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Mehrparvar Tajoddini M, Gheybi E, Rostami M, Mousavi SH, Hashemy SI, Rashidi R, Soukhtanloo M. Neuroprotective effects of hesperidin and auraptene on 6-hydroxydopamine-induced neurodegeneration in SH-SY5Y cells. AVICENNA JOURNAL OF PHYTOMEDICINE 2025; 15:1082-1090. [PMID: 40365183 PMCID: PMC12068502 DOI: 10.22038/ajp.2024.25214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Objective Destruction of dopaminergic neurons causes diseases. Various compounds with neuroprotective and antioxidant properties have been identified, including Hesperidin (HES) and Auraptene (AUR). We aimed in this study to evaluate the in vitro protective effects of these compounds in SH-SY5Y neuroblastoma cell line against the induced neurotoxicity of 6-hydroxydopamine (6-OHDA). Materials and Methods The MTT test to assess cell viability was used. Flow cytometry was conducted for the cell cycle analysis using propidium iodide (PI) stain. The intracellular production of reactive oxygen species (ROS) was assessed using 2, 7'-dichlorofluorescein diacetate (DCFDA) probe and fluorimetry. Results Following 6-OHDA treatment, cell viability decreased, and G2/M arrest and ROS levels increased. Our intervention demonstrated that only HES has neuroprotective effects against 6-OHDA-induced toxicity. Conclusion HES protects SH-SY5Y cells against 6-OHDA-induced neural damage via inhibiting G2/M arrest, reducing the amount of ROS, and increasing cell viability. However, the different effects and more precise mechanisms are still unknown, and requires new research on animal and human models.
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Affiliation(s)
- Malihe Mehrparvar Tajoddini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elaheh Gheybi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Hadi Mousavi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Roghayeh Rashidi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Soukhtanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
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Gamit N, Patil M, Soumya BS, Dharmarajan A, Warrier S. Development of In Vitro Parkinson's Disease Model Mediated by MPP+ and α-Synuclein Using Wharton's Jelly Mesenchymal Stem Cells. CNS Neurosci Ther 2025; 31:e70299. [PMID: 40260646 PMCID: PMC12012574 DOI: 10.1111/cns.70299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 04/23/2025] Open
Abstract
MAIN PROBLEM The mechanism behind Parkinson's disease (PD) is still unclear, and a cure to stop its progression is yet to be found. This is mainly due to the lack of effective human PD models. To address this, we generated an in vitro PD model using Wharton's jelly-derived mesenchymal stem cells (WJMSCs). METHODS WJMSCs were isolated from the umbilical cord using an enzymatic method. MSCs were characterized by RT-PCR, immunofluorescence, and trilineage differentiation. MSCs were differentiated into dopaminergic neuron-like cells (DAN) and further degenerated by treating them with either MPP+ iodide or the A53T mutated α-synuclein variant. Gene expression analysis by qRT-PCR and protein analysis by immunofluorescence, flow cytometry, and ELISA were performed. Assays to measure LDH, ROS, NO, GSH, and mitochondrial membrane potential were also performed after degeneration. RESULTS WJMSCs were positive for MSC markers and were able to differentiate into adipocytes, chondrocytes, and osteocytes. DAN obtained after the differentiation of WJMSCs for 48 h expressed neuronal markers such as synapsin 1, neuropilin, neurofilament, and MAPT along with dopaminergic markers such as Nurr1, DAT, TH, DDC, and KCNJ6 and were functionally active. Upon degeneration of DAN by MPP+ or A53T, elevated levels of SNCA and downregulation of TH, Nurr1, DAT, and KCNJ6 were observed. Furthermore, increased expression of α-SYN was detected at the protein level as well. Finally, reduction in mitochondrial membrane potential and GSH levels along with an increase in intracellular ROS, nitrite production, and LDH levels confirmed that the in vitro PD-like model exhibited the molecular characteristics of PD. CONCLUSION This model is rapid, cost-efficient, and effective for understanding the molecular mechanisms of the disease and can also be used for screening of emerging therapeutics for PD.
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Affiliation(s)
- Naisarg Gamit
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative MedicineManipal Academy of Higher Education (MAHE)BangaloreIndia
| | - Manasi Patil
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative MedicineManipal Academy of Higher Education (MAHE)BangaloreIndia
| | - B. S. Soumya
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative MedicineManipal Academy of Higher Education (MAHE)BangaloreIndia
| | - Arun Dharmarajan
- School of Human SciencesThe University of Western AustraliaNedlandsWestern AustraliaAustralia
- Curtin Medical SchoolCurtin UniversityPerthWestern AustraliaAustralia
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative MedicineManipal Academy of Higher Education (MAHE)BangaloreIndia
- Department of Biotechnology, Faculty of Biomedical Sciences and TechnologySri Ramachandra Institute of Higher Education and ResearchChennaiIndia
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Bhardwaj K, Roy A, Guha L, Kumar H. Evaluating the Role of Lin-11, Isl-1, and Mec-3 Kinases in Dopaminergic Neurodegeneration in a Subacute 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Model of Parkinson's Disease. ACS Pharmacol Transl Sci 2024; 7:3879-3888. [PMID: 39698285 PMCID: PMC11651167 DOI: 10.1021/acsptsci.4c00423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024]
Abstract
The malfunctioning of microtubules is highly correlated with neurodegenerative disorders such as Parkinson's disease (PD), although whether it is a cause or an effect of neurodegeneration is yet unknown. Lin-11, Isl-1, and Mec-3 kinases (LIMKs), being one of the important kinases, regulate the neuronal cytoskeleton by controlling the phosphorylation of the cofilin/actin-depolymerizing factor. Recently, we showed that upregulation of phosphorylated LIMK1 (p-LIMK1) affects the microtubule dynamics in a central nervous system traumatic injury. The goal of this study is to correlate the expression of LIMK1 with dopaminergic neuron death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD, one of the well-established subacute models of PD, where the neurotoxin acts via inhibition of mitochondrial complex I of the electron transport chain. Herein, we found that LIMK1 expression was increased and correlated to dopaminergic neuronal death. Finally, we demonstrated that the treatment with LIMK inhibitor BMS-5 significantly reversed the neurodegeneration, along with an upregulation of the dynamic tubulins, indicating the relevance of LIMKs and microtubule dynamics in neurodegeneration. Therefore, targeting the microtubules, an integral part of the neuronal cytoskeleton and neurite formation, can be a promising strategy to combat degeneration of dopaminergic neurons.
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Affiliation(s)
| | | | - Lahanya Guha
- Department of Pharmacology
and Toxicology, National Institute of Pharmaceutical
Education and Research, Ahmedabad (NIPER-A), Palaj, Gandhinagar, Gujarat 382355, India
| | - Hemant Kumar
- Department of Pharmacology
and Toxicology, National Institute of Pharmaceutical
Education and Research, Ahmedabad (NIPER-A), Palaj, Gandhinagar, Gujarat 382355, India
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Cashman JR. Practical Aspects of Flavin-Containing Monooxygenase-Mediated Metabolism. Chem Res Toxicol 2024; 37:1776-1793. [PMID: 39485380 DOI: 10.1021/acs.chemrestox.4c00316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Hepatic flavin-containing monooxygenase 3 (FMO3) is arguably the most important FMO in humans from the standpoint of drug metabolism. Recently, adult hepatic FMO3 has been linked to several conditions including cardiometabolic diseases, aging, obesity, and atherosclerosis in small animals. Despite the importance of FMO3 in drug and chemical metabolism, relative to cytochrome P-450 (CYP), fewer studies have been published describing drug and chemical metabolism. This may be due to the properties of human hepatic FMO3. For example, FMO3 is thermally labile, and often methods reported in the study of human hepatic FMO3 are not optimal. Herein, I describe some practical aspects for studying human hepatic FMO3 and other FMOs.
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Affiliation(s)
- John R Cashman
- Human BioMolecular Research Institute. 6351 Nancy Ridge Road, Suite B, San Diego, California 92121, United States
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Di Martino S, De Rosa M. The Benzoxazole Heterocycle: A Comprehensive Review of the Most Recent Medicinal Chemistry Developments of Antiproliferative, Brain-Penetrant, and Anti-inflammatory Agents. Top Curr Chem (Cham) 2024; 382:33. [PMID: 39432195 DOI: 10.1007/s41061-024-00477-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/21/2024] [Indexed: 10/22/2024]
Abstract
The benzoxazole is one of the most widely exploited heterocycles in drug discovery. Natural occurring and synthetic benzoxazoles show a broad range of biological activities. Many benzoxazoles are available for treating several diseases, and, to date, a few are in clinical trials. Moreover, an ever-increasing number of benzoxazole derivatives are under investigation in the early drug discovery phase and as potential hit or lead compounds. This perspective is an attempt to thoroughly review the rational design, the structure-activity relationship, and the biological activity of the most notable benzoxazoles developed during the past 5 years (period 2019-to date) in cancers, neurological disorders, and inflammation. We also briefly overviewed each target and its role in the disease. The huge amount of work examined suggests the great potential of the scaffold and the high interest of the scientific community in novel biologically active compounds containing the benzoxazole core.
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Affiliation(s)
- Simona Di Martino
- Medicinal Chemistry Group, Fondazione Ri.MED, via Filippo Marini 14, 90128, Palermo, Italy
| | - Maria De Rosa
- Medicinal Chemistry Group, Fondazione Ri.MED, via Filippo Marini 14, 90128, Palermo, Italy.
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He S, Ru Q, Chen L, Xu G, Wu Y. Advances in animal models of Parkinson's disease. Brain Res Bull 2024; 215:111024. [PMID: 38969066 DOI: 10.1016/j.brainresbull.2024.111024] [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: 05/12/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/07/2024]
Abstract
Parkinson's disease is a complex neurodegenerative disease characterized by progressive movement impairments. Predominant symptoms encompass resting tremor, bradykinesia, limb rigidity, and postural instability. In addition, it also includes a series of non-motor symptoms such as sleep disorders, hyposmia, gastrointestinal dysfunction, autonomic dysfunction and cognitive impairment. Pathologically, the disease manifests through dopaminergic neuronal loss and the presence of Lewy bodies. At present, no significant breakthrough has been achieved in clinical Parkinson's disease treatment. Exploring treatment modalities necessitate the establishment of scientifically sound animal models. In recent years, researchers have focused on replicating the symptoms of human Parkinson's disease, resulting in the establishment of various experimental animal models primarily through drugs and transgenic methods to mimic relevant pathologies and identify more effective treatments. This review examines traditional neurotoxin and transgenic animal models as well as α-synuclein pre-formed fibrils models, non-human primate models and non-mammalian specie models. Additionally, it introduces emerging models, including models based on optogenetics, induced pluripotent stem cells, and gene editing, aiming to provide a reference for the utilization of experimental animal models and clinical research for researchers in this field.
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Affiliation(s)
- Sui He
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan 430056, China
| | - Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan 430056, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan 430056, China
| | - Guodong Xu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan 430056, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan 430056, China.
