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Wu X, Yang Z, Zou J, Gao H, Shao Z, Li C, Lei P. Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery. Signal Transduct Target Ther 2025; 10:146. [PMID: 40328798 PMCID: PMC12056177 DOI: 10.1038/s41392-025-02179-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/03/2025] [Accepted: 02/12/2025] [Indexed: 05/08/2025] Open
Abstract
Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.
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Affiliation(s)
- Xiaolei Wu
- Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhangzhong Yang
- Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jinjun Zou
- Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huile Gao
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Zhenhua Shao
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chuanzhou Li
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Peng Lei
- Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Soni R, Pankaj V, Roy S, Khairnar A, Shah J. Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson's Disease Mouse Models. ACS Chem Neurosci 2025; 16:1402-1417. [PMID: 40127285 DOI: 10.1021/acschemneuro.5c00112] [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] [Indexed: 03/26/2025] Open
Abstract
Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.
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Affiliation(s)
- Ritu Soni
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Vaishali Pankaj
- Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Brno 61600, Czechia
| | - Sudeep Roy
- Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Brno 61600, Czechia
| | - Amit Khairnar
- International Clinical Research Centre, St. Anne's University Hospital Brno (FNUSA-ICRC), Brno 60200, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno 62500, Czechia
- International Clinical Research Centre, Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno 62500, Czechia
| | - Jigna Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
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Rahmatkar SN, Singh D. Decoding the Role of Neurotrophins in Glycogen Synthase Kinase 3-Beta Regulation in Alzheimer's Disease. Mol Neurobiol 2025:10.1007/s12035-025-04776-x. [PMID: 40014269 DOI: 10.1007/s12035-025-04776-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 02/11/2025] [Indexed: 02/28/2025]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most prevalent contributor to dementia in elderly individuals. Numerous signalling pathways influencing AD pathophysiology, involving glycogen synthase kinase-3β (Gsk-3β), have been investigated extensively as potential therapeutic targets. Gsk-3β is a critical factor in AD pathogenesis that affects several key hallmarks of the disease notably tau phosphorylation, amyloid-β generation, cognition, neurogenesis, and synaptic integrity. Neurotrophins are small proteins that are critical for maintaining neuronal health and function and may be used to treat neurodegenerative diseases. Notably, the dysregulation of certain neurotrophins and their receptors is also linked with AD which is a major contributor to neurodegeneration. Studies indicated that neurotrophins and their modulators are capable of protecting neurons by blocking the Gsk-3β activity suggesting a potential link for neuroprotection. Neurotrophins support the survival of neurons by regulating Gsk-3β activity. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) signalling pathways activate Trk receptors that trigger downstream signalling cascades that subsequently inhibit Gsk-3β activity and reduce AD-related neuropathology. We also explore the role of modulators including phosphatases, kinase cascades, and other regulatory proteins that cross paths with neurotrophin-Gsk-3β signalling. In conclusion, this manuscript summarizes both direct and indirect regulatory roles of neurotrophins and modulators on Gsk-3β to understand the intricate mechanisms driving neurodegeneration in AD.
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Affiliation(s)
- Shubham Nilkanth Rahmatkar
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR)), Ghaziabad, 201002, India
| | - Damanpreet Singh
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India.
- Academy of Scientific and Innovative Research (AcSIR)), Ghaziabad, 201002, India.
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Ren J, Bai W, Guo Y, Liu Q, Wang Y, Wang C. Maternal Bisphenol A Exposure Induces Hippocampal-Dependent Learning and Memory Deficits Through the PI3K/Akt/mTOR Pathway in Male Offspring Rats. J Biochem Mol Toxicol 2025; 39:e70100. [PMID: 39799553 DOI: 10.1002/jbt.70100] [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: 05/13/2024] [Revised: 10/18/2024] [Accepted: 12/08/2024] [Indexed: 01/15/2025]
Abstract
Bisphenol A (BPA), an environmental endocrine disrupting chemical, is one of the most widely used chemicals in the world and is widely distributed in the external environment, specifically in food, water, dust, and soil. BPA exposure is associated with abnormal cognitive behaviors. However, the underlying mechanism remains unclear. In this study, pregnant female Sprague Dawley rats were orally exposed to BPA at a low dose of 0, 0.04, 0.4, or 4 mg per kg·of body weight per day from embryonic Day 0 (ED 0) to postnatal Day 21 (PND 21). Spatial learning and memory were measured via a Morris water maze test on PND 22. PI3K/Akt/mTOR signaling pathway protein expression was detected in the hippocampi of male offspring using a western blot. The water maze test demonstrated that BPA exposure considerably reduced the learning and memory capacities of the male offspring exposure groups when compared to the control group. The male offspring rats' latency to escape increased significantly, the time taken to traverse a platform reduced, and latency to find a hidden platform showed an increasing trend. Meanwhile, maternal exposure to BPA downregulated the expression of PI3K/Akt/mTOR/p70S6K pathway in the hippocampi of the offspring. Moreover, BPA exposure improved the GSK3β and phosphorylated tau protein (T231) levels, increased malondialdehyde levels, and activated caspase-3 expression in the hippocampi of the male offspring rats. Taken together, these findings indicate that maternal exposure to BPA causes learning and memory impairment and that the PI3K/Akt/mTOR pathway participates in the mechanism of BPA-induced neurocognitive decline.
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Affiliation(s)
- Jiajia Ren
- College of Health Public, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Wenjie Bai
- College of Health Public, Shaanxi University of Chinese Medicine, Xianyang, China
- Nursing College, Shanxi Datong University, Datong, China
| | - Yi Guo
- College of Health Public, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Qiling Liu
- College of Health Public, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Yuxin Wang
- College of Health Public, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Chong Wang
- Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, China
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Soni R, Mathur K, Rathod H, Khairnar A, Shah J. Hyperglycemia-Driven Insulin Signaling Defects Promote Parkinson's Disease-like Pathology in Mice. ACS Pharmacol Transl Sci 2024; 7:4155-4164. [PMID: 39698281 PMCID: PMC11650731 DOI: 10.1021/acsptsci.4c00586] [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: 10/07/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 12/20/2024]
Abstract
This study aims to determine the effect of chronic hyperglycemia, induced by a high-fat diet and STZ-induced diabetes, on the development of Parkinson's disease-like characteristics. Understanding this relationship is crucial in pharmacology, neurology, and diabetes, as it could potentially lead to developing new therapeutic strategies for Parkinson's disease. Our study employed a comprehensive approach to investigate the effect of hyperglycemia on Parkinson's disease-like characteristics. Hyperglycemia was induced by a high-fat diet for 6- and 9-week duration with a single intraperitoneal STZ (100 mg/kg) injection at week 5 in C57/BL6 mice. Rotenone (10 mg/kg p.o.) was administered to C57/BL6 mice for 6 and 9 weeks. Time-dependent behavioral studies (wire-hang tests, pole tests, Y-maze tests, and round beam walk tests) were carried out to monitor pathology progression and deficits. Molecular protein levels (GLP1, PI3K, AKT, GSK-3β, NF-κB, and α-syn), oxidative stress (GSH and MDA) parameters, and histopathological alterations (H&E and Nissl staining) were determined after 6 weeks as well as 9 weeks. After 9 weeks of study, molecular protein expression (p-AKT and p-α-syn) was determined. Hyperglycemia induced by HFD and STZ induced significant motor impairment in mice, correlated with the rotenone group. Insulin receptor signaling (GLP1/PI3K/AKT) was found to be disrupted in the HFD+STZ group and also in rotenone-treated mice, which further enhanced phosphorylation of α-syn, suggesting its role in α-syn accumulation. Histopathological alterations indicating neuroinflammation and neurodegeneration were quite evident in the HFD+STZ and rotenone groups. Exposure to hyperglycemia induced by HFD+STZ administration exhibits PD-like characteristics after 9 weeks of duration, which was correlative with rotenone-induced PD-like symptoms.
