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Chrienova Z, Nepovimova E, Andrys R, Dolezal R, Janockova J, Muckova L, Fabova L, Soukup O, Oleksak P, Valis M, Korabecny J, Marco-Contelles J, Kuca K. Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities. J Enzyme Inhib Med Chem 2022; 37:2605-2620. [PMID: 36131624 PMCID: PMC9518283 DOI: 10.1080/14756366.2022.2122054] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
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Affiliation(s)
- Zofia Chrienova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Rudolf Andrys
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Rafael Dolezal
- Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Jana Janockova
- Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Lubica Muckova
- Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic
| | - Lenka Fabova
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Ondrej Soukup
- Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Patrik Oleksak
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Martin Valis
- Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Jan Korabecny
- Biomedical Research Centre and Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic
| | - José Marco-Contelles
- Institute of General Organic Chemistry (CSIC), Laboratory of Medicinal Chemistry, Madrid, Spain
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
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Bi Y, Zhang J, Zeng D, Chen L, Ye W, Yang Q, Ling Y. Cholinesterase is Associated With Prognosis and Response to Chemotherapy in Advanced Gastric Cancer. Pathol Oncol Res 2021; 27:580800. [PMID: 34257526 PMCID: PMC8262142 DOI: 10.3389/pore.2021.580800] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 02/15/2021] [Indexed: 01/26/2023]
Abstract
Background: Cholinesterase (CHE) is a routine serum biomarker in gastric cancer (GC). However, little research has been done on its clinical value in advanced GC. In addition, it is not clear whether it can be used as biomarker for the response and prognosis of advanced GC patients. Methods: Between Jan. 2013 and Dec. 2016, a total of 150 patients with advanced GC treated with first-line chemotherapy were admitted to Changzhou Tumor Hospital Affiliated to Soochow University. We retrospectively identified serum CHE level on the day before chemotherapy and at the end of chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between serum CHE levels and progression-free survival (PFS) and overall survival (OS). Results: A total of 150 advanced GC patients were included and divided into serum level ≥5,000 IU/L and serum level <5,000 IU/L. CHE level lower than 5,000 IU/L was associated with poorer PFS (HR, 1.60; 95% CI, 1.141–2.243; p = 0.006), poorer OS (HR, 1.76; 95% CI, 1.228–2.515; p = 0.002) and trend of poorer response (HR, 0.56; 95% CI, 0.272–1.129; p = 0.104). In univariate and multivariate logistic regression analysis, only liver metastasis and PS score were significantly associated with objective response (p < 0.05). The medium PFS was 8.0 months in patients with post-treatment CHE increased vs. 3.8 months in patients with CHE decreased after chemotherapy (HR, 1.82; 95% CI 1.28–2.57; p = 0.0002). The medium OS was 13.1 months in patients with increased post-treatment CHE vs. 8.1 months in patients with decreased post-treatment CHE (HR, 1.87; 95% CI 1.29–2.71; p = 0.0002). Conclusion: Advanced GC with CHE levels below 5,000 IU/L was significantly associated with poor PFS and OS. The results suggested that CHE analysis before chemotherapy was a promising prognostic marker for advanced GC.
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Affiliation(s)
- Yanzhi Bi
- Department of Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, China
| | - Junling Zhang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Dongxiang Zeng
- Department of Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, China
| | - Lili Chen
- Department of Hematology, The Suqian Affiliated Hospital of Xuzhou Medicine University, Suqian, China
| | - Wei Ye
- Department of Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, China
| | - Quanliang Yang
- Department of Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, China
| | - Yang Ling
- Department of Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, China
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Brimson JM, Brimson S, Chomchoei C, Tencomnao T. Using sigma-ligands as part of a multi-receptor approach to target diseases of the brain. Expert Opin Ther Targets 2020; 24:1009-1028. [PMID: 32746649 DOI: 10.1080/14728222.2020.1805435] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The sigma receptors are found abundantly in the central nervous system and are targets for the treatment of various diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), depression, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). However, for many of these diseases, other receptors and targets have been the focus of the most, such as acetylcholine esterase inhibitors in Alzheimer's and dopamine replacement in Parkinson's. The currently available drugs for these diseases have limited success resulting in the requirement of an alternative approach to their treatment. AREAS COVERED In this review, we discuss the potential role of the sigma receptors and their ligands as part of a multi receptor approach in the treatment of the diseases mentioned above. The literature reviewed was obtained through searches in databases, including PubMed, Web of Science, Google Scholar, and Scopus. EXPERT OPINION Given sigma receptor agonists provide neuroprotection along with other benefits such as potentiating the effects of other receptors, further development of multi-receptor targeting ligands, and or the development of multi-drug combinations to target multiple receptors may prove beneficial in the future treatment of degenerative diseases of the CNS, especially when coupled with better diagnostic techniques.