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Price NJ, Nakamura A, Castagnoli N, Tanko JM. Why Does Monoamine Oxidase (MAO) Catalyze the Oxidation of Some Tetrahydropyridines? Chembiochem 2024; 25:e202400126. [PMID: 38602445 DOI: 10.1002/cbic.202400126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/18/2024] [Indexed: 04/12/2024]
Abstract
Results pertaining to the mechanism of the oxidation of the tertiary amine 1-methyl-4-(1-methyl-1-H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP, a close analog of the Parkinsonism inducing compound MPTP) by 3-methyllumiflavin (3MLF), a chemical model for the FAD cofactor of monoamine oxidase, are reported. MMTP and related compounds are among the few tertiary amines that are monoamine oxidase B (MAO-B) substrates. The MMTP/3MLF reaction is catalytic in the presence of O2 and the results under anaerobic conditions strongly suggest the involvement of radical intermediates, consistent with a single electron transfer mechanism. These observations support a new hypothesis to explain the MAO-catalyzed oxidations of amines. In general, electron transfer is thermodynamically unfavorable, and as a result, most 1° and 2° amines react via one of the currently accepted polar pathways. Steric constraints prevent 3° amines from reacting via a polar pathway. Those select 3° amines that are MAO substrates possess certain structural features (e. g., a C-H bond that is α- both to nitrogen and a C=C) that dramatically lower the pKa of the corresponding radical cation. Consequently, the thermodynamically unfavorable electron transfer equilibrium is driven towards products by an extremely favorable deprotonation step in the context of Le Chatelier's principle.
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Affiliation(s)
- Nathan J Price
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Akiko Nakamura
- Department of Chemistry, Colorado State University, Fort Collins, CO, 80523, USA
| | - Neal Castagnoli
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24061, USA
| | - James M Tanko
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24061, USA
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8
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Santos TB, de Moraes LGC, Pacheco PAF, dos Santos DG, Ribeiro RMDAC, Moreira CDS, da Rocha DR. Naphthoquinones as a Promising Class of Compounds for Facing the Challenge of Parkinson's Disease. Pharmaceuticals (Basel) 2023; 16:1577. [PMID: 38004442 PMCID: PMC10674926 DOI: 10.3390/ph16111577] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Parkinson's disease (PD) is a degenerative disease that affects approximately 6.1 million people and is primarily caused by the loss of dopaminergic neurons. Naphthoquinones have several biological activities explored in the literature, including neuroprotective effects. Therefore, this review shows an overview of naphthoquinones with neuroprotective effects, such as shikonin, plumbagin and vitamin K, that prevented oxidative stress, in addition to multiple mechanisms. Synthetic naphthoquinones with inhibitory activity on the P2X7 receptor were also found, leading to a neuroprotective effect on Neuro-2a cells. It was found that naphthazarin can act as inhibitors of the MAO-B enzyme. Vitamin K and synthetic naphthoquinones hybrids with tryptophan or dopamine showed inhibition of the aggregation of α-synuclein. Synthetic derivatives of juglone and naphthazarin were able to protect Neuro-2a cells against neurodegenerative effects of neurotoxins. In addition, routes for producing synthetic derivatives were also discussed. With the data presented, 1,4-naphthoquinones can be considered as a promising class in the treatment of PD and this review aims to assist the scientific community in the application of these compounds. The derivatives presented can also support further research that explores their structures as synthetic platforms, in addition to helping to understand the interaction of naphthoquinones with biological targets related to PD.
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Affiliation(s)
- Thaís Barreto Santos
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
| | - Leonardo Gomes Cavalieri de Moraes
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
| | - Paulo Anastácio Furtado Pacheco
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
| | - Douglas Galdino dos Santos
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
| | - Rafaella Machado de Assis Cabral Ribeiro
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
| | - Caroline dos Santos Moreira
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
- Instituto Federal do Rio de Janeiro, Campus Paracambi, Rua Sebastião Lacerda s/n°, Fábrica, Paracambi CEP 26.600-000, RJ, Brazil
| | - David Rodrigues da Rocha
- Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista s/n°, Niterói CEP 24.020-141, RJ, Brazil; (T.B.S.); (L.G.C.d.M.); (P.A.F.P.); (D.G.d.S.); (R.M.d.A.C.R.); (C.d.S.M.)
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9
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Kaya I, Nilsson A, Luptáková D, He Y, Vallianatou T, Bjärterot P, Svenningsson P, Bezard E, Andrén PE. Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson's disease primate model. NPJ Parkinsons Dis 2023; 9:118. [PMID: 37495571 PMCID: PMC10372136 DOI: 10.1038/s41531-023-00558-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 07/11/2023] [Indexed: 07/28/2023] Open
Abstract
Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP+ in the brain causes permanent Parkinson's disease-like symptoms by destroying dopaminergic neurons in the pars compacta of the substantia nigra in humans and non-human primates. However, the complete molecular pathology underlying MPTP-induced parkinsonism remains poorly understood. We used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging to thoroughly image numerous glycerophospholipids and sphingolipids in coronal brain tissue sections of MPTP-lesioned and control non-human primate brains (Macaca mulatta). The results revealed specific distributions of several sulfatide lipid molecules based on chain-length, number of double bonds, and importantly, hydroxylation stage. More specifically, certain long-chain hydroxylated sulfatides with polyunsaturated chains in the molecular structure were depleted within motor-related brain regions in the MPTP-lesioned animals, e.g., external and internal segments of globus pallidus and substantia nigra pars reticulata. In contrast, certain long-chain non-hydroxylated sulfatides were found to be elevated within the same brain regions. These findings demonstrate region-specific dysregulation of sulfatide metabolism within the MPTP-lesioned macaque brain. The depletion of long-chain hydroxylated sulfatides in the MPTP-induced pathology indicates oxidative stress and oligodendrocyte/myelin damage within the pathologically relevant brain regions. Hence, the presented findings improve our current understanding of the molecular pathology of MPTP-induced parkinsonism within primate brains, and provide a basis for further research regarding the role of dysregulated sulfatide metabolism in PD.
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Affiliation(s)
- Ibrahim Kaya
- Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Anna Nilsson
- Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Dominika Luptáková
- Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Yachao He
- Section of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Theodosia Vallianatou
- Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Patrik Bjärterot
- Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Per Svenningsson
- Section of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Erwan Bezard
- University of Bordeaux, CNRS, IMN, UMR 5293, F-33000, Bordeaux, France
| | - Per E Andrén
- Department of Pharmaceutical Biosciences, Spatial Mass Spectrometry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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Thomas Parambi DG, Oh JM, Kumar S, Sudevan ST, Hendawy OM, Abdelgawad MA, Musa A, Al-Sanea MM, Ahmad I, Patel H, Kim H, Mathew B. Halogenated class of oximes as a new class of monoamine oxidase-B inhibitors for the treatment of Parkinson's disease: Synthesis, biochemistry, and molecular dynamics study. Comput Biol Chem 2023; 105:107899. [PMID: 37315342 DOI: 10.1016/j.compbiolchem.2023.107899] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/11/2023] [Accepted: 05/31/2023] [Indexed: 06/16/2023]
Abstract
Oximes are the promising structural scaffold for inhibiting monoamine oxidase (MAO)-B. Eight chalcone-based oxime derivatives were synthesized by microwave-assisted technique, and their ability to inhibit human MAO (hMAO) enzymes were tested. All compounds showed higher inhibitory activity of hMAO-B than hMAO-A. In the CHBO subseries, CHBO4 most potently inhibited hMAO-B with an IC50 value of 0.031 μM, followed by CHBO3 (IC50 = 0.075 μM). In the CHFO subseries, CHFO4 showed the highest inhibition of hMAO-B with an IC50 value of 0.147 μM. Compound CHBO4 had the highest selectivity index (SI) value of 1290.3. However, CHBO3 and CHFO4 showed relatively low SI values of 27.7 and 19.2, respectively. The -Br substituent in the CHBO subseries at the para-position in the B-ring showed higher hMAO-B inhibition than the -F substituent in the CHFO subseries. In both series, hMAO-B inhibition increased with the substituents at para-position in A-ring (-F > -Br > -Cl > -H in order). Compound CHBO4 (-F in A-ring and -Br in B-ring) was 12.6-times potent than the substituents-reversed compound CHFO3 (-Br in A-ring and -F in B-ring; IC50 = 0.391 μM). In the kinetic study, Ki values of CHBO4 and CHFO4 for hMAO-B were 0.010 ± 0.005 and 0.040 ± 0.007 μM, respectively, with competitive inhibitions. Reversibility experiments showed that CHBO4 and CHFO4 were reversible hMAO-B inhibitors. In the cytotoxicity test using the Vero cells by the MTT technique, CHBO4 had low toxicity with an IC50 value of 128.8 µg/mL. In H2O2-induced cells, CHBO4 significantly reduced cell damage by scavenging reactive oxygen species (ROS). Molecular docking and dynamics showed the stable binding mode of the lead molecule CHBO4 on the active site of hMAO-B. These results suggest that CHBO4 is a potent reversible, competitive, and selective hMAO-B inhibitor and can be used as a treatment agent for neurological disorders.
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Affiliation(s)
- Della Grace Thomas Parambi
- College of Pharmacy, Department of Pharmaceutical Chemistry, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia.
| | - Jong Min Oh
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea
| | - Sunil Kumar
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India
| | - Sachithra Thazhathuveedu Sudevan
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India
| | - Omnia Magdy Hendawy
- College of Pharmacy, Department of Clinical Pharmacology, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia
| | - Mohamed A Abdelgawad
- College of Pharmacy, Department of Pharmaceutical Chemistry, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia
| | - Arafa Musa
- College of Pharmacy, Department of Pharmacognosy, Jouf University, Sakaka, 72341, Al Jouf, Saudi Arabia
| | - Mohammad M Al-Sanea
- College of Pharmacy, Department of Pharmaceutical Chemistry, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia
| | - Iqrar Ahmad
- Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule 424002, Maharashtra, India
| | - Harun Patel
- Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India
| | - Hoon Kim
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India.