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Affiliation(s)
- Ritu Soni
- Department
of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Kirti Mathur
- Department
of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Hritik Rathod
- Department
of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Amit Khairnar
- International
Clinical Research Centre, St. Anne’s
University Hospital, Brno, Czech Republic, ICRC, FNUSA, Brno 60200, Czechia
- Department
of Physiology, Faculty of Medicine, Masaryk
University, Kamenice
753/5, Brno 62500, Czechia
- International
Clinical Research Centre, Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno 62500, Czechia
| | - Jigna Shah
- Department
of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
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Mathuram TL. GSK-3: An "Ace" Among Kinases. Cancer Biother Radiopharm 2024; 39:619-631. [PMID: 38746994 DOI: 10.1089/cbr.2024.0025] [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] [Indexed: 11/13/2024] Open
Abstract
Background: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase known to participate in the regulation of β-catenin signaling (Wnt signaling). This aids in the establishment of a multicomponent destruction complex that stimulates phosphorylation, leading to the destruction of β-catenin. Evidence about the role of increasingly active β-catenin signaling is involved in many forms of human cancer. The understanding of GSK-3 remains elusive as recent research aims to focus on developing potent GSK-3 inhibitors to target this kinase. Objective: This short review aims to highlight the regulation of GSK-3 with emphasis on Wnt signaling while highlighting its interaction with miRNAs corresponding to pluripotency and epithelial mesenchymal transition substantiating this kinase as an "Ace" among kinases in regulation of cellular processes. Result: Significant findings of miRNA regulation by GSK-3 exemplify the underpinnings of kinase-mediated transcriptional regulation in cancers. Conclusion: The review provides evidence on the role of GSK-3 as a possible master regulator of proteins and noncoding RNA, thereby implicating the fate of a cell.
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Patel D, Soni R, Shah J. Decoding the Role of Nuclear Sirtuins in Parkinson's Pathogenesis. ACS Chem Neurosci 2024. [PMID: 39331405 DOI: 10.1021/acschemneuro.4c00507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2024] Open
Abstract
Parkinson's disease (PD) is the second most prevailing degenerative disease that deals with dopaminergic neuronal loss and deficiency of dopamine in SNpc and striatum. Manifestations primarily include motor symptoms like tremor, rigidity, and akinesia/dyskinesia along with some nonmotor symptoms like GI and olfactory dysfunction. α-Synuclein pathogenesis is the major cause behind progression of PD; however there are many underlying molecular mechanisms behind the pathophysiology of PD. Sirtuins are small molecular deacetylases that have an imperative role in pathology of such neurodegenerative disorders like PD. Sirtuins are majorly classified according to their location; nuclear (SIRT1,7,6), mitochondrial sirtuins (SIRT3-5), and cytosolic (SIRT2). These actively take part in pathological development and possess independent actions. In this review, the role of nuclear sirtuins is individualistically explored for better understanding of PD pathology and development of advanced therapeutics targeting sirtuins.
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Affiliation(s)
- Dishank Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Ritu Soni
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Jigna Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
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8
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Turkistani A, Al-Kuraishy HM, Al-Gareeb AI, Albuhadily AK, Alexiou A, Papadakis M, Elfiky MM, Saad HM, Batiha GES. Therapeutic Potential Effect of Glycogen Synthase Kinase 3 Beta (GSK-3β) Inhibitors in Parkinson Disease: Exploring an Overlooked Avenue. Mol Neurobiol 2024; 61:7092-7108. [PMID: 38367137 PMCID: PMC11338983 DOI: 10.1007/s12035-024-04003-z] [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: 09/24/2023] [Accepted: 01/20/2024] [Indexed: 02/19/2024]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease of the brain due to degeneration of dopaminergic neurons in the substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3β) is implicated in the pathogenesis of PD. Therefore, the purpose of the present review was to revise the mechanistic role of GSK-3β in PD neuropathology, and how GSK-3β inhibitors affect PD neuropathology. GSK-3 is a conserved threonine/serine kinase protein that is intricate in the regulation of cellular anabolic and catabolic pathways by modulating glycogen synthase. Over-expression of GSK-3β is also interconnected with the development of different neurodegenerative diseases. However, the underlying mechanism of GSK-3β in PD neuropathology is not fully clarified. Over-expression of GSK-3β induces the development of PD by triggering mitochondrial dysfunction and oxidative stress in the dopaminergic neurons of the SN. NF-κB and NLRP3 inflammasome are activated in response to dysregulated GSK-3β in PD leading to progressive neuronal injury. Higher expression of GSK-3β in the early stages of PD neuropathology might contribute to the reduction of neuroprotective brain-derived neurotrophic factor (BDNF). Thus, GSK-3β inhibitors may be effective in PD by reducing inflammatory and oxidative stress disorders which are associated with degeneration of dopaminergic in the SN.
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Affiliation(s)
- Areej Turkistani
- Department of Pharmacology and Toxicology, College of Medicine, Taif University, 21944, Taif, Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq
| | - Ali K Albuhadily
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq
| | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India
- Department of Research & Development, Funogen, Athens, Greece
- Department of Research & Development, AFNP Med, 1030, Vienna, Austria
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, 2770, Australia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, Heusnerstrasse 40, University of Witten-Herdecke, 42283, Wuppertal, Germany.
| | - Mohamed M Elfiky
- Anatomy Department, General Medicine Practice Program, Batterjee Medical College, Jeddah, Saudi Arabia
- Anatomy Department, Faculty of Medicine, Menoufia University, Shibin El Kom, Al Minufya, Egypt
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, 51744, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt
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Gundam SR, Bansal A, Kethamreddy M, Ghatamaneni S, Lowe VJ, Murray ME, Pandey MK. Synthesis and preliminary evaluation of novel PET probes for GSK-3 imaging. Sci Rep 2024; 14:15960. [PMID: 38987294 PMCID: PMC11237012 DOI: 10.1038/s41598-024-65943-z] [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: 11/20/2023] [Accepted: 06/25/2024] [Indexed: 07/12/2024] Open
Abstract
Non-invasive imaging of GSK-3 expression in the brain will help to understand the role of GSK-3 in disease pathology and progression. Herein, we report the radiosynthesis and evaluation of two novel isonicotinamide based 18F labeled PET probes, [18F]2 and [18F]6 for noninvasive imaging of GSK3. Among the developed PET probes, the in vitro blood-brain permeability coefficient of 2 (38 ± 20 × 10-6 cm/s, n = 3) was found to be better than 6 (8.75 ± 3.90 × 10-6 cm/s, n = 5). The reference compounds 2 and 6 showed nanomolar affinity towards GSK-3α and GSK-3β. PET probe [18F]2 showed higher stability (100%) in mouse and human serums compared to [18F]6 (67.01 ± 4.93%, n = 3) in mouse serum and 66.20 ± 6.38%, n = 3) in human serum at 120 min post incubation. The in vivo imaging and blocking studies were performed in wild-type mice only with [18F]2 due to its observed stability. [18F]2 showed a SUV of 0.92 ± 0.28 (n = 6) in mice brain as early as 5 min post-injection followed by gradual clearance over time.
