to the N- and C-terminal hydrophobic pockets. Confocal imaging and Western blot analyses revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increased α-syn expression/aggregation and neurodegeneration in both SN pars compacta and hippocampus. In contrast, DPCPX and 1-aminoindan attenuated the CPA-induced α-syn expression/aggregation and neurodegeneration in SN and hippocampus. Conclusions The results indicate that A1R agonists and drugs promoting a “knot” conformation of α-syn can cause α-synucleinopathy and increase neuronal degeneration, whereas A1R antagonists and drugs promoting a “loop” conformation of α-syn can be harnessed for possible neuroprotective therapies to decrease α-synucleinopathy in PD. Supplementary Information The online version contains supplementary material available at 10.1186/s40035-022-00284-3.
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Affiliation(s)
- Elisabet Jakova
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Mohamed Taha Moutaoufik
- Department of Chemistry and Biochemistry, Faculty of Science, University of Regina, Regina, SK, Canada
| | - Jeremy S Lee
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Mohan Babu
- Department of Chemistry and Biochemistry, Faculty of Science, University of Regina, Regina, SK, Canada
| | - Francisco S Cayabyab
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
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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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Ntetsika T, Papathoma PE, Markaki I. Novel targeted therapies for Parkinson's disease. Mol Med 2021; 27:17. [PMID: 33632120 PMCID: PMC7905684 DOI: 10.1186/s10020-021-00279-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s disease (PD) is the second more common neurodegenerative disease with increasing incidence worldwide associated to the population ageing. Despite increasing awareness and significant research advancements, treatment options comprise dopamine repleting, symptomatic therapies that have significantly increased quality of life and life expectancy, but no therapies that halt or reverse disease progression, which remain a great, unmet goal in PD research. Large biomarker development programs are undertaken to identify disease signatures that will improve patient selection and outcome measures in clinical trials. In this review, we summarize PD-related mechanisms that can serve as targets of therapeutic interventions aiming to slow or modify disease progression, as well as previous and ongoing clinical trials in each field, and discuss future perspectives.
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Affiliation(s)
- Theodora Ntetsika
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Center of Neurology, Academic Specialist Center, Solnavägen 1E, 113 65, Stockholm, Sweden
| | - Paraskevi-Evita Papathoma
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Department of Neurology, Danderyd Hospital Stockholm, Stockholm, Sweden
| | - Ioanna Markaki
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. .,Center of Neurology, Academic Specialist Center, Solnavägen 1E, 113 65, Stockholm, Sweden.
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Jenner P, Mori A, Aradi SD, Hauser RA. Istradefylline - a first generation adenosine A 2A antagonist for the treatment of Parkinson's disease. Expert Rev Neurother 2021; 21:317-333. [PMID: 33507105 DOI: 10.1080/14737175.2021.1880896] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction It is now accepted that Parkinson's disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of PD.Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A2A antagonist currently in clinical use.Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a 'levodopa sparing' strategy in earlier PD would seem warranted.
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Affiliation(s)
- Peter Jenner
- Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Akihisa Mori
- Medical Affairs Department, Kyowa Kirin Co Ltd, Otemachi, Chiyoda-ku, Tokyo, Japan
| | - Stephen D Aradi
- Department of Neurology, University of South Florida, Tampa, Florida, USA
| | - Robert A Hauser
- Department of Neurology, University of South Florida, Tampa, Florida, USA
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Chen JF, Cunha RA. The belated US FDA approval of the adenosine A 2A receptor antagonist istradefylline for treatment of Parkinson's disease. Purinergic Signal 2020; 16:167-174. [PMID: 32236790 DOI: 10.1007/s11302-020-09694-2] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/02/2020] [Indexed: 01/08/2023] Open
Abstract
After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist Nourianz® (istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A2A receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.
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Affiliation(s)
- Jiang-Fan Chen
- Molecular Neuropharmacology Laboratory, Wenzhou Medical University, Wenzhou, China.
| | - Rodrigo A Cunha
- CNC-Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson's Disease. Biomolecules 2019; 9:biom9040142. [PMID: 30970612 PMCID: PMC6523988 DOI: 10.3390/biom9040142] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/05/2019] [Accepted: 04/06/2019] [Indexed: 12/12/2022] Open
Abstract
Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects.