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Newly Synthesized Creatine Derivatives as Potential Neuroprotective and Antioxidant Agents on In Vitro Models of Parkinson's Disease. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010139. [PMID: 36676090 PMCID: PMC9864416 DOI: 10.3390/life13010139] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023]
Abstract
Oxidative stress is one of the key factors responsible for many diseases-neurodegenerative (Parkinson and Alzheimer) diseases, diabetes, atherosclerosis, etc. Creatine, a natural amino acid derivative, is capable of exerting mild, direct antioxidant activity in cultured mammalian cells acutely injured with an array of different reactive oxygen species (ROS) generating compounds. The aim of the study was in vitro (on isolated rat brain sub-cellular fractions-synaptosomes, mitochondria and microsomes) evaluation of newly synthetized creatine derivatives for possible antioxidant and neuroprotective activity. The synaptosomes and mitochondria were obtained by multiple centrifugations with Percoll, while microsomes-only by multiple centrifugations. Varying models of oxidative stress were used to study the possible antioxidant and neuroprotective effects of the respective compounds: on synaptosomes-6-hydroxydopamine; on mitochondria-tert-butyl hydroperoxide; and on microsomes-iron/ascorbate (non-enzyme-induced lipid peroxidation). Administered alone, creatine derivatives and creatine (at concentration 38 µM) revealed neurotoxic and pro-oxidant effects on isolated rat brain subcellular fractions (synaptosomes, mitochondria and microsomes). In models of 6-hydroxydopamine (on synaptosomes), tert-butyl hydroperoxide (on mitochondria) and iron/ascorbate (on microsomes)-induced oxidative stress, the derivatives showed neuroprotective and antioxidant effects. These effects may be due to the preservation of the reduced glutathione level, ROS scavenging and membranes' stabilizers against free radicals. Thus, they play a role in the antioxidative defense system and have a promising potential as therapeutic neuroprotective agents for the treatment of neurodegenerative disorders, connected with oxidative stress, such as Parkinson's disease.
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12
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Kolacheva A, Bannikova A, Pavlova E, Bogdanov V, Ugrumov M. Modeling of the Progressive Degradation of the Nigrostriatal Dopaminergic System in Mice to Study the Mechanisms of Neurodegeneration and Neuroplasticity in Parkinson's Disease. Int J Mol Sci 2022; 24:ijms24010683. [PMID: 36614126 PMCID: PMC9820573 DOI: 10.3390/ijms24010683] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/25/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
The fight against neurodegenerative diseases, including Parkinson's disease (PD), is among the global challenges of the 21st century. The low efficiency of therapy is due to the late diagnosis and treatment of PD, which take place when there is already significant degradation of the nigrostriatal dopaminergic system, a key link in the regulation of motor function. We have developed a subchronic mouse model of PD by repeatedly administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at gradually increasing doses with a 24 h interval between injections, a period comparable to the time of MPTP metabolism and elimination from the body. This model reproduces the main hallmarks of PD: progressive degeneration of dopaminergic neurons; the appearance of motor disorders with a 70-80% decrease in the level of dopamine in the striatum; an increase in dopamine turnover in the striatum to compensate for dopamine deficiency. When comparing the degradation of the nigrostriatal dopaminergic system and motor disorders in mice in the acute and subchronic models of PD, it has turned out that the resistance of dopaminergic neurons to MPTP increases with its repeated administration. Our subchronic model of PD opens up broad prospects for studying the molecular mechanisms of PD pathogenesis and developing technologies for early diagnosis and preventive treatment.
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13
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Isoalantolactone (IAL) Regulates Neuro-Inflammation and Neuronal Apoptosis to Curb Pathology of Parkinson's Disease. Cells 2022; 11:cells11182927. [PMID: 36139502 PMCID: PMC9497122 DOI: 10.3390/cells11182927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease in which neuronal apoptosis and associated inflammation are involved in its pathogenesis. However, there is still no specific treatment that can stop PD progression. Isoalantolactone (IAL) plays a role in many inflammation-related diseases. However, its effect and mechanism in PD remain unclear. In this study, results showed that IAL administration ameliorated 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD-related pathological impairment and decreased motor activity in mice. Results from in vitro mechanistic studies showed that IAL regulated apoptosis-related proteins by activating the AKT/Nrf2 pathway, thereby suppressing the apoptosis of SN4741 cells induced by N-methyl-4-phenylpyridinium Iodide (MPP+). On the other hand, IAL inhibited LPS-induced release of pro-inflammatory mediators in BV2 cells by activating the AKT/Nrf2/HO-1 pathway and inhibiting the NF-κB pathway. In addition, IAL protected SN4741 from microglial activation-mediated neurotoxicity. Taken together, these results highlight the beneficial role of IAL as a novel therapy and potential PD drug due to its pharmacological profile.
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14
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Ferrucci M, Busceti CL, Lazzeri G, Biagioni F, Puglisi-Allegra S, Frati A, Lenzi P, Fornai F. Bacopa Protects against Neurotoxicity Induced by MPP+ and Methamphetamine. Molecules 2022; 27:molecules27165204. [PMID: 36014442 PMCID: PMC9414486 DOI: 10.3390/molecules27165204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/08/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
The neurotoxins methamphetamine (METH) and 1-methyl-4-phenylpyridinium (MPP+) damage catecholamine neurons. Although sharing the same mechanism to enter within these neurons, METH neurotoxicity mostly depends on oxidative species, while MPP+ toxicity depends on the inhibition of mitochondrial activity. This explains why only a few compounds protect against both neurotoxins. Identifying a final common pathway that is shared by these neurotoxins is key to prompting novel remedies for spontaneous neurodegeneration. In the present study we assessed whether natural extracts from Bacopa monnieri (BM) may provide a dual protection against METH- and MPP+-induced cell damage as measured by light and electron microscopy. The protection induced by BM against catecholamine cell death and degeneration was dose-dependently related to the suppression of reactive oxygen species (ROS) formation and mitochondrial alterations. These were measured by light and electron microscopy with MitoTracker Red and Green as well as by the ultrastructural morphometry of specific mitochondrial structures. In fact, BM suppresses the damage of mitochondrial crests and matrix dilution and increases the amount of healthy and total mitochondria. The present data provide evidence for a natural compound, which protects catecholamine cells independently by the type of experimental toxicity. This may be useful to counteract spontaneous degenerations of catecholamine cells.
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Affiliation(s)
- Michela Ferrucci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | | | - Gloria Lazzeri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | | | | | - Alessandro Frati
- I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Italy
- Neurosurgery Division, Department of Human Neurosciences, Sapienza University, 00135 Rome, Italy
| | - Paola Lenzi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
- I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Italy
- Correspondence: or ; Tel.: +39-050-221-8667
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15
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Chakkittukandiyil A, Sajini DV, Karuppaiah A, Selvaraj D. The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease. Neurochem Int 2022; 156:105325. [PMID: 35278519 DOI: 10.1016/j.neuint.2022.105325] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 03/03/2022] [Accepted: 03/06/2022] [Indexed: 02/07/2023]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder. PD is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Present therapies for PD provide only symptomatic relief by restoring the dopamine (DA) level. However, they are not disease modifying agents and so they do not delay the disease progression. Alpha-synuclein aggregation, oxidative stress, mitochondrial dysfunction and chronic inflammation are considered to be the major pathological mechanisms mediating neurodegeneration in PD. To resist oxidative stress, the human body has an antioxidant defence mechanism consisting of many antioxidants and cytoprotective genes. The expression of those genes are largely controlled by the Kelch-like ECH-associated protein 1/Nuclear factor - erythroid - 2 - related factor 2/Antioxidant response element (Keap1/Nrf2/ARE) signalling pathway. The transcription factor Nrf2 is activated in response to oxidative or electrophilic stress and protects the cells from oxidative stress and inflammation. Nrf2 has been widely considered as a therapeutic target for neurodegeneration and several drugs are now being tested in clinical trials. Regulation of the Keap1/Nrf2/ARE pathway by small molecules which can act as Nrf2 activators could be effective for treating oxidative stress and neuroinflammation in PD. In this review, we had discussed the principal molecular mechanisms behind the neuroprotective effects of Keap1/Nrf2/ARE pathway in PD. Additionally, we also discussed the small molecules and phytochemicals that could activate the Nrf2 mediated anti-oxidant pathway for neuroprotection in PD.
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Affiliation(s)
- Amritha Chakkittukandiyil
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
| | - Deepak Vasudevan Sajini
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
| | - Arjunan Karuppaiah
- Department of Pharmaceutics, PSG College of Pharmacy, Peelamedu, Coimbatore, Tamil Nadu, India
| | - Divakar Selvaraj
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.
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16
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He D, Hu G, Zhou A, Liu Y, Huang B, Su Y, Wang H, Ye B, He Y, Gao X, Fu S, Liu D. Echinocystic Acid Inhibits Inflammation and Exerts Neuroprotective Effects in MPTP-Induced Parkinson’s Disease Model Mice. Front Pharmacol 2022; 12:787771. [PMID: 35126128 PMCID: PMC8807489 DOI: 10.3389/fphar.2021.787771] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/29/2021] [Indexed: 01/05/2023] Open
Abstract
Parkinson’s disease (PD), the second primary neurodegenerative disease affecting human health, is mainly characterized by dopaminergic neuron damage in the midbrain and the clinical manifestation of movement disorders. Studies have shown that neuroinflammation plays an important role in the progression of PD. Excessively activated microglia produce several pro-inflammatory mediators, leading to damage to the surrounding neurons and finally inducing neurodegeneration. Echinocystic acid (EA) exhibits an anti-inflammatory effect in peripheral tissues. However, whether it inhibited neuroinflammation remains unclear. Therefore, the current study investigates the effect of EA on neuroinflammation and whether it can improve PD symptoms through inhibiting neuroinflammation. In our experiments, we discovered that EA inhibited the production of pro-inflammatory mediators in LPS-exposed BV2 cells. Further mechanism-related studies revealed that EA inhibited inflammation by activating PI3K/Akt and inhibiting NF-κB and MAPK signal pathways in LPS-induced BV2 cells. Research revealed that EA eases microglia-mediated neuron death in SN4741 and SHSY5Y cells. In in vivo studies, the results demonstrated that EA improves weight loss and behavioral impairment in MPTP-induced mice. Further studies have revealed that EA inhibited dopaminergic neuron damage and inflammation in the mice midbrain. In conclusion, our study demonstrated that EA inhibits neuroinflammation and exerts neuroprotective effects by activating PI3K/Akt and inhibiting NF-κB and MAPK signal pathways in vivo and in vitro.