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Affiliation(s)
- James Michael Brimson
- Age-related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University , Bangkok, Thailand
| | - Sirikalaya Brimson
- Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University , Bangkok, Thailand
| | - Chanichon Chomchoei
- Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University , Bangkok, Thailand
| | - Tewin Tencomnao
- Age-related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University , Bangkok, Thailand
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Uddin MS, Kabir MT, Rahman MM, Mathew B, Shah MA, Ashraf GM. TV 3326 for Alzheimer's dementia: a novel multimodal ChE and MAO inhibitors to mitigate Alzheimer's-like neuropathology. ACTA ACUST UNITED AC 2020; 72:1001-1012. [PMID: 32149402 DOI: 10.1111/jphp.13244] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/30/2020] [Accepted: 02/09/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and a well-recognized cause of dementia with ageing. In this review, we have represented the ChE and MAO inhibitory potential of TV 3326 against AD based on current scientific evidence. KEY FINDINGS The aetiology of AD is quite complex and not completely understood. However, it has been observed that AD involves the deposition of abnormal amyloid beta (Aβ), along with hyperphosphorylation of tau, oxidative stress, low acetylcholine (ACh) level and biometal dyshomeostasis. Due to the complex nature of AD aetiology, active research is required in the areas of development of multitarget drugs with 2 or more complementary biological functions, as they might represent significant progress in the AD treatment. Interestingly, it has been found that TV 3326 (i.e. ladostigil) is regarded as a novel therapeutic agent since it has the potential to cause inhibition of monoamine oxidase (MAO) A and B, and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Furthermore, it has the capacity to reverse memory impairments, which further suggests the ability of this drug to elevate cholinergic activity in the brain. SUMMARY TV 3326 can avert oxidative-nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.,Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | | | - Md Motiar Rahman
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Bijo Mathew
- Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India
| | - Muhammad Ajmal Shah
- Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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Uddin MS, Kabir MT, Rahman MH, Alim MA, Rahman MM, Khatkar A, Al Mamun A, Rauf A, Mathew B, Ashraf GM. Exploring the Multifunctional Neuroprotective Promise of Rasagiline Derivatives for Multi-Dysfunctional Alzheimer's Disease. Curr Pharm Des 2020; 26:4690-4698. [PMID: 32250219 DOI: 10.2174/1381612826666200406075044] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 02/19/2020] [Indexed: 01/07/2023]
Abstract
Alzheimer's disease (AD) is a chronic, age-related, and irreversible brain disorder that typically develops slowly and gets worse over time. The potent auspicious drug candidate for the treatment of AD is supposed to perform the simultaneous modulation of several targets linked to AD. The new therapeutic approach involves drug candidates that are designed to act on multiple targets and have various pharmacological properties. This trend has triggered the development of various multimodal drugs including TV-3326 (i.e. ladostigil) and M-30 (i.e. a new multitarget iron chelator). TV-3326 combines the neurorestorative/neuroprotective effects of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. M-30, the second derivative of rasagiline, was developed by combining the propargyl moiety of rasagiline into the skeleton of VK-28 (i.e. a novel brain permeable neuroprotective iron chelator). It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases (NDs). In this article, we have reviewed the neuroprotective molecular mechanisms and multimodal effects of TV-3326 and M-30.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | | | - Md Habibur Rahman
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
| | - Md Abdul Alim
- Department of Chemistry, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- Graduate School of Innovative Life Science, Faculty of Engineering, University of Toyama, Toyama, Japan
| | - Md Motiar Rahman
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Anurag Khatkar
- Laboratory for Preservation Technology and Enzyme Inhibition Studies, Faculty of Pharmaceutical
Sciences, Maharshi Dayanand University, Rohtak, India
| | - Abdullah Al Mamun
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Anbar 23561, Khyber Pakhtunkhwa, Pakistan
| | - Bijo Mathew
- Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University,
Jeddah, Saudi Arabia
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Youdim MBH. Monoamine oxidase inhibitors, and iron chelators in depressive illness and neurodegenerative diseases. J Neural Transm (Vienna) 2018; 125:1719-1733. [PMID: 30341696 DOI: 10.1007/s00702-018-1942-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/11/2018] [Indexed: 12/11/2022]
Abstract
In early 1920s, tyramine oxidase was discovered that metabolized tyramine and in 1933 Blaschko demonstrated that this enzyme also metabolized adrenaline, noradrenaline and dopamine. Zeller gave it the name monoamine oxidase (MAO) to distinguish it from the enzyme that oxidatively deaminated diamines. MAO was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamines (and, later, 5-hydroxytryptamine, as well). Within the few decade, the inhibitors of MAO were discovered and introduced for the treatment of depressive illness which was established clinically. However, the first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two forms, distinct forms, MAO-A and -B, and selective inhibitors for them. Selective inhibitors of MAO-B (selegiline, rasagiline and safinamide) have found a therapeutic role in the treatment of Parkinson's disease and reversible inhibitors of MAO-A offered antidepressant activity without the serious side effects of the earlier nonselective MAO inhibitors. Subsequent molecular pharmacological have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress through the accumulation of iron in the Parkinsonian and Alzheimer brains has been suggested to be critical for the initiation and progress of neurodegeneration. Selective inhibition of brain MAO could contribute importantly to lowering such stress, preventing the formation of hydrogen peroxide. Interaction of Iron with hydrogen peroxide and lead to Fenton reaction and production of the most reactive radical, namely hydroxyl radical. There are complex interactions between free iron levels in brain and MAO, and cascade of neurotoxic events may have practical outcomes for depressive disorders and neurodegenerative diseases. As consequence recent novel therapeutic drugs for neurodegenerative diseases has led to the development of multi target drugs, that possess selective brain MAO A and B inhibitory moiety, iron chelating and antioxidant activities and the ability to increase brain levels of endogenous neurotrophins, such as BDNF, GDNF VEGF and erythropoietin and induce mitochondrial biogenesis.
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Affiliation(s)
- Moussa B H Youdim
- Technion-Bruce Rappaport Faculty of Medicine, Rappaport Family Research Institute, Haifa, Israel. .,, Yokneam, Israel.