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Veyres N, Hamadjida A, Huot P. Predictive Value of Parkinsonian Primates in Pharmacologic Studies: A Comparison between the Macaque, Marmoset, and Squirrel Monkey. J Pharmacol Exp Ther 2018; 365:379-397. [PMID: 29523699 DOI: 10.1124/jpet.117.247171] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 03/06/2018] [Indexed: 03/08/2025] Open
Abstract
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold-standard animal model of Parkinson disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism, and psychosis. Three species have been used in most studies-the macaque, marmoset, and squirrel monkey-the last much less so than the first two species; however, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing pharmacologic studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism, and psychosis in each of these species and have calculated their predictive value of success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false-positive rate of 38.1%, whereas the marmoset has a positive predictive value of 76.9% and a false-positive rate of 15.6%. For parkinsonism, the macaque has a positive predictive value of 68.2% and a false-positive rate of 44.4%, whereas the marmoset has a positive predictive value of 86.9% and a false-positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, whereas the marmoset has 100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope our results will help in the design of pharmacologic experiments and will facilitate the drug discovery and development process in PD.
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Affiliation(s)
- Nicolas Veyres
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (N.V.),Montreal Neurological Institute (A.H.,P.H.), and Department of Neurology and Neurosurgery, McGill University (P.H.), Montreal, Quebec, Canada
| | - Adjia Hamadjida
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (N.V.),Montreal Neurological Institute (A.H.,P.H.), and Department of Neurology and Neurosurgery, McGill University (P.H.), Montreal, Quebec, Canada
| | - Philippe Huot
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (N.V.),Montreal Neurological Institute (A.H.,P.H.), and Department of Neurology and Neurosurgery, McGill University (P.H.), Montreal, Quebec, Canada
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Du JJ, Chen SD. Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson's Disease. Chin Med J (Engl) 2018; 130:1856-1866. [PMID: 28748860 PMCID: PMC5547839 DOI: 10.4103/0366-6999.211555] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Objective: The aim of this study was to summarize recent studies on nondopaminergic options for the treatment of motor symptoms in Parkinson's disease (PD). Data Sources: Papers in English published in PubMed, Cochrane, and Ovid Nursing databases between January 1988 and November 2016 were searched using the following keywords: PD, nondopaminergic therapy, adenosine, glutamatergic, adrenergic, serotoninergic, histaminic, and iron chelator. We also reviewed the ongoing clinical trials in the website of clinicaltrials.gov. Study Selection: Articles related to the nondopaminergic treatment of motor symptoms in PD were selected for this review. Results: PD is conventionally treated with dopamine replacement strategies, which are effective in the early stages of PD. Long-term use of levodopa could result in motor complications. Recent studies revealed that nondopaminergic systems such as adenosine, glutamatergic, adrenergic, serotoninergic, histaminic, and iron chelator pathways could include potential therapeutic targets for motor symptoms, including motor fluctuations, levodopa-induced dyskinesia, and gait disorders. Some nondopaminergic drugs, such as istradefylline and amantadine, are currently used clinically, while most such drugs are in preclinical testing stages. Transitioning of these agents into clinically beneficial strategies requires reliable evaluation since several agents have failed to show consistent results despite positive findings at the preclinical level. Conclusions: Targeting nondopaminergic transmission could improve some motor symptoms in PD, especially the discomfort of dyskinesia. Although nondopaminergic treatments show great potential in PD treatment as an adjunct therapy to levodopa, further investigation is required to ensure their success.
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Affiliation(s)
- Juan-Juan Du
- Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Sheng-Di Chen
- Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Role of adenosine A 2A receptors in motor control: relevance to Parkinson's disease and dyskinesia. J Neural Transm (Vienna) 2018; 125:1273-1286. [PMID: 29396609 DOI: 10.1007/s00702-018-1848-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 01/26/2018] [Indexed: 12/16/2022]
Abstract
Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate-putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson's disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia.