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Affiliation(s)
- Dewei He
- College of Animal Science, Jilin University, Changchun, China
| | - Guiqiu Hu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ang Zhou
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yanting Liu
- Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Bingxu Huang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yingchun Su
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Hefei Wang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Bojian Ye
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yuan He
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xiyu Gao
- College of Animal Science, Jilin University, Changchun, China
| | - Shoupeng Fu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Dianfeng Liu
- College of Animal Science, Jilin University, Changchun, China
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17
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Atractylon, a novel dopamine 2 receptor agonist, ameliorates Parkinsonian like motor dysfunctions in MPTP-induced mice. Neurotoxicology 2022; 89:121-126. [DOI: 10.1016/j.neuro.2022.01.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/14/2021] [Accepted: 01/27/2022] [Indexed: 12/16/2022]
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18
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Tayebi M, Pinczowski P, Habiba U, Khan R, David MA, Summers BA. Case Report: Synucleinopathy Associated With Phalaris Neurotoxicity in Sheep. Front Vet Sci 2021; 8:736567. [PMID: 34722702 PMCID: PMC8551671 DOI: 10.3389/fvets.2021.736567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/09/2021] [Indexed: 11/26/2022] Open
Abstract
Chronic intoxication with tryptamine-alkaloid-rich Phalaris species (spp.) pasture plants is known colloquially as Phalaris staggers syndrome, a widely occurring neurological disorder of sheep, cattle, horses, and kangaroos. Of comparative interest, structurally analogous tryptamine-alkaloids cause experimental parkinsonism in primates. This study aimed to investigate the neuropathological changes associated with spontaneous cases of Phalaris staggers in sheep with respect to those encountered in human synucleinopathy. In sheep affected with Phalaris staggers, histological, immunohistochemical, and immunofluorescence analysis revealed significant accumulation of neuromelanin and aggregated α-synuclein in the perikaryon of neurons in the cerebral cortex, thalamus, brainstem, and spinal cord. Neuronal intracytoplasmic Lewy bodies inclusions were not observed in these cases of ovine Phalaris staggers. These important findings established a clear link between synucleinopathy and the neurologic form of Phalaris plant poisoning in sheep, demonstrated in six of six affected sheep. Synucleinopathy is a feature of a number of progressive and fatal neurodegenerative disorders of man and may be a common endpoint of such disorders, which in a variety of ways perturb neuronal function. However, whether primary to the degenerative process or a consequence of it awaits clarification in an appropriate model system.
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Affiliation(s)
- Mourad Tayebi
- Department of Neuroimmunology, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Pedro Pinczowski
- New South Wales Department of Primary Industries, Elizabeth Macarthur Agricultural Institute, Menangle, NSW, Australia
| | - Umma Habiba
- Department of Neuroimmunology, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Rizwan Khan
- Department of Neuroimmunology, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Monique A David
- Department of Neuroimmunology, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Brian A Summers
- Department of Veterinary Anatomic Pathology, School of Veterinary Medicine, University of Melbourne, Werribee, VIC, Australia
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Annexin A2 degradation contributes to dopaminergic cell apoptosis via regulating p53 in neurodegenerative conditions. Neuroreport 2021; 32:1263-1268. [PMID: 34494994 DOI: 10.1097/wnr.0000000000001721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND P53 overexpression has been shown to involve in mitochondria-mediated dapaminergic neuron cell death in Parkinson's disease. However, the exactly molecular mechanisms responsible for the p53-dependent intrinsic cell death in neurodegenerative conditions remain unclearly. Annexin A2 is a multifunctional protein that negatively regulates p53 expression. The purpose of this study was to explore the mechanism of p53 dependent dopaminergic cell death and implication of Annexin A2 in cellular apoptosis in 1-methyl-4-phenylpyridinium (MPP+)-induced PC12 cells. METHODS The cell viability of neural PC12 cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-razolium bromide assay. Flow cytometry was used to evaluate the apoptosis and mitochondrial transmembrane potential of neural PC12 cells. The expression of p53 and Annexin A2 was analyzed by western blot assay. RESULTS The present study showed that the exposure of PC12 cells to neurotoxin MPP+ increased the expression levels of p53 and the discharge of mitochondrial transmembrane potential. Notably, Annexin A2 degradation was also observed in this cellular model of Parkinson's disease, in a time and dose-dependent manner. This expressing change of Annexin A2 was in direct proportion to the loss of cell viability of PC12 cells, and this expression pattern was in inverse proportion to p53 levels in this cellular model of Parkinson's disease. CONCLUSION These results indicated that Annexin A2 degradation plays a crucial role the degeneration of dapaminergic cells of Parkinson's disease, and Annexin A2 downregulation-mediated the cell death is closely associated with mitochondrial dysfunction via p53-dependent pathway; thus provide a novel therapeutic target for Parkinson's disease treatment.
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20
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Non-cytochrome P450 enzymes involved in the oxidative metabolism of xenobiotics: Focus on the regulation of gene expression and enzyme activity. Pharmacol Ther 2021; 233:108020. [PMID: 34637840 DOI: 10.1016/j.pharmthera.2021.108020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/25/2021] [Accepted: 10/04/2021] [Indexed: 12/16/2022]
Abstract
Oxidative metabolism is one of the major biotransformation reactions that regulates the exposure of xenobiotics and their metabolites in the circulatory system and local tissues and organs, and influences their efficacy and toxicity. Although cytochrome (CY)P450s play critical roles in the oxidative reaction, extensive CYP450-independent oxidative metabolism also occurs in some xenobiotics, such as aldehyde oxidase, xanthine oxidoreductase, flavin-containing monooxygenase, monoamine oxidase, alcohol dehydrogenase, or aldehyde dehydrogenase-dependent oxidative metabolism. Drugs form a large portion of xenobiotics and are the primary target of this review. The common reaction mechanisms and roles of non-CYP450 enzymes in metabolism, factors affecting the expression and activity of non-CYP450 enzymes in terms of inhibition, induction, regulation, and species differences in pharmaceutical research and development have been summarized. These non-CYP450 enzymes are detoxifying enzymes, although sometimes they mediate severe toxicity. Synthetic or natural chemicals serve as inhibitors for these non-CYP450 enzymes. However, pharmacokinetic-based drug interactions through these inhibitors have rarely been reported in vivo. Although multiple mechanisms participate in the basal expression and regulation of non-CYP450 enzymes, only a limited number of inducers upregulate their expression. Therefore, these enzymes are considered non-inducible or less inducible. Overall, this review focuses on the potential xenobiotic factors that contribute to variations in gene expression levels and the activities of non-CYP450 enzymes.
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21
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High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer's Disease through Multitarget Approach. Pharmaceuticals (Basel) 2021; 14:ph14090937. [PMID: 34577637 PMCID: PMC8466787 DOI: 10.3390/ph14090937] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 01/20/2023] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.
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22
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Frison M, Faccenda D, Abeti R, Rigon M, Strobbe D, England-Rendon BS, Cash D, Barnes K, Sadeghian M, Sajic M, Wells LA, Xia D, Giunti P, Smith K, Mortiboys H, Turkheimer FE, Campanella M. The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity. Mol Psychiatry 2021; 26:2721-2739. [PMID: 33664474 PMCID: PMC8505241 DOI: 10.1038/s41380-021-01050-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 01/13/2021] [Accepted: 02/05/2021] [Indexed: 12/14/2022]
Abstract
Dysfunctional mitochondria characterise Parkinson's Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy-lysosomal pathway during neurotoxicity.
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Affiliation(s)
- Michele Frison
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom
- MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Danilo Faccenda
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom
| | - Rosella Abeti
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square London, United Kingdom
| | - Manuel Rigon
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom
- Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, Italy
| | - Daniela Strobbe
- Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, Italy
| | - Britannie S England-Rendon
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom
| | - Diana Cash
- Department of Neuroimaging, Institute of Psychiatry, King's College London, Camberwell, United Kingdom
| | - Katy Barnes
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
| | - Mona Sadeghian
- Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Marija Sajic
- Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Lisa A Wells
- Imanova Limited, Centre for Imaging Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Dong Xia
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom
| | - Paola Giunti
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square London, United Kingdom
| | - Kenneth Smith
- Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Heather Mortiboys
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
| | - Federico E Turkheimer
- Department of Neuroimaging, Institute of Psychiatry, King's College London, Camberwell, United Kingdom
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom.
- Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, Italy.
- University College London Consortium for Mitochondrial Research, London, United Kingdom.
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23
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Nam MH, Park JH, Song HJ, Choi JW, Kim S, Jang BK, Yoon HH, Heo JY, Lee H, An H, Kim HJ, Park SJ, Cho DW, Yang YS, Han SC, Kim S, Oh SJ, Jeon SR, Park KD, Lee CJ. KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson's Disease. Neurotherapeutics 2021; 18:1729-1747. [PMID: 34611843 PMCID: PMC8608967 DOI: 10.1007/s13311-021-01097-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2021] [Indexed: 02/04/2023] Open
Abstract
Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson's disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.
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Affiliation(s)
- Min-Ho Nam
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- Department of KHU-KIST Convergence Science and Technology, Kyung Hee University, Seoul, 02453, Korea
| | - Jong-Hyun Park
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
- Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea
| | - Hyo Jung Song
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
| | - Ji Won Choi
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
| | - Siwon Kim
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
- Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea
| | - Bo Ko Jang
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
| | - Hyung Ho Yoon
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jun Young Heo
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Hyowon Lee
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Heeyoung An
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34126, Republic of Korea
| | - Hyeon Jeong Kim
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
- Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
| | - Sun Jun Park
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
- Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea
| | - Doo-Wan Cho
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeonbuk, 56212, Republic of Korea
| | - Young-Su Yang
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeonbuk, 56212, Republic of Korea
| | - Su-Cheol Han
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeonbuk, 56212, Republic of Korea
| | - Sangwook Kim
- Neurobiogen Co., LTD, Seocho-gu, Seoul, 9, Republic of Korea
| | - Soo-Jin Oh
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea
| | - Sang Ryong Jeon
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Ki Duk Park
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, 02792, Republic of Korea.
- Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
| | - C Justin Lee
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34126, Republic of Korea.
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Ma L, Gholam Azad M, Dharmasivam M, Richardson V, Quinn RJ, Feng Y, Pountney DL, Tonissen KF, Mellick GD, Yanatori I, Richardson DR. Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies. Redox Biol 2021; 41:101896. [PMID: 33799121 PMCID: PMC8044696 DOI: 10.1016/j.redox.2021.101896] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022] Open
Abstract
A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The "gold standard" histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca+2 channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected.
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Affiliation(s)
- L Ma
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - M Gholam Azad
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - M Dharmasivam
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - V Richardson
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - R J Quinn
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - Y Feng
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - D L Pountney
- School of Medical Science, Griffith University, Gold Coast, Queensland, Australia
| | - K F Tonissen
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - G D Mellick
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia
| | - I Yanatori
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - D R Richardson
- School of Environment and Science, Griffith University Nathan, Brisbane, Queensland, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
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25
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Apoferritin improves motor deficits in MPTP-treated mice by regulating brain iron metabolism and ferroptosis. iScience 2021; 24:102431. [PMID: 33997705 PMCID: PMC8105649 DOI: 10.1016/j.isci.2021.102431] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/07/2021] [Accepted: 04/12/2021] [Indexed: 01/03/2023] Open
Abstract
Iron deposition is one of the key factors in the etiology of Parkinson's disease (PD). Iron-free-apoferritin has the ability to store iron by combining with a ferric hydroxide-phosphate compound to form ferritin. In this study, we investigated the role of apoferritin in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice models and elucidated the possible underlying mechanisms. Results showed that apoferritin remarkably improved MPTP-induced motor deficits by rescuing dopaminergic neurodegeneration in the substantia nigra. Apoferritin inhibited MPTP-induced iron aggregation by down-regulating iron importer divalent metal transporter 1 (DMT1). Meanwhile, we also showed that apoferritin prevented MPTP-induced ferroptosis effectively by inhibiting the up-regulation of long-chain acyl-CoA synthetase 4 (ACSL4) and the down-regulation of ferroptosis suppressor protein 1 (FSP1). These results indicate that apoferritin exerts a neuroprotective effect against MPTP by inhibiting iron aggregation and modulating ferroptosis. This provides a promising therapeutic target for the treatment of PD.