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Affiliation(s)
- Surendra Reddy Gundam
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Aditya Bansal
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Manasa Kethamreddy
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Sujala Ghatamaneni
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Val J Lowe
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Melissa E Murray
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Mukesh K Pandey
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
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Hemmati F, Valian N, Ahmadiani A, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Hosseini Shirazi SF. Insulin and TLR4 Inhibitor Improve Motor Impairments in a Rat Model of Parkinson's Disease. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2024; 23:e144200. [PMID: 39830652 PMCID: PMC11742580 DOI: 10.5812/ijpr-144200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/12/2024] [Accepted: 05/06/2024] [Indexed: 01/22/2025]
Abstract
Background Insulin resistance is an important pathological hallmark of Parkinson's disease (PD). Proinflammatory cytokines during neuroinflammation decrease insulin sensitivity by suppressing insulin signaling elements. Toll-like receptor 4 (TLR4), the main receptor involved in neuroinflammation, is also associated with the pathogenesis of PD. Objectives The present study evaluated the effect of insulin, an insulin receptor antagonist, and a TLR4 inhibitor on behavioral deficits and insulin resistance induced by 6-hydroxydopamine (6-OHDA). Methods Male Wistar rats were divided into nine groups: (1) sham (normal saline [NS] in the medial forebrain bundle [MFB]); (2) 6-OHDA (20 µg in the MFB); (3) 6-OHDA + NS; (4) 6-OHDA + dimethyl sulfoxide (DMSO); (5) 6-OHDA + insulin (2.5 IU/day, intracerebroventricular ([ICV]); (6) 6-OHDA + insulin (5 IU/day, intranasal [IN]); (7) 6-OHDA + insulin receptor antagonist (S961; 6.5 nM/kg, ICV); (8) 6-OHDA + TLR4 inhibitor (TAK242; 0.01 µg/rat, ICV); (9) 6-OHDA + insulin + TLR4 inhibitor. All treatments were administered for seven consecutive days. Motor performance was evaluated using apomorphine-induced rotation and cylinder tests. Gene expression and protein levels of α-synuclein, TLR4, insulin receptor substrate (IRS) 1, IRS2, and glycogen synthase kinase 3β (GSK3β) were measured by real-time PCR and western blotting, respectively, in the striatum. Results Insulin, alone and with TAK242, improved motor deficits induced by 6-OHDA. Administration of the insulin receptor antagonist had no effect on motor deficits. The increased expression of α-synuclein and TLR4 following 6-OHDA was attenuated by insulin and TAK242. GSK3β levels, both mRNA and protein, were significantly increased by 6-OHDA and attenuated with insulin and TAK242. Conclusions The findings suggest that 6-OHDA induces neurodegeneration via activation of TLR4 and GSK3β, indicating insulin resistance, and that insulin can improve these impairments. Moreover, TLR4 inhibition prevents insulin signaling dysfunction and improves behavioral and molecular impairments, highlighting the critical role of TLR4 in the development of insulin resistance in PD pathology.
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Affiliation(s)
- Fatemeh Hemmati
- Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Valian
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahurin Mohamed
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Raymond Azman Ali
- Department of Medicine, University Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Norlinah Mohamed Ibrahim
- Department of Medicine, University Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Seyed Farshad Hosseini Shirazi
- Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Sai Varshini M, Reddy RA, Krishnamurthy PT, Selvaraj D. Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3β. Curr Comput Aided Drug Des 2024; 20:998-1012. [PMID: 37921183 DOI: 10.2174/0115734099270256231018072007] [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: 07/31/2023] [Revised: 09/05/2023] [Accepted: 09/13/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively. METHODS We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β. RESULTS Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies. CONCLUSION Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.
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Affiliation(s)
- Magham Sai Varshini
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | - Ramakkamma Aishwarya Reddy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | | | - Divakar Selvaraj
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
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Kakraba S, Ayyadevara S, Mainali N, Balasubramaniam M, Bowroju S, Penthala NR, Atluri R, Barger SW, Griffin ST, Crooks PA, Shmookler Reis RJ. Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan. Pharmaceuticals (Basel) 2023; 16:1498. [PMID: 37895969 PMCID: PMC10610358 DOI: 10.3390/ph16101498] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/29/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer's disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1-42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and "healthspan" (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15-30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.
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Affiliation(s)
- Samuel Kakraba
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
| | - Srinivas Ayyadevara
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
- Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA
| | - Nirjal Mainali
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
| | - Meenakshisundaram Balasubramaniam
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
| | - Suresh Bowroju
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.B.); (N.R.P.); (P.A.C.)
| | - Narsimha Reddy Penthala
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.B.); (N.R.P.); (P.A.C.)
| | - Ramani Atluri
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
| | - Steven W. Barger
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
- Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA
| | - Sue T. Griffin
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
- Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA
| | - Peter A. Crooks
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.B.); (N.R.P.); (P.A.C.)
| | - Robert J. Shmookler Reis
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (N.M.); (M.B.); (R.A.); (S.W.B.); (S.T.G.)
- Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA
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Kumar S, Senapati S, Bhattacharya N, Bhattacharya A, Maurya SK, Husain H, Bhatti JS, Pandey AK. Mechanism and recent updates on insulin-related disorders. World J Clin Cases 2023; 11:5840-5856. [PMID: 37727490 PMCID: PMC10506040 DOI: 10.12998/wjcc.v11.i25.5840] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 07/06/2023] [Accepted: 08/07/2023] [Indexed: 09/01/2023] Open
Abstract
Insulin, a small protein with 51 amino acids synthesized by pancreatic β-cells, is crucial to sustain glucose homeostasis at biochemical and molecular levels. Numerous metabolic dysfunctions are related to insulin-mediated altered glucose homeostasis. One of the significant pathophysiological conditions linked to the insulin associated disorder is diabetes mellitus (DM) (type 1, type 2, and gestational). Insulin resistance (IR) is one of the major underlying causes of metabolic disorders despite its association with several physiological conditions. Metabolic syndrome (MS) is another pathophysiological condition that is associated with IR, hypertension, and obesity. Further, several other pathophysiological disorders/diseases are associated with the insulin malfunctioning, which include polycystic ovary syndrome, neuronal disorders, and cancer. Insulinomas are an uncommon type of pancreatic β-cell-derived neuroendocrine tumor that makes up 2% of all pancreatic neoplasms. Literature revealed that different biochemical events, molecular signaling pathways, microRNAs, and microbiota act as connecting links between insulin disorder and associated pathophysiology such as DM, insuloma, neurological disorder, MS, and cancer. In this review, we focus on the insulin-related disorders and the underlying mechanisms associated with the pathophysiology.
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Affiliation(s)
- Shashank Kumar
- Department of Biochemistry, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sabyasachi Senapati
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Neetu Bhattacharya
- Department of Zoology, Dyal Singh College, University of Delhi, New Delhi 110003, India
| | - Amit Bhattacharya
- Department of Zoology, Ramjas College, University of Delhi, New Delhi 110007, India
| | | | - Hadiya Husain
- Department of Zoology, University of Lucknow, Lucknow 226007, India
| | - Jasvinder Singh Bhatti
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abhay Kumar Pandey
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, India
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Basli A, Bounaas J. Pathophysiological mechanism and natural preventive and therapeutic strategies of Alzheimer's disease. Nutr Health 2023; 29:403-413. [PMID: 36377316 DOI: 10.1177/02601060221137104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Alzheimer's disease (AD) is characterized by the presence of two types of protein deposits in the brain, amyloid plaques and neurofibrillary tangles. The first one are dense deposits of beta amyloid protein, the second one are dense deposits of the protein tau. These proteins are present in all of our brains, but in AD they act unusually, leading to neuronal degeneration. This review will provide an overview of the AD, including the role of amyloid beta and tau, and mechanisms that lead to the formation of plaques and tangles. The review will also cover the existing researches that have focused on the inhibition of amyloid beta formation, cholinesterase, tau hyperphosphorylation, the pathogenic mechanisms of apoE4, and GSK-3 as a solution that could be used to slow or prevent the disease.
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Affiliation(s)
- Abdelkader Basli
- Laboratory of Interaction Research, Biodiversity, Ecosystems and Biotechnology, Faculty of Sciences, University of Skikda, Skikda, Algeria
| | - Jihane Bounaas
- Laboratory of Interaction Research, Biodiversity, Ecosystems and Biotechnology, Faculty of Sciences, University of Skikda, Skikda, Algeria
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15
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Balboni B, Masi M, Rocchia W, Girotto S, Cavalli A. GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier? Int J Mol Sci 2023; 24:7541. [PMID: 37108703 PMCID: PMC10139115 DOI: 10.3390/ijms24087541] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.