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Korábečný J, Nepovimová E, Cikánková T, Špilovská K, Vašková L, Mezeiová E, Kuča K, Hroudová J. Newly Developed Drugs for Alzheimer's Disease in Relation to Energy Metabolism, Cholinergic and Monoaminergic Neurotransmission. Neuroscience 2017; 370:191-206. [PMID: 28673719 DOI: 10.1016/j.neuroscience.2017.06.034] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/20/2017] [Accepted: 06/21/2017] [Indexed: 11/18/2022]
Abstract
Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.
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Affiliation(s)
- Jan Korábečný
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic
| | - Eugenie Nepovimová
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 500 03 Hradec Králové, Czech Republic
| | - Tereza Cikánková
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic
| | - Katarína Špilovská
- National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic; Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Třebešská 1575, 500 01 Hradec Králové, Czech Republic
| | - Lucie Vašková
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 500 03 Hradec Králové, Czech Republic
| | - Eva Mezeiová
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic; Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic
| | - Kamil Kuča
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 500 03 Hradec Králové, Czech Republic
| | - Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00 Prague 2, Czech Republic.
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Multi-target therapeutics for neuropsychiatric and neurodegenerative disorders. Drug Discov Today 2016; 21:1886-1914. [PMID: 27506871 DOI: 10.1016/j.drudis.2016.08.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/20/2016] [Accepted: 08/01/2016] [Indexed: 12/30/2022]
Abstract
Historically, neuropsychiatric and neurodegenerative disease treatments focused on the 'magic bullet' concept; however multi-targeted strategies are increasingly attractive gauging from the escalating research in this area. Because these diseases are typically co-morbid, multi-targeted drugs capable of interacting with multiple targets will expand treatment to the co-morbid disease condition. Despite their theoretical efficacy, there are significant impediments to clinical success (e.g., difficulty titrating individual aspects of the drug and inconclusive pathophysiological mechanisms). The new and revised diagnostic frameworks along with studies detailing the endophenotypic characteristics of the diseases promise to provide the foundation for the circumvention of these impediments. This review serves to evaluate the various marketed and nonmarketed multi-targeted drugs with particular emphasis on their design strategy.
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Gene dysregulation is restored in the Parkinson's disease MPTP neurotoxic mice model upon treatment of the therapeutic drug Cu(II)(atsm). Sci Rep 2016; 6:22398. [PMID: 26928495 PMCID: PMC4772163 DOI: 10.1038/srep22398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 02/15/2016] [Indexed: 12/04/2022] Open
Abstract
The administration of MPTP selectively targets the dopaminergic system resulting in Parkinsonism-like symptoms and is commonly used as a mice model of Parkinson’s disease. We previously demonstrated that the neuroprotective compound CuII(atsm) rescues nigral cell loss and improves dopamine metabolism in the MPTP model. The mechanism of action of CuII(atsm) needs to be further defined to understand how the compound promotes neuronal survival. Whole genome transcriptomic profiling has become a popular method to examine the relationship between gene expression and function. Substantia nigra samples from MPTP-lesioned mice were evaluated using whole transcriptome sequencing to investigate the genes altered upon CuII(atsm) treatment. We identified 143 genes affected by MPTP lesioning that are associated with biological processes related to brain and cognitive development, dopamine synthesis and perturbed synaptic neurotransmission. Upon CuII(atsm) treatment, the expression of 40 genes involved in promoting dopamine synthesis, calcium signaling and synaptic plasticity were restored which were validated by qRT-PCR. The study provides the first detailed whole transcriptomic analysis of pathways involved in MPTP-induced Parkinsonism. In addition, we identify key therapeutic pathways targeted by a potentially new class of neuroprotective agents which may provide therapeutic benefits for other neurodegenerative disorders.
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Propargylamine as functional moiety in the design of multifunctional drugs for neurodegenerative disorders: MAO inhibition and beyond. Future Med Chem 2016; 7:609-29. [PMID: 25921401 DOI: 10.4155/fmc.15.12] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Much progress has been made in designing analogues that can potentially confer neuroprotection against debilitating neurodegenerative disorders, yet the multifactorial pathogenesis of this cluster of diseases remains a stumbling block for the successful design of an 'ultimate' drug. However, with the growing popularity of the "one drug, multiple targets" paradigm, many researchers have successfully synthesized and evaluated drug-like molecules incorporating a propargylamine function that shows potential to serve as multifunctional drugs or multitarget-directed ligands. It is the aim of this review to highlight the reported activities of these propargylamine derivatives and their prospect to serve as drug candidates for the treatment of neurodegenerative disorders.
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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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Youdim MBH, Kupershmidt L, Amit T, Weinreb O. Promises of novel multi-target neuroprotective and neurorestorative drugs for Parkinson's disease. Parkinsonism Relat Disord 2014; 20 Suppl 1:S132-6. [PMID: 24262165 DOI: 10.1016/s1353-8020(13)70032-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The cascade of neurotoxic events involved in neuronal degeneration suggests that it is naive to think mono-target drugs can induce disease modification by slowing the process of neurodegeneration in Parkinson's disease (PD). Employing the pharmacophore of rasagiline (N-propargyl-1-R-aminoindan), we have developed a series of novel multi-target neuroprotective drugs, including: (A) drugs [ladostigil, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)] with both cholinesterase-butyrylesterase (Ch-BuE) and brain-selective monamine oxidase-AB (MAO-AB) inhibitory activities and (B) iron chelator-radical scavenging drugs (M30) possessing brain-selective MAO-AB inhibitor activity and the neuroprotective-neurorescue propargylamine moiety of rasagiline. This was considered to be valid since brain MAO and iron increase in PD and aging, which could lead to oxidative stress-dependent neurodegeneration. The multi-target iron chelator, M30, has all the properties of ladostigil, but is not an acetylcholinesterase (CHE) inhibitor. However, M30 has both neuroprotective and neurorestorative activities for nigrostriatal dopamine neurons in post-lesion MPTP, lactacystin and 6-hydroxydopamine animal models of PD. The neurorestorative activity has been identified as being related to the ability of the drug to activate hypoxia-inducible factor (HIF) by inhibiting prolyl-4-hydroxylase. M30 regulates cell cycle arrest and induces the neurotrophins brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), as well as glia-derived neurotrophic factor (GDNF). These unique multiple actions of M30 make it potentially useful as a disease modifying drug for the treatment of PD.