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Biagioni F, Vivacqua G, Lazzeri G, Ferese R, Iannacone S, Onori P, Morini S, D’Este L, Fornai F. Chronic MPTP in Mice Damage-specific Neuronal Phenotypes within Dorsal Laminae of the Spinal Cord. Neurotox Res 2021; 39:156-169. [PMID: 33206341 PMCID: PMC7936970 DOI: 10.1007/s12640-020-00313-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/06/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023]
Abstract
The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson's disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alpha-synuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD.
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Affiliation(s)
| | - Giorgio Vivacqua
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Via Alvaro del Portillo 21, 00125 Roma, Italy
- Department of Anatomic, Histologic, Forensic and Locomotor Apparatus Sciences, Sapienza University of Roma, Via Alfonso Borelli 50, 00161 Roma, Italy
| | - Gloria Lazzeri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
| | | | - Simone Iannacone
- Department of Anatomic, Histologic, Forensic and Locomotor Apparatus Sciences, Sapienza University of Roma, Via Alfonso Borelli 50, 00161 Roma, Italy
| | - Paolo Onori
- Department of Anatomic, Histologic, Forensic and Locomotor Apparatus Sciences, Sapienza University of Roma, Via Alfonso Borelli 50, 00161 Roma, Italy
| | - Sergio Morini
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Via Alvaro del Portillo 21, 00125 Roma, Italy
| | - Loredana D’Este
- Department of Anatomic, Histologic, Forensic and Locomotor Apparatus Sciences, Sapienza University of Roma, Via Alfonso Borelli 50, 00161 Roma, Italy
| | - Francesco Fornai
- I.R.C.C.S. Neuromed, via dell’Elettronica, Pozzilli, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
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Modelling Parkinson's Disease: iPSCs towards Better Understanding of Human Pathology. Brain Sci 2021; 11:brainsci11030373. [PMID: 33799491 PMCID: PMC8000082 DOI: 10.3390/brainsci11030373] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/10/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.
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Voon SM, Ng KY, Chye SM, Ling APK, Voon KGL, Yap YJ, Koh RY. The Mechanism of Action of Salsolinol in Brain: Implications in Parkinson's Disease. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 19:725-740. [PMID: 32881676 DOI: 10.2174/1871527319666200902134129] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 07/26/2020] [Accepted: 07/29/2020] [Indexed: 11/22/2022]
Abstract
1-Methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol, commonly known as salsolinol, is a compound derived from dopamine. It was first discovered in 1973 and has gained attention for its role in Parkinson's disease. Salsolinol and its derivatives were claimed to play a role in the pathogenesis of Parkinson's disease as a neurotoxin that induces apoptosis of dopaminergic neurons due to its structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its ability to induce Parkinsonism. In this article, we discussed the biosynthesis, distribution and blood-brain barrier permeability of salsolinol. The roles of salsolinol in a healthy brain, particularly the interactions with enzymes, hormone and catecholamine, were reviewed. Finally, we discussed the involvement of salsolinol and its derivatives in the pathogenesis of Parkinson's disease.
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Affiliation(s)
- Shee Man Voon
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Khuen Yen Ng
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Soi Moi Chye
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Anna Pick Kiong Ling
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Kenny Gah Leong Voon
- Pathology Division, School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Yiing Jye Yap
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Rhun Yian Koh
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
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Wasan H, Singh D, Kh R. Safinamide in neurological disorders and beyond: Evidence from preclinical and clinical studies. Brain Res Bull 2020; 168:165-177. [PMID: 33387637 DOI: 10.1016/j.brainresbull.2020.12.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/04/2020] [Accepted: 12/27/2020] [Indexed: 01/08/2023]
Abstract
The discovery and development of safinamide, an alpha-aminoamide, has been a valuable addition to the existing clinical management of Parkinson's disease (PD). The journey of safinamide dates back to the year 1983, when an alpha-aminoamide called milacemide showed a weak anticonvulsant activity. Milacemide was then structurally modified to give rise to safinamide, which in turn produced robust anticonvulsant activity. The underlying mechanism behind this action of safinamide is attributed to the inhibition of voltage gated calcium and sodium channels. Moreover, owing to the importance of ion channels in maintaining neuronal circuitry and neurotransmitter release, numerous studies explored the potential of safinamide in neurological diseases including PD, stroke, multiple sclerosis and neuromuscular disorders such as Duchenne muscular dystrophy and non-dystrophic myotonias. Nevertheless, evidence from multiple preclinical studies suggested a potent, selective and reversible inhibitory activity of safinamide against monoamine oxidase (MAO)-B enzyme which is responsible for degrading dopamine, a neurotransmitter primarily implicated in the pathophysiology of PD. Therefore, clinical studies were conducted to assess safety and efficacy of safinamide in PD. Indeed, results from various Phase 3 clinical trials suggested strong evidence of safinamide as an add-on therapy in controlling the exacerbation of PD. This review presents a thorough developmental history of safinamide in PD and provides comprehensive insight into plausible mechanisms via which safinamide can be explored in other neurological and muscular diseases.
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Affiliation(s)
- Himika Wasan
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
| | - Devendra Singh
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
| | - Reeta Kh
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
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30
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Pisoschi AM, Pop A, Iordache F, Stanca L, Predoi G, Serban AI. Oxidative stress mitigation by antioxidants - An overview on their chemistry and influences on health status. Eur J Med Chem 2020; 209:112891. [PMID: 33032084 DOI: 10.1016/j.ejmech.2020.112891] [Citation(s) in RCA: 344] [Impact Index Per Article: 68.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/30/2020] [Accepted: 09/24/2020] [Indexed: 12/11/2022]
Abstract
The present review paper focuses on the chemistry of oxidative stress mitigation by antioxidants. Oxidative stress is understood as a lack of balance between the pro-oxidant and the antioxidant species. Reactive oxygen species in limited amounts are necessary for cell homeostasis and redox signaling. Excessive reactive oxygenated/nitrogenated species production, which counteracts the organism's defense systems, is known as oxidative stress. Sustained attack of endogenous and exogenous ROS results in conformational and oxidative alterations in key biomolecules. Chronic oxidative stress is associated with oxidative modifications occurring in key biomolecules: lipid peroxidation, protein carbonylation, carbonyl (aldehyde/ketone) adduct formation, nitration, sulfoxidation, DNA impairment such strand breaks or nucleobase oxidation. Oxidative stress is tightly linked to the development of cancer, diabetes, neurodegeneration, cardiovascular diseases, rheumatoid arthritis, kidney disease, eye disease. The deleterious action of reactive oxygenated species and their role in the onset and progression of pathologies are discussed. The results of oxidative attack become themselves sources of oxidative stress, becoming part of a vicious cycle that amplifies oxidative impairment. The term antioxidant refers to a compound that is able to impede or retard oxidation, acting at a lower concentration compared to that of the protected substrate. Antioxidant intervention against the radicalic lipid peroxidation can involve different mechanisms. Chain breaking antioxidants are called primary antioxidants, acting by scavenging radical species, converting them into more stable radicals or non-radical species. Secondary antioxidants quench singlet oxygen, decompose peroxides, chelate prooxidative metal ions, inhibit oxidative enzymes. Moreover, four reactivity-based lines of defense have been identified: preventative antioxidants, radical scavengers, repair antioxidants, and those relying on adaptation mechanisms. The specific mechanism of a series of endogenous and exogenous antioxidants in particular aspects of oxidative stress, is detailed. The final section resumes critical conclusions regarding antioxidant supplementation.
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Affiliation(s)
- Aurelia Magdalena Pisoschi
- University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania.
| | - Aneta Pop
- University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania
| | - Florin Iordache
- University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania
| | - Loredana Stanca
- University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania
| | - Gabriel Predoi
- University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania
| | - Andreea Iren Serban
- University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Bucharest, Romania
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Woitalla D, Krüger R, Lorenzl S, Müller T, Oelwein G, Storch A, Wolz M, Wüllner U. [The role of inhibitors of COMT and MAO-B in the therapy of Parkinson's disease]. FORTSCHRITTE DER NEUROLOGIE-PSYCHIATRIE 2020; 88:620-633. [PMID: 32588409 DOI: 10.1055/a-1149-9308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Inhibitors of COMT and MAO-B are well established in the pharmacotherapy of Parkinson's disease (PD). MAO-B inhibitors are used as monotherapy as well as in combination with levodopa, whereas COMT inhibitors exert their effects only in conjungtion with levodopa. Both classes of compounds prolong the response duration of levodopa and optimise its clinical benefit. As a result, the ON-times are prolonged significantly. In the past, MAO-B inhibitors were also adminstered for neuroprotection; however, despite convincing scientific reasoning in support of neuroprotective effects, these could not be substantiated in clinical studies performed so far.
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Kasabova-Angelova A, Tzankova D, Mitkov J, Georgieva M, Tzankova V, Zlatkov A, Kondeva-Burdina M. Xanthine Derivatives as Agents Affecting Non-dopaminergic Neuroprotection in Parkinson`s Disease. Curr Med Chem 2020; 27:2021-2036. [PMID: 30129404 DOI: 10.2174/0929867325666180821153316] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 07/13/2018] [Accepted: 07/18/2018] [Indexed: 12/20/2022]
Abstract
Parkinson's Disease (PD) is a neurodegenerative and debilitating disease that affects 1% of the elderly population. Patient's motor disability results in extreme difficulty to deal with daily activities. Conventional treatment is limited to dopamine replacement therapy, which fails to delay disease's progression and is often associated with a number of adverse reactions. Recent progress in understanding the mechanisms involved in PD has revealed new molecular targets for therapeutic approaches. Among them, caffeine and xanthine derivatives are promising drug candidates, because of the possible symptomatic benefits in PD. In fact, consumption of coffee correlates with a reduced risk of PD. Over the last decades, a lot of efforts have been made to uncover the therapeutic potential of xanthine structures. The substituted xanthine molecule is used as a scaffold for the synthesis of new compounds with protective effects in neurodegenerative diseases, including PD, asthma, cancer and others. The administration of the xanthines has been proposed as a non-dopaminergic strategy for neuroprotection in PD and the mechanisms of protection have been associated with antagonism of adenosine A2A receptors and Monoamine Oxidase type B (MAO-B) inhibition. The current review summarizes frequently suspected non-dopaminergic neuroprotective mechanisms and the possible beneficial effects of the xanthine derivatives in PD, along with some synthetic approaches to produce perspective xanthine derivatives as non-dopaminergic agents in PD treatment.