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Affiliation(s)
- Beatrice Balboni
- Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; (B.B.); (M.M.)
| | - Mirco Masi
- Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; (B.B.); (M.M.)
| | - Walter Rocchia
- Computational mOdelling of NanosCalE and bioPhysical sysTems (CONCEPT) Lab, Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16152 Genoa, Italy
| | - Stefania Girotto
- Structural Biophysics and Translational Pharmacology Facility, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Andrea Cavalli
- Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; (B.B.); (M.M.)
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16
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Samim Khan S, Janrao S, Srivastava S, Bala Singh S, Vora L, Kumar Khatri D. GSK-3β: An exuberating neuroinflammatory mediator in Parkinson's disease. Biochem Pharmacol 2023; 210:115496. [PMID: 36907495 DOI: 10.1016/j.bcp.2023.115496] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/02/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023]
Abstract
Neuroinflammation is a critical degradative condition affecting neurons in the brain. Progressive neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease (PD) have been strongly linked to neuroinflammation. The trigger point for inflammatory conditions in the cells and body is the physiological immune system. The immune response mediated by glial cells and astrocytes can rectify the physiological alterations occurring in the cell for the time being but prolonged activation leads to pathological progression. The proteins mediating such an inflammatory response, as per the available literature, are undoubtedly GSK-3β, NLRP3, TNF, PPARγ, and NF-κB, along with a few other mediatory proteins. NLRP3 inflammasome is undeniably a principal instigator of the neuroinflammatory response, but the regulatory pathways controlling its activation are still unclear, besides less clarity for the interplay between different inflammatory proteins. Recent reports have suggested the involvement of GSK-3β in regulating NLRP3 activation, but the exact mechanistic pathway remains vague. In the current review, we attempt to provide an elaborate description of crosstalk between inflammatory markers and GSK-3β mediated neuroinflammation progression, linking it to regulatory transcription factors and posttranslational modification of proteins. The recent clinical therapeutic advances targeting these proteins are also discussed in parallel to provide a comprehensive view of the progress made in PD management and lacunas still existing in the field.
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Affiliation(s)
- Sabiya Samim Khan
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India
| | - Sushmita Janrao
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
| | - Shashi Bala Singh
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
| | - Lalitkumar Vora
- School of Pharmacy, Queen's University Belfast, 97, Lisburn Road, Belfast BT9 7BL, UK.
| | - Dharmendra Kumar Khatri
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
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Mehta SL, Kim T, Chelluboina B, Vemuganti R. Tau and GSK-3β are Critical Contributors to α-Synuclein-Mediated Post-Stroke Brain Damage. Neuromolecular Med 2023; 25:94-101. [PMID: 36447045 PMCID: PMC10249510 DOI: 10.1007/s12017-022-08731-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/13/2022] [Indexed: 12/03/2022]
Abstract
Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn-positive inclusions are often present in tauopathies and elevated tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein-protein interaction of α-Syn with both GSK-3β and tau and elevated tau phosphorylation. Treatment with a GSK-3β inhibitor prevented post-ischemic tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-ischemic GSK-3β-dependent tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Moreover, tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3β catalyzes the α-Syn-dependent tau phosphorylation and preventing this interaction is crucial to limit post-ischemic secondary brain damage.
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Affiliation(s)
- Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave, Madison, WI, 53792, USA
| | - TaeHee Kim
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave, Madison, WI, 53792, USA
| | - Bharath Chelluboina
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave, Madison, WI, 53792, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin-Madison, Mail Code CSC-8660, 600 Highland Ave, Madison, WI, 53792, USA.
- William S. Middleton Veterans Administration Hospital, Madison, WI, USA.
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18
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Role of Tau in Various Tauopathies, Treatment Approaches, and Emerging Role of Nanotechnology in Neurodegenerative Disorders. Mol Neurobiol 2023; 60:1690-1720. [PMID: 36562884 DOI: 10.1007/s12035-022-03164-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022]
Abstract
A few protein kinases and phosphatases regulate tau protein phosphorylation and an imbalance in their enzyme activity results in tau hyper-phosphorylation. Aberrant tau phosphorylation causes tau to dissociate from the microtubules and clump together in the cytosol to form neurofibrillary tangles (NFTs), which lead to the progression of neurodegenerative disorders including Alzheimer's disease (AD) and other tauopathies. Hence, targeting hyperphosphorylated tau protein is a restorative approach for treating neurodegenerative tauopathies. The cyclin-dependent kinase (Cdk5) and the glycogen synthase kinase (GSK3β) have both been implicated in aberrant tau hyperphosphorylation. The limited transport of drugs through the blood-brain barrier (BBB) for reaching the central nervous system (CNS) thus represents a significant problem in the development of drugs. Drug delivery systems based on nanocarriers help solve this problem. In this review, we discuss the tau protein, regulation of tau phosphorylation and abnormal hyperphosphorylation, drugs in use or under clinical trials, and treatment strategies for tauopathies based on the critical role of tau hyperphosphorylation in the pathogenesis of the disease. Pathology of neurodegenerative disease due to hyperphosphorylation and various therapeutic approaches including nanotechnology for its treatment.
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Smart K, Zheng MQ, Holden D, Felchner Z, Zhang L, Han Y, Ropchan J, Carson RE, Vasdev N, Huang Y. In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [ 11C]OCM-44 and [ 18F]OCM-50 in Non-Human Primates. Pharmaceuticals (Basel) 2023; 16:194. [PMID: 37259346 PMCID: PMC9959234 DOI: 10.3390/ph16020194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 11/19/2023] Open
Abstract
Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39-0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.
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Affiliation(s)
- Kelly Smart
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada
- Department of Psychiatry, University of Toronto, 250 College St., Toronto, ON M5T 1R8, Canada
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Ming-Qiang Zheng
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Daniel Holden
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Zachary Felchner
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Li Zhang
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Yanjiang Han
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
- Nanfang Hospital, Southern Medical University, 1838 Guangzhou Blvd North, Guangzhou 510515, China
| | - Jim Ropchan
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Richard E. Carson
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
| | - Neil Vasdev
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada
- Department of Psychiatry, University of Toronto, 250 College St., Toronto, ON M5T 1R8, Canada
| | - Yiyun Huang
- Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA
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Holubiec MI, Gellert M, Hanschmann EM. Redox signaling and metabolism in Alzheimer's disease. Front Aging Neurosci 2022; 14:1003721. [PMID: 36408110 PMCID: PMC9670316 DOI: 10.3389/fnagi.2022.1003721] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/14/2022] [Indexed: 08/11/2023] Open
Abstract
Reduction and oxidation reactions are essential for biochemical processes. They are part of metabolic pathways and signal transduction. Reactive oxygen species (ROS) as second messengers and oxidative modifications of cysteinyl (Cys) residues are key to transduce and translate intracellular and intercellular signals. Dysregulation of cellular redox signaling is known as oxidative distress, which has been linked to various pathologies, including neurodegeneration. Alzheimer's disease (AD) is a neurodegenerative pathology linked to both, abnormal amyloid precursor protein (APP) processing, generating Aβ peptide, and Tau hyperphosphorylation and aggregation. Signs of oxidative distress in AD include: increase of ROS (H2O2, O2 •-), decrease of the levels or activities of antioxidant enzymes, abnormal oxidation of macromolecules related to elevated Aβ production, and changes in mitochondrial homeostasis linked to Tau phosphorylation. Interestingly, Cys residues present in APP form disulfide bonds that are important for intermolecular interactions and might be involved in the aggregation of Aβ. Moreover, two Cys residues in some Tau isoforms have been shown to be essential for Tau stabilization and its interaction with microtubules. Future research will show the complexities of Tau, its interactome, and the role that Cys residues play in the progression of AD. The specific modification of cysteinyl residues in redox signaling is also tightly connected to the regulation of various metabolic pathways. Many of these pathways have been found to be altered in AD, even at very early stages. In order to analyze the complex changes and underlying mechanisms, several AD models have been developed, including animal models, 2D and 3D cell culture, and ex-vivo studies of patient samples. The use of these models along with innovative, new redox analysis techniques are key to further understand the importance of the redox component in Alzheimer's disease and the identification of new therapeutic targets in the future.