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Affiliation(s)
- Moussa B H Youdim
- Technion-Rappaport Faculty of Medicine, Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases, Haifa, Israel Abital Pharma Pipeline Ltd., Tel Aviv, Israel.
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Chen Y, Ni YY, Liu J, Lu JW, Wang F, Wu XL, Gu MM, Lu ZY, Wang ZG, Ren ZH. Dopamine receptor 3 might be an essential molecule in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. BMC Neurosci 2013; 14:76. [PMID: 23902361 PMCID: PMC3734004 DOI: 10.1186/1471-2202-14-76] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 07/15/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease (PD)-like neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) via its oxidized product, 1-methyl-4-phenylpyridinium (MPP+), which is transported by the dopamine (DA) transporter into DA nerve terminals. DA receptor subtype 3 (D3 receptor) participates in neurotransmitter transport, gene regulation in the DA system, physiological accommodation via G protein-coupled superfamily receptors and other physiological processes in the nervous system. This study investigated the possible correlation between D3 receptors and MPTP-induced neurotoxicity. A series of behavioral experiments and histological analyses were conducted in D3 receptor-deficient mice, using an MPTP-induced model of PD. RESULTS After the fourth MPTP injection, wild-type animals that received 15 mg/kg per day displayed significant neurotoxin-related bradykinesia. D3 receptor-deficient mice displayed attenuated MPTP-induced locomotor activity changes. Consistent with the behavioral observations, further neurohistological assessment showed that MPTP-induced neuronal damage in the SNpc was reduced in D3 receptor-deficient mice. CONCLUSIONS Our study indicates that the D3 receptor might be an essential molecule in MPTP-induced PD and provides a new molecular mechanism for MPTP neurotoxicity.
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Affiliation(s)
- Yan Chen
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ying-yin Ni
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jie Liu
- Shanghai Institute of Traumatology and Orthopaedics, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jia-wei Lu
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Fang Wang
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiao-lin Wu
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ming-min Gu
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhen-yu Lu
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhu-gang Wang
- Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Research Centre for Experimental Medicine, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Research Centre for Model Organisms, Shanghai 201210, China
| | - Zhi-hua Ren
- Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215126, China
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14
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Youdim MBH. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp Neurobiol 2013; 22:1-10. [PMID: 23585716 PMCID: PMC3620452 DOI: 10.5607/en.2013.22.1.1] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 03/04/2013] [Accepted: 03/04/2013] [Indexed: 11/28/2022] Open
Abstract
Present anti-PD and -AD drugs have limited symptomatic activity and devoid of neuroprotective and neurorestorative property that is needed for disease modifying action. The complex pathology of PD and AD led us to develop several multi-target neuroprotective and neurorestorative drugs with several CNS targets with the ability for possible disease modifying activity. Employing the pharmacophore of our anti-parkinson drug rasagiline (Azilect, N-propagrgyl-1-R-aminoindan), we have developed a series of novel multi-functional neuroprotective drugs (A) [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase and brain selective monoamine-oxidase (MAO) A/B inhibitory activities and (B) the iron chelator-radical scavenging-brain selective monoamine oxidase (MAO) A/B inhibitor and M30 possessing the neuroprotective and neurorescuing propargyl moiety of rasagiline, as potential treatment of AD, DLB and PD with dementia. Another series of multi-target drugs (M30, HLA-20 series) which are brain permeable iron chelators and potent selective brain MAO inhibitors were also developed. These series of drugs have the ability of regulating and processing amyloid precursor protein (APP) since APP and alpha-synuclein are metaloproteins (iron-regulated proteins), with an iron responsive element 5"UTR mRNA similar to transferring and ferritin. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats after oral doses. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain. Ladostigil acts like an anti-depressant in the forced swim test in rats, indicating a potential for anti-depressant activity. Ladostigil prevents the destruction of nigrostriatal neurons induced by infusion of neurotoxin MPTP in mice. The propargylamine moiety of ladostigil confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells. The multi-target iron chelator M30 has all the properties of ladostigil and similar neuroprotective activity to ladostigil, but is not a ChE inhibitor. M30 has a neurorestorative activity in post-lesion of nigrostriatal dopamine neurons in MPTP, lacatcystin and 6-hydroxydopamine animal models of PD. The neurorestorative activity is related to the ability of the drug to activate hypoxia inducing factor (HIF) which induces the production of such neurotrophins as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and erythropoietin as well as glia-derived neurotrophic factor (GDNF). The unique multiple actions of ladostigil and M30 make the potentially useful drugs for the treatment of dementia with Parkinsonian-like symptoms and depression.