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Affiliation(s)
- Alexandra Kasabova-Angelova
- Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Diana Tzankova
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Javor Mitkov
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Maya Georgieva
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Virginia Tzankova
- Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Alexander Zlatkov
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Magdalena Kondeva-Burdina
- Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
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33
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Nitroxide Radical-Containing Redox Nanoparticles Protect Neuroblastoma SH-SY5Y Cells against 6-Hydroxydopamine Toxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9260748. [PMID: 32377313 PMCID: PMC7196160 DOI: 10.1155/2020/9260748] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/06/2020] [Accepted: 04/01/2020] [Indexed: 12/19/2022]
Abstract
Parkinson's disease (PD) patients can benefit from antioxidant supplementation, and new efficient antioxidants are needed. The aim of this study was to evaluate the protective effect of selected nitroxide-containing redox nanoparticles (NRNPs) in a cellular model of PD. Antioxidant properties of NRNPs were studied in cell-free systems by protection of dihydrorhodamine 123 against oxidation by 3-morpholino-sydnonimine and protection of fluorescein against bleaching by 2,2-azobis(2-amidinopropane) hydrochloride and sodium hypochlorite. Model blood-brain barrier penetration was studied using hCMEC/D3 cells. Human neuroblastoma SH-SY5Y cells, exposed to 6-hydroxydopamine (6-OHDA), were used as an in vitro model of PD. Cells were preexposed to NRNPs or free nitroxides (TEMPO or 4-amino-TEMPO) for 2 h and treated with 6-OHDA for 1 h and 24 h. The reactive oxygen species (ROS) level was estimated with dihydroethidine 123 and Fluorimetric Mitochondrial Superoxide Activity Assay Kit. Glutathione level (GSH) was measured with ortho-phtalaldehyde, ATP by luminometry, changes in mitochondrial membrane potential with JC-1, and mitochondrial mass with 10-Nonyl-Acridine Orange. NRNP1, TEMPO, and 4-amino-TEMPO (25-150 μM) protected SH-SY5Y cells from 6-OHDA-induced viability loss; the protection was much higher for NRNP1 than for free nitroxides. NRNP1 were better antioxidants in vitro and permeated better the model BBB than free nitroxides. Exposure to 6-OHDA decreased the GSH level after 1 h and increased it considerably after 24 h (apparently a compensatory overresponse); NRNPs and free nitroxides prevented this increase. NRNP1 and free nitroxides prevented the decrease in ATP level after 1 h and increased it after 24 h. 6-OHDA increased the intracellular ROS level and mitochondrial superoxide level. Studied antioxidants mostly decreased ROS and superoxide levels. 6-OHDA decreased the mitochondrial potential and mitochondrial mass; both effects were prevented by NRNP1 and nitroxides. These results suggest that the mitochondria are the main site of 6-OHDA-induced cellular damage and demonstrate a protective effect of NRNP1 in a cellular model of PD.
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34
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Parambi DGT. Treatment of Parkinson's Disease by MAO-B Inhibitors, New Therapies and Future Challenges - A Mini-Review. Comb Chem High Throughput Screen 2020; 23:847-861. [PMID: 32238135 DOI: 10.2174/1386207323666200402090557] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 12/30/2019] [Accepted: 01/23/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND One of the most prevalent neurodegenerative diseases with increasing age is Parkinson's disease (PD). Its pathogenesis is unclear and mainly confined to glutamate toxicity and oxidative stress. The dyskinesia and motor fluctuations and neuroprotective potential are the major concerns which are still unmet in PD therapy. OBJECTIVE This article is a capsulization of the role of MAO-B in the treatment of PD, pharmacological properties, safety and efficiency, clinical evidence through random trials, future therapies and challenges. CONCLUSION MAO-B inhibitors are well tolerated for the treatment of PD because of their pharmacokinetic properties and neuroprotective action. Rasagiline and selegiline were recommended molecules for early PD and proven safe and provide a modest to significant rise in motor function, delay the use of levodopa and used in early PD. Moreover, safinamide is antiglutamatergic in action. When added to Levodopa, these molecules significantly reduce the offtime with a considerable improvement of non-motor symptoms. This review also discusses the new approaches in therapy like the use of biomarkers, neurorestorative growth factors, gene therapy, neuroimaging, neural transplantation, and nanotechnology. Clinical evidence illustrated that MAOB inhibitors are recommended as monotherapy and added on therapy to levodopa. A large study and further evidence are required in the field of future therapies to unwind the complexity of the disease.
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Affiliation(s)
- Della G T Parambi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jouf University, Sakaka, Jouf, Saudi Arabia
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35
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Cenci MA, Björklund A. Animal models for preclinical Parkinson's research: An update and critical appraisal. PROGRESS IN BRAIN RESEARCH 2020; 252:27-59. [PMID: 32247366 DOI: 10.1016/bs.pbr.2020.02.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Animal models of Parkinson's disease (PD) are essential to investigate pathogenic pathways at the whole-organism level. Moreover, they are necessary for a preclinical investigation of potential new therapies. Different pathological features of PD can be induced in a variety of invertebrate and vertebrate species using toxins, drugs, or genetic perturbations. Each model has a particular utility and range of applicability. Invertebrate PD models are particularly useful for high throughput-screening applications, whereas mammalian models are needed to explore complex motor and non-motor features of the human disease. Here, we provide a comprehensive review and critical appraisal of the most commonly used mammalian models of PD, which are produced in rats and mice. A substantial loss of nigrostriatal dopamine neurons is necessary for the animal to exhibit a hypokinetic motor phenotype responsive to dopaminergic agents, thus resembling clinical PD. This level of dopaminergic neurodegeneration can be induced using specific neurotoxins, environmental toxicants, or proteasome inhibitors. Alternatively, nigrostriatal dopamine degeneration can be induced via overexpression of α-synuclein using viral vectors or transgenic techniques. In addition, protein aggregation pathology can be triggered by inoculating preformed fibrils of α-synuclein in the substantia nigra or the striatum. Thanks to the conceptual and technical progress made in the past few years a vast repertoire of well-characterized animal models are currently available to address different aspects of PD in the laboratory.
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Affiliation(s)
- M Angela Cenci
- Department of Experimental Medical Science, Wallenberg Neuroscience Centre, Lund University, Lund, Sweden.
| | - Anders Björklund
- Department of Experimental Medical Science, Wallenberg Neuroscience Centre, Lund University, Lund, Sweden
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36
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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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37
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Xie J, Liang R, Wang Y, Huang J, Cao X, Niu B. Progress in Target Drug Molecules for Alzheimer's Disease. Curr Top Med Chem 2020; 20:4-36. [DOI: 10.2174/1568026619666191203113745] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 10/20/2019] [Accepted: 10/31/2019] [Indexed: 12/25/2022]
Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disease that 4 widespread in the elderly.
The etiology of AD is complicated, and its pathogenesis is still unclear. Although there are many
researches on anti-AD drugs, they are limited to reverse relief symptoms and cannot treat diseases.
Therefore, the development of high-efficiency anti-AD drugs with no side effects has become an urgent
need. Based on the published literature, this paper summarizes the main targets of AD and their drugs,
and focuses on the research and development progress of these drugs in recent years.
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Affiliation(s)
- Jiayang Xie
- School of Life Science, Shanghai University, 99 Shangda Road, Shanghai 200444, China
| | - Ruirui Liang
- School of Life Science, Shanghai University, 99 Shangda Road, Shanghai 200444, China
| | - Yajiang Wang
- School of Life Science, Shanghai University, 99 Shangda Road, Shanghai 200444, China
| | - Junyi Huang
- School of Life Science, Shanghai University, 99 Shangda Road, Shanghai 200444, China
| | - Xin Cao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai, China
| | - Bing Niu
- School of Life Science, Shanghai University, 99 Shangda Road, Shanghai 200444, China
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38
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Nakamura A, Latif MA, Deck PA, Castagnoli N, Tanko JM. Evidence for a Proton-Coupled Electron Transfer Mechanism in a Biomimetic System for Monoamine Oxidase B Catalysis. Chemistry 2020; 26:823-829. [PMID: 31658386 DOI: 10.1002/chem.201904634] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Indexed: 11/11/2022]
Abstract
Mechanistic studies with 5-ethyl-3-methyllumiflavinium (Fl+ ) perchlorate, a biomimetic model for flavoenzyme monoamine oxidase B (MAO-B) catalysis, and the tertiary, allyl amine 1-methyl-4-(1-methyl-1 H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP) reveal that proton-coupled electron transfer (PCET) may be an important pathway for MAO catalysis. The first step involves a single-electron transfer (SET) leading to the free radicals Fl. and MMTP. , the latter produced by deprotonation of the initially formed and highly acidic MMTP.+ . Molecular oxygen (O2 ) is found to play a hitherto unrecognized role in the early steps of the oxidation. MMTP and several structurally similar tertiary amines are the only tertiary amines oxidized by MAO, and their structural/electronic properties provide the key to understanding this behavior. A general hypothesis about the role of SET in MAO catalysis, and the recognition that PCET occurs with appropriately substituted substrates is presented.
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Affiliation(s)
- Akiko Nakamura
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24060, USA
| | | | - Paul A Deck
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24060, USA
| | - Neal Castagnoli
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24060, USA
| | - James M Tanko
- Department of Chemistry, Virginia Tech, Blacksburg, VA, 24060, USA
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39
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de Melo Pereira GV, de Carvalho Neto DP, Magalhães Júnior AI, do Prado FG, Pagnoncelli MGB, Karp SG, Soccol CR. Chemical composition and health properties of coffee and coffee by-products. ADVANCES IN FOOD AND NUTRITION RESEARCH 2020; 91:65-96. [PMID: 32035601 DOI: 10.1016/bs.afnr.2019.10.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Coffee can be an ally in the fight against diseases such as type 2 diabetes, cancer, hepatic injury, cirrhosis, depression, suicidal behavior, and neurological and cardiovascular disorders. The properties of coffee also favor gastrointestinal tract and gut microbiota establishment. Coffee bioactive components include phenolic compounds (chlorogenic acids, cafestol and kahweol), alkaloids (caffeine and trigonelin), diterpenes (cafestol and kahweol) and other secondary metabolites. The image of coffee as a super functional food has helped to increase coffee consumption across the globe. This chapter addresses the main health promotion mechanisms associated with coffee consumption. Related topics on coffee production chain, world consumption and reuse of coffee by-products in the production of high-value-adding molecules with potential applications in the food industry are addressed and discussed.
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Affiliation(s)
- Gilberto V de Melo Pereira
- Bioprocess Engineering and Biotechnology Department, Federal University of Paraná (UFPR), Curitiba, Paraná, Brazil
| | - Dão Pedro de Carvalho Neto
- Bioprocess Engineering and Biotechnology Department, Federal University of Paraná (UFPR), Curitiba, Paraná, Brazil
| | - Antonio I Magalhães Júnior
- Bioprocess Engineering and Biotechnology Department, Federal University of Paraná (UFPR), Curitiba, Paraná, Brazil
| | - Fernanda Guilherme do Prado
- Bioprocess Engineering and Biotechnology Department, Federal University of Paraná (UFPR), Curitiba, Paraná, Brazil
| | - Maria Giovana B Pagnoncelli
- Department of Chemistry and Biology, Federal University of Technology-Paraná (UTFPR), Curitiba, Paraná, Brazil
| | - Susan Grace Karp
- Bioprocess Engineering and Biotechnology Department, Federal University of Paraná (UFPR), Curitiba, Paraná, Brazil
| | - Carlos Ricardo Soccol
- Bioprocess Engineering and Biotechnology Department, Federal University of Paraná (UFPR), Curitiba, Paraná, Brazil.