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Rascol O. Pharmacological Insights into Levodopa-induced Motor Fluctuations in Patients with Parkinson's Disease. Mov Disord Clin Pract 2016; 3:523-526. [PMID: 30363537 PMCID: PMC6178700 DOI: 10.1002/mdc3.12389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 11/11/2022] Open
Affiliation(s)
- Olivier Rascol
- Clinical Investigation Center INSERM 1436Department of Clinical Pharmacology and NeurosciencesUniversity Hospital of ToulouseUMR Tonic 1214, University of Toulouse IIIToulouseFrance
- NS‐Park/French Clinical Research Infrastructure Network (F‐CRIN) and Toulouse Neuro‐Degenerative Center (NeuroToul)Network of Centers of Excellence in Neurodegeneration (COEN)ToulouseFrance
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15
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Cunha RA. How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 2016; 139:1019-1055. [PMID: 27365148 DOI: 10.1111/jnc.13724] [Citation(s) in RCA: 350] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/23/2016] [Accepted: 06/23/2016] [Indexed: 12/11/2022]
Abstract
The adenosine modulation system mostly operates through inhibitory A1 (A1 R) and facilitatory A2A receptors (A2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: high-frequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A2A R; A2A R switch off A1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A2A R, probably to bolster adaptive changes, but this heightens brain damage since A2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A2A R, whereas astrocytic and microglia A2A R might control the spread of damage. The A2A R signaling mechanisms are largely unknown since A2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A1 R preconditioning and preventing excessive A2A R function might afford maximal neuroprotection. The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A2A receptors (A2A R) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1 R in all surrounding synapses. Brain insults trigger an up-regulation of A2A R in an attempt to bolster adaptive plasticity together with adenosine release and A1 R desensitization; this favors synaptotocity (increased A2A R) and decreases the hurdle to undergo degeneration (decreased A1 R). Maximal neuroprotection is expected to result from a combined A2A R blockade and increased A1 R activation. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
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Affiliation(s)
- Rodrigo A Cunha
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Buqué A, Bloy N, Aranda F, Cremer I, Eggermont A, Fridman WH, Fucikova J, Galon J, Spisek R, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy. Oncoimmunology 2016; 5:e1149674. [PMID: 27471617 PMCID: PMC4938376 DOI: 10.1080/2162402x.2016.1149674] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 01/29/2016] [Indexed: 12/21/2022] Open
Abstract
Progressing malignancies establish robust immunosuppressive networks that operate both systemically and locally. In particular, as tumors escape immunosurveillance, they recruit increasing amounts of myeloid and lymphoid cells that exert pronounced immunosuppressive effects. These cells not only prevent the natural recognition of growing neoplasms by the immune system, but also inhibit anticancer immune responses elicited by chemo-, radio- and immuno therapeutic interventions. Throughout the past decade, multiple strategies have been devised to counteract the accumulation or activation of tumor-infiltrating immunosuppressive cells for therapeutic purposes. Here, we review recent preclinical and clinical advances on the use of small molecules that target the immunological tumor microenvironment for cancer therapy. These agents include inhibitors of indoleamine 2,3-dioxigenase 1 (IDO1), prostaglandin E2, and specific cytokine receptors, as well as modulators of intratumoral purinergic signaling and arginine metabolism.
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Affiliation(s)
- Aitziber Buqué
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Norma Bloy
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Fernando Aranda
- Group of Immune receptors of the Innate and Adaptive System, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Isabelle Cremer
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Centre de Recherche des Cordeliers, Paris, France
| | | | - Wolf Hervé Fridman
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Centre de Recherche des Cordeliers, Paris, France
| | - Jitka Fucikova
- Sotio, Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Jérôme Galon
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers, Paris, France
| | - Radek Spisek
- Sotio, Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Eric Tartour
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- INSERM, U970, Paris, France
- Paris-Cardiovascular Research Center (PARCC), Paris, France
- Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France
- INSERM, U1015, CICBT507, Villejuif, France
| | - Guido Kroemer
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Lorenzo Galluzzi
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
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Robinson SJ, Petzer JP, Terre'Blanche G, Petzer A, van der Walt MM, Bergh JJ, Lourens ACU. 2-Aminopyrimidines as dual adenosine A1/A2A antagonists. Eur J Med Chem 2015; 104:177-88. [PMID: 26462195 DOI: 10.1016/j.ejmech.2015.09.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 09/25/2015] [Accepted: 09/29/2015] [Indexed: 11/26/2022]
Abstract
In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A2A receptor antagonists.