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Affiliation(s)
- Moussa B H Youdim
- Technion Rappaort Faculty of Medicine, Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Haifa, Haifa 30196, Israel. ; Department of Systems Biology, Yonsei University, Seoul 120-749, Korea
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15
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Propargylamine-derived multitarget-directed ligands: fighting Alzheimer’s disease with monoamine oxidase inhibitors. J Neural Transm (Vienna) 2012; 120:893-902. [DOI: 10.1007/s00702-012-0948-y] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 12/02/2012] [Indexed: 01/16/2023]
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16
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Van der Schyf CJ. The use of multi-target drugs in the treatment of neurodegenerative diseases. Expert Rev Clin Pharmacol 2012; 4:293-8. [PMID: 22114774 DOI: 10.1586/ecp.11.13] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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17
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Lesemann A, Reinel C, Hühnchen P, Pilhatsch M, Hellweg R, Klaissle P, Winter C, Steiner B. MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice. Brain Res 2012; 1457:51-69. [DOI: 10.1016/j.brainres.2012.03.046] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 02/27/2012] [Accepted: 03/20/2012] [Indexed: 12/20/2022]
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18
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Terry AV, Callahan PM, Hall B, Webster SJ. Alzheimer's disease and age-related memory decline (preclinical). Pharmacol Biochem Behav 2011; 99:190-210. [PMID: 21315756 PMCID: PMC3113643 DOI: 10.1016/j.pbb.2011.02.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 01/21/2011] [Accepted: 02/01/2011] [Indexed: 01/05/2023]
Abstract
An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.
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Affiliation(s)
- Alvin V Terry
- Department of Pharmacology and Toxicology and Small Animal Behavior Core, Medical College of Georgia, Augusta, GA 30912, USA.
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19
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The emergence of designed multiple ligands for neurodegenerative disorders. Prog Neurobiol 2011; 94:347-59. [PMID: 21536094 DOI: 10.1016/j.pneurobio.2011.04.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Revised: 04/13/2011] [Accepted: 04/15/2011] [Indexed: 12/21/2022]
Abstract
The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline.
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20
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Multimodal drugs and their future for Alzheimer's and Parkinson's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2011; 100:107-25. [DOI: 10.1016/b978-0-12-386467-3.00006-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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21
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Youdim MBH. Why do we need multifunctional neuroprotective and neurorestorative drugs for Parkinson's and Alzheimer's disorders? Rambam Maimonides Med J 2010; 1:e0011. [PMID: 23908783 PMCID: PMC3678780 DOI: 10.5041/rmmj.10011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD, and all drug treatments are symptomatic and monomodal in their action. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that result in neuronal death and predisposition to depression and eventual dementia, and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) is the development and use of multifunctional pharmaceuticals which can act at different brain regions and neurons. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD, some of which are under development. The compounds discussed originate from synthetic chemistry as well as from natural sources.
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22
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Youdim MBH. Why do we need multifunctional neuroprotective and neurorestorative drugs for Parkinson's and Alzheimer's diseases as disease modifying agents. Exp Neurobiol 2010; 19:1-14. [PMID: 22110336 PMCID: PMC3214798 DOI: 10.5607/en.2010.19.1.1] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Accepted: 06/20/2010] [Indexed: 01/01/2023] Open
Abstract
Parkinson's disease (PD) and Alzheimer's Disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD and all drug treatment are synptomactic. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that results in neuronal death and predisposition to depression and eventual dementia and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) may be the development and use of multifunctional pharmaceuticals. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD. The compounds discussed originate from synthetic chemistry as well as from natural sources.
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Affiliation(s)
- Moussa B H Youdim
- Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Technion-Faculty of Medicine, Efron St., Haifa 31096, Israel
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23
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Why should we use multifunctional neuroprotective and neurorestorative drugs for Parkinson's disease? Parkinsonism Relat Disord 2009; 13 Suppl 3:S281-91. [PMID: 18267251 DOI: 10.1016/s1353-8020(08)70017-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Parkinson's disease (PD) is a severe neurodegenerative disorder, with no available drugs able to prevent the neuronal cell loss characteristic in brains of patients suffering from PD. Due to the complex cascade of molecular events involved in the etiology of PD, an innovative approach towards neuroprotection or neurorescue may entail the use of multifunctional pharmaceuticals that target an array of pathological pathways, each of which is believed to contribute to events that ultimately lead to neuronal cell death. Here we discuss examples of novel multifunctional ligands that may have potential as neuroprotective and neurorestorative therapeutics in PD. The compounds discussed originate from synthetic chemistry as well as from natural sources where various moieties, identified in research to possess neuroprotective and neurorestorative properties, have been introduced into the structures of several monomodal drugs, some of which are used in the clinic.
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Abstract
The marked decline in FDA-approved new drug candidates in recent years suggests the possibility that the "low-hanging fruit" has been almost entirely harvested. This might be particularly applicable to drugs acting on the central nervous system. Fortunately, there are several examples extant for the utility of multifunctional drugs, compounds, or drug mixtures that act on multiple additive or synergistic targets. However, to exploit this approach may require the willingness to consider the possibility that drug targets might be addressed by molecules of rather low specificity and moderate potency. The expectation is that single target molecules with high specificity might not have access to complex interacting neural pathways, and that moderate potency could engender fewer off-target side effects. Though novel compounds might be developed by combining the active functional groups of two or more drug molecules, the approach still lends itself to high throughput screening of large chemical libraries. Multifunctional compounds might be designed with the ability to: 1) offer both palliative and disease modifying actions, 2) act on targets that produce additive or synergistic therapeutic responses, 3) simultaneously evoke a therapeutic response at the desired target and prevent an undesired response mediated by an alternate target, 4) allow one component to promote the drugable characteristics (e.g., brain penetration) of the therapeutic component, and 5) prolong the duration of effectiveness of one compound by contributing the pharmacodynamic actions of another. The author takes the liberty to include examples of the situations just mentioned from studies in his laboratory in the following discussion.