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40
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Monoamine oxidase polymorphisms in rhesus and Japanese macaques (Macaca mulatta and M. fuscata). J Chem Neuroanat 2020; 103:101726. [DOI: 10.1016/j.jchemneu.2019.101726] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 12/31/2022]
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Vivacqua G, Biagioni F, Busceti CL, Ferrucci M, Madonna M, Ryskalin L, Yu S, D'Este L, Fornai F. Motor Neurons Pathology After Chronic Exposure to MPTP in Mice. Neurotox Res 2019; 37:298-313. [PMID: 31721049 DOI: 10.1007/s12640-019-00121-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/18/2019] [Accepted: 09/25/2019] [Indexed: 12/12/2022]
Abstract
The neurotoxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism in rodents and primates. Among different administration protocols, continuous or chronic exposure to small amounts of MPTP is reported to better mimic cell pathology reminiscent of Parkinson's disease (PD). Catecholamine neurons are the most sensitive to MPTP neurotoxicity; however, recent studies have found that MPTP alters the fine anatomy of the spinal cord including motor neurons, thus overlapping again with the spinal cord involvement documented in PD. In the present study, we demonstrate that chronic exposure to low amounts of MPTP (10 mg/kg daily, × 21 days) significantly reduces motor neurons in the ventral lumbar spinal cord while increasing α-synuclein immune-staining within the ventral horn. Spinal cord involvement in MPTP-treated mice extends to Calbindin D28 KDa immune-reactive neurons other than motor neurons within lamina VII. These results were obtained in the absence of significant reduction of dopaminergic cell bodies in the Substantia Nigra pars compacta, while a slight decrease was documented in striatal tyrosine hydroxylase immune-staining. Thus, the present study highlights neuropathological similarities between dopaminergic neurons and spinal motor neurons and supports the pathological involvement of spinal cord in PD and experimental MPTP-induced parkinsonism. Remarkably, the toxic threshold for motor neurons appears to be lower compared with nigral dopaminergic neurons following a chronic pattern of MPTP intoxication. This sharply contrasts with previous studies showing that MPTP intoxication produces comparable neuronal loss within spinal cord and Substantia Nigra.
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Affiliation(s)
- Giorgio Vivacqua
- Department of Anatomy, Histology, Forensic Medicine and Locomotor Sciences, Via A. Borelli 50, 00161, Rome, Italy
- Department of Neurobiology, Xuan Wu Hospital, Capital University of Medical Sciences, 45 Changchun St, Beijing, 100053, China
| | | | | | - Michela Ferrucci
- Department of Traslational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy
| | | | - Larisa Ryskalin
- Department of Traslational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy
| | - Shun Yu
- Department of Neurobiology, Xuan Wu Hospital, Capital University of Medical Sciences, 45 Changchun St, Beijing, 100053, China
| | - Loredana D'Este
- Department of Anatomy, Histology, Forensic Medicine and Locomotor Sciences, Via A. Borelli 50, 00161, Rome, Italy
| | - Francesco Fornai
- I.R.C.C.S. Neuromed, Via Atinense, 18, Pozzilli, Italy.
- Department of Traslational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy.
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Tayebi M, El-Hage CM, Pinczowski P, Whiteley P, David M, Li QX, Varghese S, Mikhael M, Habiba U, Harman D, Tatarczuch L, Bogeski M, Birchall I, Ferguson K, Walker L, Masters C, Summers BA. Plant poisoning leads to alpha-synucleinopathy and neuromelanopathy in kangaroos. Sci Rep 2019; 9:16546. [PMID: 31723225 PMCID: PMC6853926 DOI: 10.1038/s41598-019-53396-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 10/31/2019] [Indexed: 11/09/2022] Open
Abstract
The pathogenesis of synucleinopathies, common neuropathological lesions normally associated with some human neurodegenerative disorders such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, remains poorly understood. In animals, ingestion of the tryptamine-alkaloid-rich phalaris pastures plants causes a disorder called Phalaris staggers, a neurological syndrome reported in kangaroos. The aim of the study was to characterise the clinical and neuropathological changes associated with spontaneous cases of Phalaris staggers in kangaroos. Gross, histological, ultrastructural and Immunohistochemical studies were performed to demonstrate neuronal accumulation of neuromelanin and aggregated α-synuclein. ELISA and mass spectrometry were used to detect serum-borne α-synuclein and tryptamine alkaloids respectively. We report that neurons in the central and enteric nervous systems of affected kangaroos display extensive accumulation of neuromelanin in the perikaryon without affecting neuronal morphology. Ultrastructural studies confirmed the typical structure of neuromelanin. While we demonstrated strong staining of α-synuclein, restricted to neurons, intracytoplasmic Lewy bodies inclusions were not observed. α-synuclein aggregates levels were shown to be lower in sera of the affected kangaroos compared to unaffected herd mate kangaroos. Finally, mass spectrometry failed to detect the alkaloid toxins in the sera derived from the affected kangaroos. Our preliminary findings warrant further investigation of Phalaris staggers in kangaroos, potentially a valuable large animal model for environmentally-acquired toxic synucleinopathy.
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Affiliation(s)
- Mourad Tayebi
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia. .,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
| | | | - Pedro Pinczowski
- New South Wales Department of Primary Industries, Menangle, New South Wales, Australia
| | - Pam Whiteley
- University of Melbourne, Parkville, Victoria, Australia
| | - Monique David
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Qiao-Xin Li
- New South Wales Department of Primary Industries, Menangle, New South Wales, Australia
| | - Shiji Varghese
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Meena Mikhael
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Umma Habiba
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - David Harman
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | | | - Mirjana Bogeski
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Ian Birchall
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Kirsty Ferguson
- MGV Mt Annan, Mt Annan, NSW, Australia.,Sydney Metropolitan Wildlife Services, Lindfield, NSW, Australia
| | - Larry Walker
- Southern Scientific, Hamilton, Victoria, Australia
| | - Colin Masters
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
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Ke M, Chong CM, Su H. Using induced pluripotent stem cells for modeling Parkinson’s disease. World J Stem Cells 2019; 11:634-649. [PMID: 31616540 PMCID: PMC6789186 DOI: 10.4252/wjsc.v11.i9.634] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/26/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Parkinson’s disease (PD) is an age-related neurodegenerative disease caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. As DA neurons degenerate, PD patients gradually lose their ability of movement. To date no effective therapies are available for the treatment of PD and its pathogenesis remains unknown. Experimental models that appropriately mimic the development of PD are certainly needed for gaining mechanistic insights into PD pathogenesis and identifying new therapeutic targets. Human induced pluripotent stem cells (iPSCs) could provide a promising model for fundamental research and drug screening. In this review, we summarize various iPSCs-based PD models either derived from PD patients through reprogramming technology or established by gene-editing technology, and the promising application of iPSC-based PD models for mechanistic studies and drug testing.
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Affiliation(s)
- Minjing Ke
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Cheong-Meng Chong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
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Santos SF, de Oliveira HL, Yamada ES, Neves BC, Pereira A. The Gut and Parkinson's Disease-A Bidirectional Pathway. Front Neurol 2019; 10:574. [PMID: 31214110 PMCID: PMC6558190 DOI: 10.3389/fneur.2019.00574] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 05/15/2019] [Indexed: 12/13/2022] Open
Abstract
Humans evolved a symbiotic relationship with their gut microbiome, a complex microbial community composed of bacteria, archaea, protists, and viruses, including bacteriophages. The enteric nervous system (ENS) is a gateway for the bidirectional communication between the brain and the gut, mostly through the vagus nerve (VN). Environmental exposure plays a pivotal role in both the composition and functionality of the gut microbiome and may contribute to susceptibility to neurodegenerative disorders, such as Parkinson's disease (PD). The neuropathological hallmark of PD is the widespread appearance of alpha-synuclein aggregates in both the central and peripheral nervous systems, including the ENS. Many studies suggest that gut toxins can induce the formation of α-syn aggregates in the ENS, which may then be transmitted in a prion-like manner to the CNS through the VN. PD is strongly associated with aging and its negative effects on homeostatic mechanisms protecting from inflammation, oxidative stress, and protein malfunction. In this mini-review, we revisit some landmark discoveries in the field of Parkinson's research and focus on the gut-brain axis. In the process, we highlight evidence showing gut-associated dysbiosis and related microbial-derived components as important players and risk factors for PD. Therefore, the gut microbiome emerges as a potential target for protective measures aiming to prevent PD onset.
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Affiliation(s)
- Susanne Fonseca Santos
- Graduate Program in Neuroscience and Cell Biology, Institute of Biology, Federal University of Pará, Belém, Brazil
| | - Hadassa Loth de Oliveira
- Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Elizabeth Sumi Yamada
- Graduate Program in Neuroscience and Cell Biology, Institute of Biology, Federal University of Pará, Belém, Brazil
| | - Bianca Cruz Neves
- Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Antonio Pereira
- Graduate Program in Neuroscience and Cell Biology, Institute of Biology, Federal University of Pará, Belém, Brazil.,Department of Electrical and Biomedical Engineering, Institute of Technology, Federal University of Pará, Belém, Brazil
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46
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Chattopadhyay M, Chowdhury AR, Feng T, Assenmacher CA, Radaelli E, Guengerich FP, Avadhani NG. Mitochondrially targeted cytochrome P450 2D6 is involved in monomethylamine-induced neuronal damage in mouse models. J Biol Chem 2019; 294:10336-10348. [PMID: 31113867 DOI: 10.1074/jbc.ra119.008848] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 05/06/2019] [Indexed: 11/06/2022] Open
Abstract
Parkinson's disease (PD) is a major human disease associated with degeneration of the central nervous system. Evidence suggests that several endogenously formed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mimicking chemicals that are metabolic conversion products, especially β-carbolines and isoquinolines, act as neurotoxins that induce PD or enhance progression of the disease. We have demonstrated previously that mitochondrially targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the conversion of MPTP to the toxic 1-methyl-4-phenylpyridinium ion. In this study, we show that the mitochondrially targeted CYP2D6 can efficiently catalyze MPTP-mimicking compounds, i.e. 2-methyl-1,2,3,4-tetrahydroisoquinoline, 2-methyl-1,2,3,4-tetrahydro-β-carboline, and 9-methyl-norharmon, suspected to induce PD in humans. Our results reveal that activity and respiration in mouse brain mitochondrial complex I are significantly affected by these toxins in WT mice but remain unchanged in Cyp2d6 locus knockout mice, indicating a possible role of CYP2D6 in the metabolism of these compounds both in vivo and in vitro These metabolic effects were minimized in the presence of two CYP2D6 inhibitors, quinidine and ajmalicine. Neuro-2a cells stably expressing predominantly mitochondrially targeted CYP2D6 were more sensitive to toxin-mediated respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Exposure to these toxins also induced the autophagic marker Parkin and the mitochondrial fission marker Dynamin-related protein 1 (Drp1) in differentiated neurons expressing mitochondrial CYP2D6. Our results show that monomethylamines are converted to their toxic cationic form by mitochondrially directed CYP2D6 and result in neuronal degradation in mice.