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Affiliation(s)
- M. I. Holubiec
- IBioBA-MPSP Instituto de Investigación en Biomedicina de Buenos Aires, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - M. Gellert
- Institute for Medical Biochemistry and Molecular Biology, University Medicine Greifwald, University Greifswald, Greifswald, Germany
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Soni R, Shah J. Deciphering Intertwined Molecular Pathways Underlying Metabolic Syndrome Leading to Parkinson's Disease. ACS Chem Neurosci 2022; 13:2240-2251. [PMID: 35856649 DOI: 10.1021/acschemneuro.2c00165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is dopaminergic deficiency in Substantia nigra Pars Compacta (SNpc) due to neuronal degeneration. However, there are other factors that are not only associated with it but also somehow responsible for inception of pathology. Metabolic syndrome is one such risk factor for PD. Metabolic syndrome is a cluster of diseases mainly including diabetes, hypertension, obesity, and hyperlipidemia which pose a risk for developing cardiovascular disorders. All of these disorders have their own pathological pathways that intertwine with PD pathology. This leads to alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress which are facets in initiating PD pathology. Although few reports are available, this area is underexplored and has contradictory views. Hence, further studies are needed in order to establish a definite relationship between PD and metabolic syndrome. In this review, we aim to elucidate the molecular mechanisms to confirm the association between them and pave the way for potential repurposing of therapies.
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Affiliation(s)
- Ritu Soni
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Jigna Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
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22
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Matysek A, Kimmantudawage SP, Feng L, Maier AB. Targeting Impaired Nutrient Sensing via the Glycogen Synthase Kinase-3 Pathway With Therapeutic Compounds to Prevent or Treat Dementia: A Systematic Review. FRONTIERS IN AGING 2022; 3:898853. [PMID: 35923682 PMCID: PMC9341294 DOI: 10.3389/fragi.2022.898853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/27/2022] [Indexed: 12/15/2022]
Abstract
Background: Dementia is a global challenge with 10 million individuals being diagnosed every year. Currently, there are no established disease-modifying treatments for dementia. Impaired nutrient sensing has been implicated in the pathogenesis of dementia. Compounds that inhibit the glycogen synthase kinase-3 (GSK3) pathway have been investigated as a possible treatment to attenuate the progression of the disease, particularly the suppression of the hyper-phosphorylation process of the tau protein. Aims: Systematically summarizing compounds which have been tested to inhibit the GSK3 pathway to treat cognitive impairment and dementia. Methods: PubMed, Embase and Web of Science databases were searched from inception until 28 July 2021 for articles published in English. Interventional animal studies inhibiting the GSK3 pathway in Alzheimer’s disease (AD), Parkinson’s dementia, Lewy body dementia, vascular dementia, mild cognitive impairment (MCI) and normal cognitive ageing investigating the change in cognition as the outcome were included. The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias tool for animal studies was applied. Results: Out of 4,154 articles, 29 described compounds inhibiting the GSK3 pathway. All studies were based on animal models of MCI, AD or normal cognitive ageing. Thirteen out of 21 natural compounds and five out of nine synthetic compounds tested in MCI and dementia animal models showed an overall positive effect on cognition. No articles reported human studies. The risk of bias was largely unclear. Conclusion: Novel therapeutics involved in the modulation of the GSK3 nutrient sensing pathway have the potential to improve cognitive function. Overall, there is a clear lack of translation from animal models to humans.
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Affiliation(s)
- Adrian Matysek
- Department of Human Genetics, University of Amsterdam, Amsterdam UMC, University Medical Centers, Amsterdam, Netherlands
| | - Sumudu Perera Kimmantudawage
- Department of Medicine and Aged Care, Royal Melbourne Hospital, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - Lei Feng
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Healthy Longevity, National University Health System, Singapore, Singapore
| | - Andrea B. Maier
- Department of Medicine and Aged Care, Royal Melbourne Hospital, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Healthy Longevity, National University Health System, Singapore, Singapore
- Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit, Amsterdam, Netherlands
- *Correspondence: Andrea B. Maier,
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23
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Fan X, Xia L, Zhou Z, Qiu Y, Zhao C, Yin X, Qian W. Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction. Front Aging Neurosci 2022; 14:908881. [PMID: 35711910 PMCID: PMC9196307 DOI: 10.3389/fnagi.2022.908881] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/28/2022] [Indexed: 11/24/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by two pathological features: neurofibrillary tangles (NFTs), formed by microtubule-associated protein tau, and abnormal accumulation of amyloid-β (Aβ). Multiple evidence placed synaptic tau as the vital fact of AD pathology, especially at the very early stage of AD. In the present review, we discuss tau phosphorylation, which is critical for the dendritic localization of tau and synaptic plasticity. We review the related kinases and phosphatases implicated in the synaptic function of tau. We also review the synergistic effects of these kinases and phosphatases on tau-associated synaptic deficits. We aim to open a new perspective on the treatment of AD.
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Affiliation(s)
- Xing Fan
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Liye Xia
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Zheng Zhou
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yanyan Qiu
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Chenhao Zhao
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xiaomin Yin
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
- NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Wei Qian
- Department of Biochemistry and Molecular Biology, Medical School, Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
- NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
- *Correspondence: Wei Qian
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24
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Kazemi Shariat Panahi H, Dehhaghi M, Heng B, Lane DJR, Bush AI, Guillemin GJ, Tan VX. Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis. Neurotox Res 2022; 40:614-635. [PMID: 35023054 DOI: 10.1007/s12640-021-00455-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/22/2021] [Accepted: 11/30/2021] [Indexed: 02/08/2023]
Abstract
The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding.
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Affiliation(s)
- Hamed Kazemi Shariat Panahi
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mona Dehhaghi
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
- PANDIS.Org, Bendigo, Australia
- Department of Microbial Biotechnology, School of Biology and Centre of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Benjamin Heng
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Ashley I Bush
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Gilles J Guillemin
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
- PANDIS.Org, Bendigo, Australia.
| | - Vanessa X Tan
- Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
- PANDIS.Org, Bendigo, Australia
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25
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Aourz N, Van Leuven F, Allaoui W, Van Eeckhaut A, De Bundel D, Smolders I. Unraveling the Effects of GSK-3β Isoform Modulation against Limbic Seizures and in the 6 Hz Electrical Kindling Model for Epileptogenesis. ACS Chem Neurosci 2022; 13:796-805. [PMID: 35253420 DOI: 10.1021/acschemneuro.1c00782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Two closely related glycogen synthase kinase-3 (GSK-3) isoforms have been identified in mammals: GSK-3α and GSK-3β. GSK-3β is the most prominent in the central nervous system and was previously shown to control neuronal excitability. We previously demonstrated that indirubin and its structural analogue and the nonselective GSK-3 inhibitor BIO-acetoxime exerted anticonvulsant effects in acute seizure models in zebrafish, mice, and rats. We here examined for the first time the anticonvulsant effect of TCS2002, a specific and potent inhibitor of GSK-3β, in two models for limbic seizures: the pilocarpine rat model for focal seizures and the acute 6 Hz corneal mouse model for refractory seizures. Next, we additionally used the 6 Hz kindling model to establish differences in seizure susceptibility and seizure progression in mice that either overexpress human GSK-3β (GSK-3β OE) or lack GSK-3β (GSK-3β-/-) in neurons. We demonstrate that TCS2002 exerts anticonvulsant actions against pilocarpine- and 6 Hz-evoked seizures. Compared to wild-type littermates, GSK-3β OE mice are less susceptible to seizures but are more rapidly kindled. Interestingly, compared to GSK-3β+/+ mice, neuronal GSK-3β-/- mice show increased susceptibility to 6 Hz-induced seizures. These contrasting observations suggest compensatory neurodevelopmental mechanisms that alter seizure susceptibility in GSK-3β OE and GSK-3β-/- mice. Although the pronounced anticonvulsant effects of selective and acute GSK-3β inhibition in the 6 Hz model identify GSK-3β as a potential drug target for pharmacoresistant seizures, our data on the sustained disruption of GSK-3β activity in the transgenic mice suggest a role for GSK-3 in kindling and warrants further research into the long-term effects of selective pharmacological GSK-3β inhibition.