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Affiliation(s)
- Sarel J Robinson
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Jacobus P Petzer
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Gisella Terre'Blanche
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Anél Petzer
- Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Mietha M van der Walt
- Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Jacobus J Bergh
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
| | - Anna C U Lourens
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
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18
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Pourcher E, Huot P. Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson's Disease. Mov Disord Clin Pract 2015; 2:331-340. [PMID: 30363540 DOI: 10.1002/mdc3.12187] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 03/20/2015] [Accepted: 03/25/2015] [Indexed: 12/20/2022] Open
Abstract
Background Treatment of motor fluctuations in Parkinson's disease (PD) remains an unmet challenge. Adenosine 2A (A2A) receptors are located along the indirect pathway and represent a potential target to enhance l-3,4-dihydroxyphenylalanine (l-DOPA) antiparkinsonian action. Methods This article summarizes the preclinical and clinical literature on A2A antagonists in PD, with a specific focus on their effect on off time, on time, and dyskinesia. Findings Several A2A receptor antagonists have been tested in preclinical studies and clinical trials. In preclinical studies, A2A antagonists enhanced l-DOPA antiparkinsonian action without exacerbating dyskinesia, but A2A antagonists were generally administered in combination with a subthreshold dose of l-DOPA, which is different to the paradigms used in clinical trials, where A2A antagonists were usually added to an optimal antiparkinsonian regimen. In clinical settings, A2A antagonists generally reduced duration of off time, by as much as 25% in some studies. The effect of on time duration is less clear, and in a few studies an exacerbation of dyskinesia was reported. Two A2A antagonists have been tested in phase III settings: istradefylline and preladenant. Istradefylline was effective in two phase III trials, but ineffective in another; the drug has been commercially available in Japan since 2013. In contrast, preladenant was ineffective in a phase III trial and the drug was discontinued. A phase III study with tozadenant will begin in 2015; the drug was effective at reducing off time in a phase IIb study. Other A2A antagonists are in development at the preclinical and early clinical levels.
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Affiliation(s)
- Emmanuelle Pourcher
- Clinique Sainte-Anne Mémoire et Mouvement Faculty of Medicine Laval University Quebec City Quebec Canada.,Centre Thématique de Recherche en Neuroscience Laval University Quebec City Quebec Canada
| | - Philippe Huot
- Department of Pharmacology Faculty of Medicine University of Montreal Montreal Quebec Canada.,Division of Neurology Centre Hospitalier de l'Université de Montréal Montreal Quebec Canada
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19
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Van der Schyf CJ. Rational drug discovery design approaches for treating Parkinson’s disease. Expert Opin Drug Discov 2015; 10:713-41. [DOI: 10.1517/17460441.2015.1041495] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Preti D, Baraldi PG, Moorman AR, Borea PA, Varani K. History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents. Med Res Rev 2015; 35:790-848. [PMID: 25821194 DOI: 10.1002/med.21344] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.
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Affiliation(s)
- Delia Preti
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121, Ferrara, Italy
| | - Pier Giovanni Baraldi
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121, Ferrara, Italy
| | | | - Pier Andrea Borea
- Section of Pharmacology, Department of Medical Science, University of Ferrara, 44121, Ferrara, Italy
| | - Katia Varani
- Section of Pharmacology, Department of Medical Science, University of Ferrara, 44121, Ferrara, Italy
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21
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Jenner P. Treatment of the later stages of Parkinson's disease - pharmacological approaches now and in the future. Transl Neurodegener 2015; 4:3. [PMID: 25973178 PMCID: PMC4429454 DOI: 10.1186/2047-9158-4-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 02/01/2015] [Indexed: 11/10/2022] Open
Abstract
The problems associated with the pharmacological treatment of the later stages of Parkinson's disease (PD) remain those seen over many years. These centre on a loss of drug effect ('wearing off') with disease progression, the occurrence of dyskinesia, notably with L-dopa use and the appearance of non-motor symptoms that are largely refractory to dopaminergic medication. Treatment strategies in late PD have been dominated by the use of drug combinations and the subtle manipulation of drug dosage. However, change is occurring as the understanding of the basis of motor complications and fluctuations and non-motor symptoms improves. New pharmacological options are expanding with the advent of longer acting versions of existing dopaminergic drugs, new drug delivery systems and the introduction of non-dopaminergic agents able to manipulate motor function both within the basal ganglia and in other brain regions. Non-dopaminergic agents are also being investigated for the treatment of dyskinesia and for the relief of non-motor symptoms. However, while therapy continues to improve, the treatment of late stage PD remains problematic with non-motor symptoms dominating the unmet need in this patient group.