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Affiliation(s)
- Jerry J Buccafusco
- Alzheimer's Research Center, Medical College of Georgia, Augusta, Georgia 30912 and Charlie Norwood VA Medical Center, Augusta, Georgia 30904, USA.
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25
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Van der Schyf CJ, Geldenhuys WJ. Polycyclic compounds: ideal drug scaffolds for the design of multiple mechanism drugs? Neurotherapeutics 2009; 6:175-86. [PMID: 19110208 PMCID: PMC5084265 DOI: 10.1016/j.nurt.2008.10.037] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Recently there has been a resurging interest in developing multi-functional drugs to treat diseases with complex pathological mechanisms. Such drug molecules simultaneously target multiple etiologies that have been found to be important modulators in specific diseases. This approach has significant promise and may be more effective than using one compound specific for one drug target or, by a polypharmaceutical approach, using a cocktail of two or more drugs. Polycyclic ring structures are useful as starting scaffolds in medicinal chemistry programs to develop multi-functional drugs, and may also be useful moieties added to existing structures to improve the pharmacokinetic properties of drugs currently used in the clinic or under development. This review attempts to provide a synopsis of current published research to exemplify the use of polycyclic compounds as starting molecules to develop multi-functional drugs.
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Affiliation(s)
- Cornelis J Van der Schyf
- Department of Pharmaceutical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA.
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26
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Jenner P. Functional models of Parkinson's disease: a valuable tool in the development of novel therapies. Ann Neurol 2008; 64 Suppl 2:S16-29. [PMID: 19127585 DOI: 10.1002/ana.21489] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Functional models of Parkinson's disease (PD) have led to effective treatment for the motor symptoms. Toxin-based models, such as the 6-hydroxydopamine-lesioned rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primate, have resulted in novel dopaminergic therapies and new therapeutic strategies. They have also been used to study processes underlying motor complications, particularly dyskinesia, and for developing pharmacological approaches to dyskinesia avoidance and suppression. Symptomatic models of PD based on nigrostriatal degeneration have a high degree of predictability of clinical effect of dopaminergic drugs on motor symptoms in humans. However, the effects of nondopaminergic drugs in these models do not translate effectively into clinical efficacy. Newer experimental models of PD have attempted to reproduce the pathogenic process and to involve all areas of the brain pathologically affected in humans. In addition, models showing progressive neuronal death have been sought but so far unsuccessfully. Pathogenic modeling has been attempted using a range of toxins, as well as through the use of transgenic models of gene defects in familial PD and mutant rodent strains. However, there are still no accepted progressive models of PD that mimic the processes known to occur during cell death and that result in the motor deficits, pathology, biochemistry, and drug responsiveness as seen in humans. Nevertheless, functional models of PD have led to many advances in treating the motor symptoms of the disorder, and we have been fortunate to have them available. They are an important reason the treatment of PD is so much better compared with treatments for related illnesses.
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Affiliation(s)
- Peter Jenner
- Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom.
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Van der Schyf CJ, Gal S, Geldenhuys WJ, Youdim MBH. Multifunctional neuroprotective drugs targeting monoamine oxidase inhibition, iron chelation, adenosine receptors, and cholinergic and glutamatergic action for neurodegenerative diseases. Expert Opin Investig Drugs 2007; 15:873-86. [PMID: 16859391 DOI: 10.1517/13543784.15.8.873] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
A new paradigm is emerging in the targeting of multiple disease aetiologies that collectively lead to neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, post-stroke neurodegeneration and others. This paradigm challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' when it comes to drug therapy. Accumulating evidence in the literature suggests that many neurodegenerative diseases have multiple mechanisms in their aetiologies, thus suggesting that a drug with at least two mechanisms of action targeted at multiple aetiologies of the same disease may offer more therapeutic benefit in certain disorders compared with a drug that only targets one disease aetiology. This review offers a synopsis of therapeutic strategies and novel investigative drugs developed in the authors' own and other laboratories that modulate multiple disease targets associated with neurodegenerative diseases.
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Affiliation(s)
- Cornelis J Van der Schyf
- Texas Tech University Health Sciences Center, Department of Pharmaceutical Sciences, School of Pharmacy, 1300 Coulter Drive, Amarillo, TX 79106, USA
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Van der Schyf CJ, Geldenhuys WJ, Youdim MBH. Multifunctional neuroprotective–neurorescue drugs for Parkinson’s disease. FUTURE NEUROLOGY 2007. [DOI: 10.2217/14796708.2.4.411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Parkinson’s disease (PD) is a severe neurodegenerative disorder, with no drugs currently approved to prevent the neuronal cell loss characteristic of brains of patients suffering from PD. Owing to the complex etiology of PD, an innovative approach towards neuroprotection or neurorescue may be the use of multifunctional pharmaceuticals that target an array of pathological pathways, each of which is believed to contribute to the cascade that ultimately leads to neuronal cell death. In this review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective–neurorescue therapeutics in PD. The compounds discussed originate from synthetic chemistry as well as from natural sources.