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Affiliation(s)
- Najat Aourz
- Vrije Universiteit Brussel (VUB), Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information/Center for Neurosciences (C4N), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Fred Van Leuven
- Experimental Genetics Group (LEGTEGG), Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium
| | - Wissal Allaoui
- Vrije Universiteit Brussel (VUB), Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information/Center for Neurosciences (C4N), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Ann Van Eeckhaut
- Vrije Universiteit Brussel (VUB), Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information/Center for Neurosciences (C4N), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Dimitri De Bundel
- Vrije Universiteit Brussel (VUB), Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information/Center for Neurosciences (C4N), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Ilse Smolders
- Vrije Universiteit Brussel (VUB), Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information/Center for Neurosciences (C4N), Laarbeeklaan 103, 1090 Brussels, Belgium
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26
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Tideglusib Ameliorates Ischemia/Reperfusion Damage by Inhibiting GSK-3β and Apoptosis in Rat Model of Ischemic Stroke. J Stroke Cerebrovasc Dis 2022; 31:106349. [PMID: 35152130 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/23/2022] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVES Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, gets activated and worsen stroke outcome after ischemia/reperfusion (I/R) injury by inducing inflammation and apoptosis. In this study, tideglusib, a selective irreversible and non-ATP competitive inhibitor of GSK-3β, was explored in cerebral I/R damage using middle cerebral artery occlusion (MCAo) model in rats. MATERIALS AND METHODS MCAo was done for 90 min in male Wistar rats (250-280 g) using doccol suture. In pre-treatment group, tideglusib (50 mg/kg) was administered once daily for 2 days and on the day of surgery, 30 min before MCAo. Next day, rats were examined for neurobehavioral parameters and MRI was performed to assess brain damage. In post-treatment group, tideglusib was started at 30 min after MCAo and continued for the next 2 days. After 72 h of MCAo, behavioral parameters and brain damage by MRI were assessed. Further, oxidative stress markers (MDA and GSH), inflammatory cytokines (TNF-α, IL-1β and IL-10) and expression levels of pGSK-3β S9, Bcl-2 and Bax were estimated in pre-treatment group. RESULTS Tideglusib pre-treatment but not post-treatment significantly improved neurobehavioral parameters (p < 0.05) and reduced brain damage (p < 0.01) when compared with MCAo group. I/R induced changes in MDA (p < 0.01), TNF-α and IL-1β (p < 0.05) were significantly attenuated by pre-treatment. Further, tideglusib pre-treatment ameliorated MCAo induced altered expressions of pGSK-3β S9, Bcl-2 and Bax. CONCLUSION The results of our exploratory study indicated prophylactic potential of tideglusib in I/R injury by modulating pGSK-3β S9, apoptosis and neuro-inflammation.
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27
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Ogbodo JO, Agbo CP, Njoku UO, Ogugofor MO, Egba SI, Ihim SA, Echezona AC, Brendan KC, Upaganlawar AB, Upasani CD. Alzheimer's Disease: Pathogenesis and Therapeutic Interventions. Curr Aging Sci 2022; 15:2-25. [PMID: 33653258 DOI: 10.2174/1874609814666210302085232] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/04/2020] [Accepted: 11/20/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Alzheimer's Disease (AD) is the most common cause of dementia. Genetics, excessive exposure to environmental pollutants, as well as unhealthy lifestyle practices are often linked to the development of AD. No therapeutic approach has achieved complete success in treating AD; however, early detection and management with appropriate drugs are key to improving prognosis. INTERVENTIONS The pathogenesis of AD was extensively discussed in order to understand the reasons for the interventions suggested. The interventions reviewed include the use of different therapeutic agents and approaches, gene therapy, adherence to healthy dietary plans (Mediterranean diet, Okinawan diet and MIND diet), as well as the use of medicinal plants. The potential of nanotechnology as a multidisciplinary and interdisciplinary approach in the design of nano-formulations of AD drugs and the use of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as theranostic tools for early detection of Alzheimer's disease were also discussed.
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Affiliation(s)
- John O Ogbodo
- Department of Science Laboratory Technology, University of Nigeria, Nsukka, Nigeria
| | - Chinazom P Agbo
- Department of Pharmaceutics, University of Nigeria, Nsukka, Nigeria
| | - Ugochi O Njoku
- Department of Biochemistry, University of Nigeria, Nsukka, Nigeria
| | | | - Simeon I Egba
- Department of Biochemistry, Michael Okpara University of Agriculture, Umudike, Nigeria
| | - Stella A Ihim
- Department of Pharmacology and Toxicology, University of Nigeria, Nsukka, Nigeria
| | | | | | - Aman B Upaganlawar
- Department of Pharmacology, Sureshdada Shriman\'s College of Pharmacy, New Dehli, India
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28
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Chen Z, Haider A, Chen J, Xiao Z, Gobbi L, Honer M, Grether U, Arnold SE, Josephson L, Liang SH. The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO. J Med Chem 2021; 64:17656-17689. [PMID: 34905377 PMCID: PMC9094091 DOI: 10.1021/acs.jmedchem.1c01571] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Neuroinflammation is an adaptive response of the central nervous system to diverse potentially injurious stimuli, which is closely associated with neurodegeneration and typically characterized by activation of microglia and astrocytes. As a noninvasive and translational molecular imaging tool, positron emission tomography (PET) could provide a better understanding of neuroinflammation and its role in neurodegenerative diseases. Ligands to translator protein (TSPO), a putative marker of neuroinflammation, have been the most commonly studied in this context, but they suffer from serious limitations. Herein we present a repertoire of different structural chemotypes and novel PET ligand design for classical and emerging neuroinflammatory targets beyond TSPO. We believe that this Perspective will support multidisciplinary collaborations in academic and industrial institutions working on neuroinflammation and facilitate the progress of neuroinflammation PET probe development for clinical use.
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Affiliation(s)
- Zhen Chen
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, United States
| | - Ahmed Haider
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, United States
| | - Jiahui Chen
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, United States
| | - Zhiwei Xiao
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, United States
| | - Luca Gobbi
- Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
| | - Michael Honer
- Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
| | - Uwe Grether
- Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
| | - Steven E. Arnold
- Department of Neurology and the Massachusetts Alzheimer’s Disease Research Center, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, USA
| | - Lee Josephson
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, United States
| | - Steven H. Liang
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, United States
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29
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Bernabeu-Zornoza A, Coronel R, Palmer C, López-Alonso V, Liste I. Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells. Int J Mol Sci 2021; 22:ijms22179537. [PMID: 34502444 PMCID: PMC8430695 DOI: 10.3390/ijms22179537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/30/2022] Open
Abstract
Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.
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Affiliation(s)
- Adela Bernabeu-Zornoza
- Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain; (A.B.-Z.); (R.C.); (C.P.)
| | - Raquel Coronel
- Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain; (A.B.-Z.); (R.C.); (C.P.)
| | - Charlotte Palmer
- Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain; (A.B.-Z.); (R.C.); (C.P.)
| | - Victoria López-Alonso
- Unidad de Biología Computacional, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain;
| | - Isabel Liste
- Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain; (A.B.-Z.); (R.C.); (C.P.)