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Affiliation(s)
- Peter Jenner
- Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Health Sciences and Medicine, King's College, London, SE1 1UL UK
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22
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Abdel-Salam OME. Drug therapy for Parkinson’s disease: An update. World J Pharmacol 2015; 4:117. [DOI: 10.5497/wjp.v4.i1.117] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 01/26/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
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Pilleri M, Antonini A. Therapeutic strategies to prevent and manage dyskinesias in Parkinson's disease. Expert Opin Drug Saf 2014; 14:281-94. [PMID: 25483147 DOI: 10.1517/14740338.2015.988137] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Chronic treatment with levodopa is associated with the development of motor fluctuations and dyskinesias particularly in young Parkinson patients. In some cases, dyskinesias become so severe that they interfere with normal movement and negatively impact quality of life. AREAS COVERED In this review, we discuss benefits and limits of available therapeutic approaches aimed at delaying or managing dyskinesias as well as new strategies that are currently under investigation. EXPERT OPINION Among available treatments, monotherapy with dopamine agonists in the early phases of the disease reduces the risk for dyskinesias compared with levodopa. Nevertheless, dopamine agonists are unable to prevent dyskinesias once levodopa is added, which is always required once disease severity progresses. Convincing evidence of dyskinesia improvement has been shown only for deep brain stimulation and to some extent also for duodenal levodopa infusion and subcutaneous apomorphine. These approaches are expensive, have restrictive inclusion criteria and can cause potentially serious side effects. Alternative therapies include drugs targeting nondopaminergic neurotransmitter systems. Amantadine improves dyskinesias but its long-term effect is often unsatisfactory. Glutamatergic and gabaergic compounds have been tested in clinical trials, with promising results. By contrast, adrenergic drugs, fipamezole and idazoxan, did not show antidyskinetic effect.
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Affiliation(s)
- Manuela Pilleri
- Parkinson Disease and Movement Disorders Unit, "Fondazione Ospedale San Camillo" - I.R.C.C.S , Via Alberoni 7030126 Venice , Italy , +39 41 2207554 ,
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Schaeffer E, Pilotto A, Berg D. Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease. CNS Drugs 2014; 28:1155-84. [PMID: 25342080 DOI: 10.1007/s40263-014-0205-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
L-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson's disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of L-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.
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Affiliation(s)
- Eva Schaeffer
- Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Hoppe Seyler-Strasse 3, 72076, Tübingen, Germany
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Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, Kozyolkin O, Neale A, Resburg C, Meya U, Kenney C, Bandak S. Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol 2014; 13:767-76. [PMID: 25008546 DOI: 10.1016/s1474-4422(14)70148-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. METHODS We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594. FINDINGS Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1·1 h, 95% CI -1·8 to -0·5; p=0·0006), the tozadenant 120 mg twice-daily group (-1·1 h, -1·8 to -0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (-1·2 h, -1·9 to -0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients). INTERPRETATION Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted. FUNDING Biotie Therapies.
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Affiliation(s)
- Robert A Hauser
- University of South Florida Parkinson's Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Tampa, FL, USA.
| | - C Warren Olanow
- Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
| | - Karl D Kieburtz
- University of Rochester School of Medicine, Rochester, NY, USA
| | - Emmanuelle Pourcher
- Clinique Sainte-Anne Mémoire et Mouvement, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Any Docu-Axelerad
- Department of General Medicine, Ovidius University of Constanta, Constanta, Romania
| | - Mark Lew
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Olexandr Kozyolkin
- Department of General Neurology, Zaporizhzhya State Medical University, Zaporizhzhya, Ukraine
| | - Ann Neale
- Biotie Therapies, South San Francisco, CA, USA
| | | | - Uwe Meya
- Biotie Therapies, South San Francisco, CA, USA
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Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease. J Neuropathol Exp Neurol 2014; 73:414-24. [PMID: 24709676 DOI: 10.1097/nen.0000000000000064] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation,is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.