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Affiliation(s)
- Cornelis J Van der Schyf
- Northeastern Ohio Universities College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA
| | - Werner J Geldenhuys
- Northeastern Ohio Universities College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA
| | - Moussa BH Youdim
- Eve Topf and National Parkinson Foundation (US) Centers of Excellence for Neurodegenerative Diseases, Technion-Faculty of Medicine, Efron St, PO Box 9697, Haifa 31096, Israel
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29
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Martinez A, Castro A. Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer's disease. Expert Opin Investig Drugs 2006; 15:1-12. [PMID: 16370929 DOI: 10.1517/13543784.15.1.1] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Current pharmacotherapy for Alzheimer's disease involves compounds that are aimed at increasing the levels of acetylcholine in the brain by facilitating cholinergic neurotransmission through inhibition of cholinesterase. These drugs, known as acetylcholinesterase inhibitors, have been shown to improve cognition and global functions but have little impact on improving the eventual progression of the disease; however, there is evidence that other cholinesterases such as butyrylcholinesterase can play an important role in cholinergic function in the brain, and the long-suspected non-cholinergic actions of acetylcholinesterase, mainly the interference with the beta-amyloid protein cascade, have recently driven a profound revolution in cholinesterase drug research. Several disease-modifying agents are under development that target these enzymes and have hope of becoming the next generation of effective drugs in the treatment of Alzheimer's disease.
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Affiliation(s)
- Ana Martinez
- NeuroPharma, Avda de la Industria 52, 28760 Madrid, Spain.
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Van der Schyf CJ, Geldenhuys WJ, Youdim MBH. Multifunctional drugs with different CNS targets for neuropsychiatric disorders. J Neurochem 2006; 99:1033-48. [PMID: 17054441 DOI: 10.1111/j.1471-4159.2006.04141.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders.
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Affiliation(s)
- Cornelis J Van der Schyf
- Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, Rootstow, Ohio, USA
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Obata T. Imidaprilat, an angiotensin-converting enzyme inhibitor exerts neuroprotective effect via decreasing dopamine efflux and hydroxyl radical generation induced by bisphenol A and MPP+ in rat striatum. Brain Res 2006; 1071:250-3. [PMID: 16406270 DOI: 10.1016/j.brainres.2005.11.100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2005] [Revised: 11/20/2005] [Accepted: 11/22/2005] [Indexed: 10/25/2022]
Abstract
The present study examined the ability of antioxidant effects of angiotensin-converting enzyme (ACE) inhibitor, imidaprilat, on the synergistic effect of bisphenol A and 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (*OH) formation and dopamine (DA) efflux in extracellular fluid of rat striatum. Bisphenol A clearly enhanced OH formation and DA efflux induced by MPP(+). When imidaprilat was infused in bisphenol A and MPP(+)-treated rats, DA efflux and OH formation significantly decreased, as compared with that in the bisphenol A and MPP(+) treated control. These results suggest that ACE inhibitors may protect against the synergistic effect of bisphenol A and MPP(+)-induced OH formation via suppressing DA efflux in the rat striatum.
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Affiliation(s)
- Toshio Obata
- Department of Analytical Chemistry, School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611, Japan.
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32
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Fumagalli F, Racagni G, Riva MA. Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease. THE PHARMACOGENOMICS JOURNAL 2006; 6:95-104. [PMID: 16402079 DOI: 10.1038/sj.tpj.6500360] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) is a chronic, neurodegenerative disease with a 1% incidence in the population over 55 years of age. Movement impairments represent undoubtedly the hallmark of the disorder; however, extensive evidence implicates cognitive deficits as concomitant peculiar features. Brain-derived neurotrophic factor (BDNF) colocalizes with dopamine neurons in the substantia nigra, where dopaminergic cell bodies are located, and it has recently garnered attention as a molecule crucial for cognition, a function that is also compromised in PD patients. Thus, due to its colocalization with dopaminergic neurons and its role in cognition, BDNF might possess a dual role in PD, both as a neuroprotective molecule, since its inhibition leads to loss of nigral dopaminergic neurons, and as a neuromodulator, as its enhanced expression ameliorates cognitive processes. In this review, we discuss the mechanism of action of established as well as novel drugs for PD with a particular emphasis to those interfering with BDNF biosynthesis.
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Affiliation(s)
- F Fumagalli
- Department of Pharmacological Sciences, Center of Neuropharmacology, Milan, Italy.
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Sagi Y, Driguès N, Youdim MBH. The neurochemical and behavioral effects of the novel cholinesterase-monoamine oxidase inhibitor, ladostigil, in response to L-dopa and L-tryptophan, in rats. Br J Pharmacol 2005; 146:553-60. [PMID: 16086033 PMCID: PMC1751181 DOI: 10.1038/sj.bjp.0706355] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2005] [Revised: 06/23/2005] [Accepted: 07/01/2005] [Indexed: 11/09/2022] Open
Abstract
The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L-dopa- or L-tryptophan-induced rats. Chronic treatment of rats with ladostigil (52 mg kg(-1) for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by approximately 50%. Chronic TV3279 (26 mg kg(-1) for 21 days) similarly inhibited approximately 50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg(-1)) or L-tryptophan (100 mg kg(-1)), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg(-1)) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg(-1)) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors.Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB).
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Affiliation(s)
- Yotam Sagi
- Eve Topf and U.S.A. National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel
| | - Noam Driguès
- Eve Topf and U.S.A. National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel
| | - Moussa B H Youdim
- Eve Topf and U.S.A. National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel
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Youdim MBH, Buccafusco JJ. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 2005; 26:27-35. [PMID: 15629202 DOI: 10.1016/j.tips.2004.11.007] [Citation(s) in RCA: 269] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Individuals with neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease are benefiting from drugs developed to act on a single molecular target. However, current pharmacological approaches are limited in their ability to modify significantly the course of the disease, and offer incomplete and transient benefit to patients. New therapeutic strategies comprise drug candidates designed specifically to act on multiple neural and biochemical targets for the treatment of cognition impairment, motor dysfunction, depression and neurodegeneration. Examples include the development of single molecular entities that combine two or more of the following properties: (i) cholinesterase inhibition; (ii) activation or inhibition of specific subtypes of acetylcholine receptors or alpha-adrenoceptors; (iii) anti-inflammatory activity; (iv) monoamine oxidase inhibition; (v) catechol-O-methyl transferase inhibition; (vi) nitric oxide production; (vii) neuroprotection; (viii) anti-apoptotic activity; and (ix) activation of mitochondrial-dependent cell-survival genes and proteins. These bi- or multi-functional compounds might provide greater symptomatic efficacy, and better utility as potential neuroprotective disease-modifying drugs.