- Correspondence: ; Tel.: +34-918223292; Fax: +34-918223269
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30
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Reilley DJ, Arraf Z, Alexandrova AN. Contrasting Effects of Inhibitors Li + and Be 2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β. J Phys Chem B 2021; 125:9480-9489. [PMID: 34404214 DOI: 10.1021/acs.jpcb.1c05099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Ionic lithium shows rare effectiveness for treating bipolar disorder and is a potential drug for neurodegenerative diseases. Unfortunately, lithium suffers from significant drawbacks, mainly a narrow therapeutic window. Among the targets of lithium, glycogen synthase kinase 3β (GSK-3β) may be responsible for its therapeutic effects. The development of alternative, selective inhibitors of this kinase could prevent lithium side effects, but such efforts have met little success so far. An atomistic understanding of Li+ inhibition and the GSK-3β phosphorylation reaction would therefore facilitate the development of new drugs. In this study, we use extensive sampling of catalytic states with our mixed quantum-classical dynamics method QM/DMD and binding affinities from a competitive metal affinity (CMA) approach to expand the atomistic picture of Li+ GSK-3β inhibition. We compare Li+ action with Be2+ and find our results in agreement with in vitro kinetics studies. Ultimately, our simulations show that Li+ inhibition is driven by decreasing the phosphorylation reaction rate, rather than reducing catalytic turnover through tight binding to different GSK-3β states like Be2+ inhibition. The effect of these metals derive from electrostatic differences and especially their smaller atomic radii compared to the native Mg2+ and thus provide insight for the development of GSK-3β inhibitors based on other paradigms.
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Affiliation(s)
- David J Reilley
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States
| | - Zaher Arraf
- Department of Education in Technology and Science, Technion-Israel Institute of Technology, 32000, Haifa, Israel
| | - Anastassia N Alexandrova
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States.,California NanoSystems Institute, Los Angeles California 90095-1569, United States
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31
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Demuro S, Di Martino RMC, Ortega JA, Cavalli A. GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways. Int J Mol Sci 2021; 22:9098. [PMID: 34445804 PMCID: PMC8396491 DOI: 10.3390/ijms22169098] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood-brain barrier (BBB) permeability and drug-like properties.
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Affiliation(s)
- Stefania Demuro
- Computational and Chemical Biology, Italian Institute of Technology, 16163 Genoa, Italy; (S.D.); (R.M.C.D.M.); (J.A.O.)
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Rita M. C. Di Martino
- Computational and Chemical Biology, Italian Institute of Technology, 16163 Genoa, Italy; (S.D.); (R.M.C.D.M.); (J.A.O.)
| | - Jose A. Ortega
- Computational and Chemical Biology, Italian Institute of Technology, 16163 Genoa, Italy; (S.D.); (R.M.C.D.M.); (J.A.O.)
| | - Andrea Cavalli
- Computational and Chemical Biology, Italian Institute of Technology, 16163 Genoa, Italy; (S.D.); (R.M.C.D.M.); (J.A.O.)
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
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32
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Neuroprotective Studies of Evodiamine in an Okadaic Acid-Induced Neurotoxicity. Int J Mol Sci 2021; 22:ijms22105347. [PMID: 34069531 PMCID: PMC8161163 DOI: 10.3390/ijms22105347] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 12/18/2022] Open
Abstract
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of Evodia rutaecarpa, has been reported to ameliorate blood–brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models. Methods: A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry. Results: The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine. Conclusions: Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment.
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Süer C, Yıldız N, Barutçu Ö, Tan B, Dursun N. Long-term depression-related tau phosphorylation is enhanced by methylene blue in healthy rat hippocampus. Pharmacol Rep 2021; 73:828-840. [PMID: 33797746 DOI: 10.1007/s43440-021-00254-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND The present study examined whether inhibition of guanylate cyclase (GC) is associated with the plasticity-related microtubule-stabilizing protein tau phosphorylation in the dentate gyrus (DG) of hippocampal formation. METHODS To address this issue, methylene blue (MB 50 μM) or saline was infused into the DG starting from the induction of long-term potentiation (LTP) or depression (LTD) for 1 h. Then, protein phosphatase 1 alpha (PP1α), glycogen synthase kinase 3 beta (GSK3β), and tau total and phosphorylated protein levels were measured in these hippocampi using western blotting. LTP and LTD were induced by application of high- and low-frequency stimulation protocols (HFS and LFS), respectively. 5-min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike amplitudes at the end of recording were averaged to measure the magnitude of LTP or LTD. RESULTS Low-frequency stimulation protocols was unable to phosphorylate thr181 and thr231epitopes of tau, but possessed kinase activity similar to the HFS in phosphorylation of ser396 and ser416 epitopes. MB infusion during LTD induction attenuated LTD, prevented EPSP/spike dissociation and increased tau phosphorylation at ser396 and ser416 epitopes, without changing tau phosphorylation at thr181 and thr231 epitopes. Neither LTP nor LTP-related tau phosphorylation state was changed by MB infusion. CONCLUSION Although MB can benefit to stabilize the balance between LTP and LTD, and to fix the increased spike wave discharges, it might trigger deregulation of tau phosphorylation, leading to the development of Alzheimer's disease by a mechanism that goes awry during induction of LTD. Thereby detailed studies to reveal more precise evidence for the use of MB in this disease are needed.
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Affiliation(s)
- Cem Süer
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Nurbanu Yıldız
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Özlem Barutçu
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Burak Tan
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey.
| | - Nurcan Dursun
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey.
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Sowa AS, Popova TG, Harmuth T, Weber JJ, Pereira Sena P, Schmidt J, Hübener-Schmid J, Schmidt T. Neurodegenerative phosphoprotein signaling landscape in models of SCA3. Mol Brain 2021; 14:57. [PMID: 33741019 PMCID: PMC7980345 DOI: 10.1186/s13041-020-00723-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/28/2020] [Indexed: 01/01/2023] Open
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disorder resulting from an aberrant expansion of a polyglutamine stretch in the ataxin-3 protein and subsequent neuronal death. The underlying intracellular signaling pathways are currently unknown. We applied the Reverse-phase Protein MicroArray (RPMA) technology to assess the levels of 50 signaling proteins (in phosphorylated and total forms) using three in vitro and in vivo models expressing expanded ataxin-3: (i) human embryonic kidney (HEK293T) cells stably transfected with human ataxin-3 constructs, (ii) mouse embryonic fibroblasts (MEF) from SCA3 transgenic mice, and (iii) whole brains from SCA3 transgenic mice. All three models demonstrated a high degree of similarity sharing a subset of phosphorylated proteins involved in the PI3K/AKT/GSK3/mTOR pathway. Expanded ataxin-3 strongly interfered (by stimulation or suppression) with normal ataxin-3 signaling consistent with the pathogenic role of the polyglutamine expansion. In comparison with normal ataxin-3, expanded ataxin-3 caused a pro-survival stimulation of the ERK pathway along with reduced pro-apoptotic and transcriptional responses.
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Affiliation(s)
- Anna S Sowa
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany
| | - Taissia G Popova
- Center for Applied Proteomics and Molecular Medicine, College of Science, George Mason University, Manassas, VA, USA
| | - Tina Harmuth
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany
| | - Jonasz J Weber
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany.,Department of Human Genetics, Ruhr-University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany
| | - Priscila Pereira Sena
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany
| | - Jana Schmidt
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany
| | - Jeannette Hübener-Schmid
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany
| | - Thorsten Schmidt
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany. .,Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany.
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Varlow C, Mossine AV, Bernard-Gauthier V, Scott PJH, Vasdev N. Radiofluorination of oxazole-carboxamides for preclinical PET neuroimaging of GSK-3. J Fluor Chem 2021; 245. [PMID: 33840834 DOI: 10.1016/j.jfluchem.2021.109760] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Glycogen synthase kinase 3 (GSK-3) is an enzyme that is dysregulated in oncology neurodegeneration, neuroinflammation and several mental health illnesses. As such, GSK-3 is a long-sought after target for positron emission tomography (PET) imaging and therapeutic intervention. Herein, we report on the development and radiofluorination of two oxazole-4-carboxamides, including one bearing a non-activated aromatic ring. Both compounds demonstrated excellent selectivity in a kinase screen and inhibit GSK-3 with high affinity. [18F]OCM-49 was synthesized from [18F]fluoride using a copper-mediated reaction of an aryl boronic acid precursor, while [18F]OCM-50 used a trimethylammonium triflate precursor, and both radiotracers were translated for preclinical PET imaging in rodents. Due to superior radiochemical yields and brain uptake (peak standardized uptake value of ~2.0), [18F]OCM-50 was further evaluated in non-human primate and also showed good brain uptake and rapid clearance. Further studies to consider clinical translation of both radiotracers are underway.