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Stayte S, Vissel B. Advances in non-dopaminergic treatments for Parkinson's disease. Front Neurosci 2014; 8:113. [PMID: 24904259 PMCID: PMC4033125 DOI: 10.3389/fnins.2014.00113] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Accepted: 04/30/2014] [Indexed: 01/05/2023] Open
Abstract
Since the 1960's treatments for Parkinson's disease (PD) have traditionally been directed to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has resulted in extensive efforts to develop new therapies that work in ways other than restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a detailed account of their success in animal models and their translation to human clinical trials. We then consider how advances in understanding the mechanisms of PD, genetics, the possibility that PD may consist of multiple disease states, understanding of the etiology of PD in non-dopaminergic regions as well as advances in clinical trial design will be essential for ongoing advances. We conclude that despite the challenges ahead, patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable.
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Affiliation(s)
- Sandy Stayte
- Neuroscience Department, Neurodegenerative Disorders Laboratory, Garvan Institute of Medical Research, Sydney NSW, Australia ; Faculty of Medicine, University of New South Wales, Sydney NSW, Australia
| | - Bryce Vissel
- Neuroscience Department, Neurodegenerative Disorders Laboratory, Garvan Institute of Medical Research, Sydney NSW, Australia ; Faculty of Medicine, University of New South Wales, Sydney NSW, Australia
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Adenosine A2A receptor antagonists in Parkinson's disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 2014; 28:455-74. [PMID: 24687255 DOI: 10.1007/s40263-014-0161-7] [Citation(s) in RCA: 134] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatology. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates. The development of new highly selective adenosine A2A receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clinical research regarding A2A antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivatives in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compounds have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A2A antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. In addition, early findings suggest that A2A antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacological and clinical data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.
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29
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Human abuse liability evaluation of CNS stimulant drugs. Neuropharmacology 2014; 87:81-90. [PMID: 24793872 DOI: 10.1016/j.neuropharm.2014.04.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 04/01/2014] [Accepted: 04/16/2014] [Indexed: 01/16/2023]
Abstract
Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'.
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Tomiyama M. Adenosine receptors and dyskinesia in pathophysiology. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 119:117-26. [PMID: 25175963 DOI: 10.1016/b978-0-12-801022-8.00005-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
First, the recent progress in the pathogenesis of levodopa-induced dyskinesia was described. Serotonin neurons play an important role in conversion from levodopa to dopamine and in the release of converted dopamine into the striatum in the Parkinsonian state. Since serotonin neurons lack buffering effects on synaptic dopamine concentration, the synaptic dopamine markedly fluctuates depending on the fluctuating levodopa concentration in the serum after taking levodopa. The resultant pulsatile stimulation makes the striatal direct-pathway neurons get potential that releases excessive GABA into the output nuclei of the basal ganglia. When levodopa is administered, the stored GABA is released, the output nuclei become hypoactive, and then dyskinesias emerge. Second, effects of adenosine A2A receptor antagonists on dyskinesia were described. It has been demonstrated that the expression of adenosine A2A receptors is increased in Parkinson's disease (PD) patients with dyskinesias, suggesting that blockade of A2A receptors is beneficial for dyskinesias. Preclinical studies have shown that A2A receptor antagonists reduce liability of dyskinesias in PD models. Clinical trials have demonstrated that A2A antagonists increase functional ON-time (ON without troublesome dyskinesia) in PD patients suffering from wearing-off phenomenon, although they may increase dyskinesia in patients with advanced PD.
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Affiliation(s)
- Masahiko Tomiyama
- Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan.