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Affiliation(s)
- Moussa B H Youdim
- Eve Topf and US National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research, Technion-Rappaport Faculty of Medicine and Department of Pharmacology, Haifa 31096, Israel.
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Abstract
AIM: To understand the correlation of serum cholinesterase (CHE) activity with gastric cancer and to assess their clinical significance.
METHODS: The velocity method was adopted to detect the activity of serum CHE in patients with gastric cancer and in patients with non-malignant tumor as controls.
RESULTS: The serum CHE activity in the treatment group was significantly lower than that in the control group with a very significant difference between the two groups (83.3:113.1,P = 0.0003). Age was significantly associated with the incidence of gastric caner.
CONCLUSION: Serum CHE activity has a close relation with the incidence of gastric cancer.
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Affiliation(s)
- Shan-Zhi Gu
- Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Medical College of of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
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Poltyrev T, Gorodetsky E, Bejar C, Schorer-Apelbaum D, Weinstock M. Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic-pituitary-adrenal axis in male and female prenatally stressed rats. Psychopharmacology (Berl) 2005; 181:118-25. [PMID: 15830235 DOI: 10.1007/s00213-005-2229-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2004] [Accepted: 02/06/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVE The aim of the study is to investigate the effect of ladostigil, a cholinesterase and brain-selective monoamine oxidase (MAO) inhibitor, on anxiogenic and depressive-like behaviour and the response of the hypothalamic-pituitary-adrenal axis to stress in prenatally stressed (PS) male and female rats. METHODS Ladostigil (17 mg/kg/day) was administered daily for 6 weeks to control and PS rats aged 6 weeks. Behaviour was assessed in the elevated plus maze (EPM) and forced swim tests (FST). Plasma corticosterone (COR) was measured before, 30 and 90 min after exposure to stress. RESULTS Ladostigil inhibited brain MAO-A and B by more than 60%, significantly reduced hyperanxiety of male and female PS rats in the EPM and depressive-like behaviour in the FST without affecting that of controls and restored the delayed return to baseline of plasma COR in PS rats after exposure to stress to that of control rats. CONCLUSIONS A novel brain-selective MAO inhibitor, ladostigil can selectively reverse the behavioural and neurochemical effects induced by prenatal stress without affecting the behaviour of controls.
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Affiliation(s)
- Tatyana Poltyrev
- Department of Pharmacology, Hebrew University Hadassah School of Medicine, Ein Kerem, Jerusalem 91120, Israel
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Youdim MBH, Fridkin M, Zheng H. Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech Ageing Dev 2005; 126:317-26. [PMID: 15621213 DOI: 10.1016/j.mad.2004.08.023] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.
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Affiliation(s)
- Moussa B H Youdim
- Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion Faculty of Medicine, Efron St., PO Box 9697, Haifa 31096, Israel.
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Mandel S, Weinreb O, Amit T, Youdim MBH. Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J Neurochem 2004; 88:1555-69. [PMID: 15009657 DOI: 10.1046/j.1471-4159.2003.02291.x] [Citation(s) in RCA: 253] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Accumulating evidence supports the hypothesis that brain iron misregulation and oxidative stress (OS), resulting in reactive oxygen species (ROS) generation from H2O2 and inflammatory processes, trigger a cascade of events leading to apoptotic/necrotic cell death in neurodegenerative disorders, such as Parkinson's (PD), Alzheimer's (AD) and Huntington's diseases, and amyotrophic lateral sclerosis (ALS). Thus, novel therapeutic approaches aimed at neutralization of OS-induced neurotoxicity, support the application of ROS scavengers, transition metals (e.g. iron and copper) chelators and non-vitamin natural antioxidant polyphenols, in monotherapy, or as part of antioxidant cocktail formulation for these diseases. Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols, particularly from green tea and blueberries, improve age-related cognitive decline and are neuroprotective in models of PD, AD and cerebral ischemia/reperfusion injuries. However, recent studies indicate that the radical scavenger property of green tea polyphenols is unlikely to be the sole explanation for their neuroprotective capacity and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this article, the currently established mechanisms involved in the beneficial health action and emerging studies concerning the putative novel molecular neuroprotective activity of green tea and its major polyphenol (-)-epigallocatechin-3-gallate (EGCG), will be reviewed and discussed.
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Affiliation(s)
- Silvia Mandel
- Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Faculty of Medicine, Haifa, Israel
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Youdim MBH, Amit T, Falach-Yogev M, Bar Am O, Maruyama W, Naoi M. The essentiality of Bcl-2, PKC and proteasome–ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochem Pharmacol 2003; 66:1635-41. [PMID: 14555244 DOI: 10.1016/s0006-2952(03)00535-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.
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Affiliation(s)
- Moussa B H Youdim
- Eve Topf and National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Technion-Faculty of Medicine, Efron Street, P.O. Box 9697, Haifa 31096, Israel.
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