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Affiliation(s)
- Mrittika Chattopadhyay
- From the Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Anindya Roy Chowdhury
- From the Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Ting Feng
- From the Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Charles-Antoine Assenmacher
- the Department of Pathobiology, MJR-VHUP, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and
| | - Enrico Radaelli
- the Department of Pathobiology, MJR-VHUP, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and
| | - F Peter Guengerich
- the Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232
| | - Narayan G Avadhani
- From the Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,
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Seshadri A, Alladi PA. Divergent Expression Patterns of Drp1 and HSD10 in the Nigro-Striatum of Two Mice Strains Based on their MPTP Susceptibility. Neurotox Res 2019; 36:27-38. [PMID: 30993548 DOI: 10.1007/s12640-019-00036-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/26/2019] [Accepted: 03/29/2019] [Indexed: 12/13/2022]
Abstract
Alterations in the basal ganglia circuitry are critical events in the pathophysiology of Parkinson's disease (PD). We earlier compared MPTP-susceptible C57BL/6J and MPTP-resistant CD-1 mice to understand the differential prevalence of PD in different ethnic populations like Caucasians and Asian-Indians. The MPTP-resistant CD-1 mice had 33% more nigral neurons and lost only 15-17% of them following MPTP administration. In addition to other cytomorphological features, their basal ganglia neurons had higher calcium-buffering protein levels. During disease pathogenesis as well as in MPTP-induced parkinsonian models, the loss of nigral neurons is associated with reduction in mitochondrial complex-1. Under these conditions, mitochondria respond by undergoing fusion or fission. 17β-hydroxysteroid type 10, i.e., hydroxysteroid dehydrogenase10 (HSD10) and dynamin-related peptide1 (Drp1) are proteins involved in mitochondrial hyperfusion and fission, respectively. Each plays an important role in mitochondrial structure and homeostasis. Their role in determining susceptibility to the neurotoxin MPTP in basal ganglia is however unclear. We studied their expression using immunohistochemistry and Western blotting in the dorsolateral striatum, ventral tegmental area, and substantia nigra pars compacta (SNpc) of C57BL/6J and CD-1 mice. In the SNpc, which exhibits more neuron loss following MPTP, C57BL/6J had higher baseline Drp1 levels; suggesting persistence of fission under normal conditions. Whereas, HSD10 levels increased in CD-1 following MPTP administration. This suggests mitochondrial hyperfusion, as an attempt towards neuroprotection. Thus, the baseline differences in HSD10 and DRP1 levels as well as their contrasting MPTP-responses may be critical determinants of the magnitude of neuronal loss/survival. Similar differences may determine the variable susceptibility to PD in humans.
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Affiliation(s)
- Akshaya Seshadri
- Department of Neuroscience, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India
| | - Phalguni Anand Alladi
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India.
- Department of Clinical Pharmacology and Toxicology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bengaluru, 560029, India.
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Sbodio JI, Snyder SH, Paul BD. Redox Mechanisms in Neurodegeneration: From Disease Outcomes to Therapeutic Opportunities. Antioxid Redox Signal 2019; 30:1450-1499. [PMID: 29634350 PMCID: PMC6393771 DOI: 10.1089/ars.2017.7321] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 03/16/2018] [Accepted: 03/18/2018] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Once considered to be mere by-products of metabolism, reactive oxygen, nitrogen and sulfur species are now recognized to play important roles in diverse cellular processes such as response to pathogens and regulation of cellular differentiation. It is becoming increasingly evident that redox imbalance can impact several signaling pathways. For instance, disturbances of redox regulation in the brain mediate neurodegeneration and alter normal cytoprotective responses to stress. Very often small disturbances in redox signaling processes, which are reversible, precede damage in neurodegeneration. Recent Advances: The identification of redox-regulated processes, such as regulation of biochemical pathways involved in the maintenance of redox homeostasis in the brain has provided deeper insights into mechanisms of neuroprotection and neurodegeneration. Recent studies have also identified several post-translational modifications involving reactive cysteine residues, such as nitrosylation and sulfhydration, which fine-tune redox regulation. Thus, the study of mechanisms via which cell death occurs in several neurodegenerative disorders, reveal several similarities and dissimilarities. Here, we review redox regulated events that are disrupted in neurodegenerative disorders and whose modulation affords therapeutic opportunities. CRITICAL ISSUES Although accumulating evidence suggests that redox imbalance plays a significant role in progression of several neurodegenerative diseases, precise understanding of redox regulated events is lacking. Probes and methodologies that can precisely detect and quantify in vivo levels of reactive oxygen, nitrogen and sulfur species are not available. FUTURE DIRECTIONS Due to the importance of redox control in physiologic processes, organisms have evolved multiple pathways to counteract redox imbalance and maintain homeostasis. Cells and tissues address stress by harnessing an array of both endogenous and exogenous redox active substances. Targeting these pathways can help mitigate symptoms associated with neurodegeneration and may provide avenues for novel therapeutics. Antioxid. Redox Signal. 30, 1450-1499.
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Affiliation(s)
- Juan I. Sbodio
- The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Solomon H. Snyder
- The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bindu D. Paul
- The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Chen D, Zhang XY, Sun J, Cong QJ, Chen WX, Ahsan HM, Gao J, Qian JJ. Asiatic Acid Protects Dopaminergic Neurons from Neuroinflammation by Suppressing Mitochondrial Ros Production. Biomol Ther (Seoul) 2019; 27:442-449. [PMID: 30971058 PMCID: PMC6720531 DOI: 10.4062/biomolther.2018.188] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/20/2018] [Accepted: 02/20/2019] [Indexed: 11/05/2022] Open
Abstract
This study sought to evaluate the effects of Asiatic acid in LPS-induced BV2 microglia cells and 1-methyl-4-phenyl-pyridine (MPP+)-induced SH-SY5Y cells, to investigate the potential anti-inflammatory mechanisms of Asiatic acid in Parkinsons disease (PD). SH-SY5Y cells were induced using MPP+ to establish as an in vitro model of PD, so that the effects of Asiatic acid on dopaminergic neurons could be examined. The NLRP3 inflammasome was activated in BV2 microglia cells to explore potential mechanisms for the neuroprotective effects of Asiatic acid. We showed that Asiatic acid reduced intracellular production of mitochondrial reactive oxygen species and altered the mitochondrial membrane potential to regulate mitochondrial dysfunction, and suppressed the NLRP3 inflammasome in microglia cells. We additionally found that treatment with Asiatic acid directly improved SH-SY5Y cell viability and mitochondrial dysfunction induced by MPP+. These data demonstrate that Asiatic acid both inhibits the activation of the NLRP3 inflammasome by downregulating mitochondrial reactive oxygen species directly to protect dopaminergic neurons from, and improves mitochondrial dysfunction in SH-SY5Y cells, which were established as a model of Parkinsons disease. Our finding reveals that Asiatic acid protects dopaminergic neurons from neuroinflammation by suppressing NLRP3 inflammasome activation in microglia cells as well as protecting dopaminergic neurons directly. This suggests a promising clinical use of Asiatic acid for PD therapy.
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Affiliation(s)
- Dong Chen
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Xiao-Ya Zhang
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Jing Sun
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qi-Jie Cong
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Wei-Xiong Chen
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Hafiz Muhammad Ahsan
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China.,Department of Pharmacology, Faculty of Pharmacy, University of Central Punjab, Lahore 53000, Pakistan
| | - Jing Gao
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Jin-Jun Qian
- Department of Neurology, The Fourth People's Hospital of Zhenjiang, Zhenjiang 212013, China
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Arige V, Agarwal A, Khan AA, Kalyani A, Natarajan B, Gupta V, Reddy SS, Barthwal MK, Mahapatra NR. Regulation of Monoamine Oxidase B Gene Expression: Key Roles for Transcription Factors Sp1, Egr1 and CREB, and microRNAs miR-300 and miR-1224. J Mol Biol 2019; 431:1127-1147. [PMID: 30738894 DOI: 10.1016/j.jmb.2019.01.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/18/2019] [Accepted: 01/29/2019] [Indexed: 11/15/2022]
Abstract
Monoamine oxidase B (MAO-B), a flavoenzyme located in the outer mitochondrial membrane, is involved in the catabolism of monoamines. Altered levels of MAO-B are associated with cardiovascular/neuronal diseases. However, molecular mechanisms of MAO-B gene regulation are partially understood. We undertook a systematic analysis of the MAO-B gene to identify the key transcriptional/post-transcriptional regulatory molecules. Expression of MAO-B promoter-reporter constructs in cultured cells identified the -144/+25-bp domain as the core promoter region. Stringent in silico analysis of this core promoter predicted binding sites for several transcription factors. Over-expression/down-regulation of transcription factors Sp1/Egr1/CREB increased/decreased the MAO-B promoter-reporter activity and endogenous MAO-B protein level. Electrophoretic mobility shift assays and ChIP assays provided evidence for interactions of Sp1/Egr1/CREB with the MAO-B promoter. MAOB transcript level also positively correlated with the transcript level of Sp1/Egr1/CREB in various human tissue samples. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed direct interactions of the microRNAs miR-1224 and miR-300 with MAO-B 3'-UTR. Dopamine dose-dependently enhanced MAO-B transcript and protein levels via increased binding of CREB to MAO-B promoter and reduced miR-1224/miR-300 levels. 8-Bromo-cAMP and forskolin augmented MAO-B expression, whereas inhibition of PKA diminished the gene expression suggesting involvement of cAMP-PKA axis. Interestingly, Sp1/Egr1/CREB/miR-1224 levels correlate with MAO-B expression in rodent models of hypertension/MPTP-induced neurodegeneration, indicating their roles in governing MAO-B gene expression in these disease states. Taken together, this study elucidates the previously unknown roles of the transcription factors Sp1/Egr1/CREB and microRNAs miR-1224/miR-300 in regulating MAO-B gene expression under basal/disease states involving dysregulated catecholamine levels.
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Affiliation(s)
- Vikas Arige
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Anshu Agarwal
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Abrar A Khan
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Ananthamohan Kalyani
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Bhargavi Natarajan
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - Vinayak Gupta
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
| | - S Santosh Reddy
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
| | - Manoj K Barthwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Nitish R Mahapatra
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
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