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31
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Jenner P. An Overview of Adenosine A2A Receptor Antagonists in Parkinson's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 119:71-86. [DOI: 10.1016/b978-0-12-801022-8.00003-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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32
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Hung AY, Schwarzschild MA. Treatment of Parkinson's disease: what's in the non-dopaminergic pipeline? Neurotherapeutics 2014; 11:34-46. [PMID: 24310604 PMCID: PMC3899482 DOI: 10.1007/s13311-013-0239-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Dopamine depletion resulting from degeneration of nigrostriatal dopaminergic neurons is the primary neurochemical basis of the motor symptoms of Parkinson's disease (PD). While dopaminergic replacement strategies are effective in ameliorating these symptoms early in the disease process, more advanced stages of PD are associated with the development of treatment-related motor complications and dopamine-resistant symptoms. Other neurotransmitter and neuromodulator systems are expressed in the basal ganglia and contribute to the extrapyramidal refinement of motor function. Furthermore, neuropathological studies suggest that they are also affected by the neurodegenerative process. These non-dopaminergic systems provide potential targets for treatment of motor fluctuations, levodopa-induced dyskinesias, and difficulty with gait and balance. This review summarizes recent advances in the clinical development of novel pharmacological approaches for treatment of PD motor symptoms. Although the non-dopaminergic pipeline has been slow to yield new drugs, further development will likely result in improved treatments for PD symptoms that are induced by or resistant to dopamine replacement.
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Affiliation(s)
- Albert Y Hung
- Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA,
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33
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Abstract
Despite advances in the treatment of Parkinson's disease there are still many unmet needs, including neuroprotection, treatment of motor complications, treatment of dyskinesia, treatment of psychosis, and treatment of nondopaminergic symptoms. In this review, I highlight the obstacles to develop a neuroprotective drug and some of the treatment strategies recently approved or still in clinical trials designed to meet these unmet needs.
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Affiliation(s)
- Fabrizio Stocchi
- Institute for Research and Medical Care, IRCCS San Raffaele, Via della Pisana 235, 00163, Rome, Italy,
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34
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Kanda T, Uchida SI. Clinical/Pharmacological Aspect of Adenosine A2A Receptor Antagonist for Dyskinesia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 119:127-50. [DOI: 10.1016/b978-0-12-801022-8.00006-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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35
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Ramirez-Zamora A, Molho E. Treatment of motor fluctuations in Parkinson’s disease: recent developments and future directions. Expert Rev Neurother 2013; 14:93-103. [DOI: 10.1586/14737175.2014.868306] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Zúñiga-Ramírez C, Micheli F. Preladenant: an adenosine A2A receptor antagonist for Parkinson’s disease. FUTURE NEUROLOGY 2013. [DOI: 10.2217/fnl.13.52] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Preladenant (SCH 420814) is a potent selective antagonist at the adenosine A2A receptor that is being studied for treatment in early Parkinson’s disease (PD) as a monotherapy, and in moderate-to-severe PD as an add on to levodopa therapy. Unlike other drugs used for this disease, preladenant modulates adenosine action at the striatal level in order to block the inhibitory action of the basal ganglia output nuclei. Animal models of PD suggested that preladenant could be an effective treatment, which was further supported in a Phase II study of subjects with idiopathic PD who demonstrated a benefit in reducing off-time with an increase in on-time. In this article, we review current perspectives concerning pharmacological approaches to PD, the pharmacological properties of preladenant, its efficiency and safety, as well as the results reported for parkinsonian subjects treated with this drug.
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Affiliation(s)
- Carlos Zúñiga-Ramírez
- Movement Disorders & Neurodegenerative Diseases Unit, Hospital Civil de Guadalajara ‘Fray Antonio Alcalde’, Guadalajara, Mexico
| | - Federico Micheli
- Parkinson’s Disease & Movement Disorders Program, Hospital de Clínicas ‘José de San Martín’, Buenos Aires, Argentina
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Bargiotas P, Konitsiotis S. Levodopa-induced dyskinesias in Parkinson's disease: emerging treatments. Neuropsychiatr Dis Treat 2013; 9:1605-17. [PMID: 24174877 PMCID: PMC3808152 DOI: 10.2147/ndt.s36693] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Parkinson's disease therapy is still focused on the use of L-3,4-dihydroxyphenylalanine (levodopa or L-dopa) for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs). LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson's disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development.
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Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci U S A 2013; 110:14711-6. [PMID: 23964122 DOI: 10.1073/pnas.1308209110] [Citation(s) in RCA: 297] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A(-/-) mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function. Interestingly, A2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73(+) tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A2A or A2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A2A/A2B receptor antagonists have already entered clinical trials in other therapeutic settings.
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