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Affiliation(s)
- Cassis Varlow
- Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, M5T 1R8, Canada
| | - Andrew V Mossine
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
| | - Vadim Bernard-Gauthier
- Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada
| | - Peter J H Scott
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
| | - Neil Vasdev
- Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, M5T 1R8, Canada
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Reich N, Hölscher C. Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease. Front Neurosci 2020; 14:614828. [PMID: 33381011 PMCID: PMC7767977 DOI: 10.3389/fnins.2020.614828] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/27/2020] [Indexed: 12/13/2022] Open
Abstract
Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.
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Affiliation(s)
- Niklas Reich
- Biomedical & Life Sciences Division, Lancaster University, Lancaster, United Kingdom
| | - Christian Hölscher
- Neurology Department, A Second Hospital, Shanxi Medical University, Taiyuan, China.,Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, China
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37
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Chou CH, Hsu KC, Lin TE, Yang CR. Anti-Inflammatory and Tau Phosphorylation-Inhibitory Effects of Eupatin. Molecules 2020; 25:E5652. [PMID: 33266202 PMCID: PMC7731404 DOI: 10.3390/molecules25235652] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 11/26/2020] [Accepted: 11/28/2020] [Indexed: 11/25/2022] Open
Abstract
Alzheimer's disease (AD), which is among the most prevalent neurodegenerative diseases, manifests as increasing memory loss and cognitive decline. Tau phosphorylation and aggregation are strongly linked to neurodegeneration, as well as associated with chronic neuroinflammatory processes. The anti-inflammation effects of natural products have led to wide recognition of their potential for use in treating and preventing AD. This study investigated whether eupatin, a polymethoxyflavonoid found in Artemisia species, has inhibitory effects on neuroinflammation and tau phosphorylation. We treated mouse macrophages and microglia cells with lipopolysaccharides (LPSs) to activate inflammatory signals, and we treated neuronal cells with a protein phosphatase 2A inhibitor, okadaic acid (OA), or transfection with pRK5-EGFP-Tau P301L plasmid to induce tau phosphorylation. The results indicated that eupatin significantly reduced the LPS-induced protein expression and phosphorylation of p65 and inducible nitric oxide synthase as well as downstream products interleukin 6 and nitrite, respectively. Furthermore, eupatin markedly inhibited the expression of phospho-tau in response to OA treatment and plasmid transfection. We discovered that this inhibition was achieved through the inhibition of glycogen synthase kinase 3β (GSK3β), and molecular docking results suggested that eupatin can sufficiently bind to the GSK3β active site. Our results demonstrate that eupatin has neuroprotective effects, making it suitable for AD treatment.
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Affiliation(s)
- Ching-Hsuan Chou
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan;
| | - Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (K.-C.H.); (T.E.L.)
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
- Biomedical Commercialization Center, Taipei Medical University, Taipei 11031, Taiwan
| | - Tony Eight Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (K.-C.H.); (T.E.L.)
- Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Chia-Ron Yang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan;
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Lei P, Ayton S, Bush AI. The essential elements of Alzheimer's disease. J Biol Chem 2020; 296:100105. [PMID: 33219130 PMCID: PMC7948403 DOI: 10.1074/jbc.rev120.008207] [Citation(s) in RCA: 187] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 02/05/2023] Open
Abstract
Treatments for Alzheimer’s disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the AD brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here, we review these essential elements of AD for their broad potential to contribute to Alzheimer’s pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.
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Affiliation(s)
- Peng Lei
- Department of Neurology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China; Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
| | - Scott Ayton
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia
| | - Ashley I Bush
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
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Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis. Brain Sci 2020; 10:brainsci10100675. [PMID: 32993098 PMCID: PMC7600609 DOI: 10.3390/brainsci10100675] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/19/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.
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40
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Hernández-Rodríguez M, Arciniega-Martínez IM, García-Marín ID, Correa-Basurto J, Rosales-Hernández MC. Chronic Administration of Scopolamine Increased GSK3βP9, Beta Secretase, Amyloid Beta, and Oxidative Stress in the Hippocampus of Wistar Rats. Mol Neurobiol 2020; 57:3979-3988. [PMID: 32638218 DOI: 10.1007/s12035-020-02009-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/01/2020] [Indexed: 10/23/2022]
Abstract
The increase of amyloid beta (Aβ) release and hyperphosphorylation of Tau protein represents the main events related to Alzheimer's disease (AD). Furthermore, the sporadic type represents the most common form of AD. Therefore, the establishment of a non-transgenic animal model that resembles the characteristics of the disease is of particular importance. Scopolamine has been linked to increases in both Aβ production and oxidative stress in rat and mice brains. Thus, the purpose of the present work was to identify changes in biomarkers that are related to AD after chronic administration of scopolamine (2 mg/kg i.p., during 6 and 12 weeks) to male Wistar rats. The results showed increased Aβ deposition at rat hippocampus which could be due to an increase of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) expression and activity. These findings could be related to the increase of glycogen synthase kinase 3 phosphorylated (GSK3βP9) expression. Finally, the establishment of a state of oxidative stress in groups treated with scopolamine was demonstrated by an increase in free radical content and MDA levels. The present study facilitates our understanding of the changes that occur in biomolecules related to AD in Wistar rats after the chronic administration of scopolamine.
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Affiliation(s)
- Maricarmen Hernández-Rodríguez
- Laboratorio de Modelado Molecular y Bioinformática, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico.,Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico
| | - Ivonne Maciel Arciniega-Martínez
- Laboratorio de Inmunidad de Mucosas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico
| | - Iohanan Daniel García-Marín
- Laboratorio de Modelado Molecular y Bioinformática, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico.,Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico
| | - José Correa-Basurto
- Laboratorio de Modelado Molecular y Bioinformática, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico.
| | - Martha Cecilia Rosales-Hernández
- Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340, Mexico, Mexico.
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Augello G, Emma MR, Cusimano A, Azzolina A, Montalto G, McCubrey JA, Cervello M. The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment. Cells 2020; 9:cells9061427. [PMID: 32526891 PMCID: PMC7348946 DOI: 10.3390/cells9061427] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/31/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified because of its key role in the regulation of glycogen synthesis. However, it is now well-established that GSK-3 performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis. Aberrant GSK-3 activity has been associated with many human diseases, including cancer, highlighting its potential therapeutic relevance as a target for anticancer therapy. Recently, newly emerging data have demonstrated the pivotal role of GSK-3 in the anticancer immune response. In the last few years, many GSK-3 inhibitors have been developed, and some are currently being tested in clinical trials. This review will discuss preclinical and initial clinical results with GSK-3β inhibitors, highlighting the potential importance of this target in cancer immunotherapy. As described in this review, GSK-3 inhibitors have been shown to have antitumor activity in a wide range of human cancer cells, and they may also contribute to promoting a more efficacious immune response against tumor target cells, thus showing a double therapeutic advantage.
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Affiliation(s)
- Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90144 Palermo, Italy; (G.A.); (M.R.E.); (A.C.); (A.A.); (G.M.)
| | - Maria R. Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90144 Palermo, Italy; (G.A.); (M.R.E.); (A.C.); (A.A.); (G.M.)
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90144 Palermo, Italy; (G.A.); (M.R.E.); (A.C.); (A.A.); (G.M.)
| | - Antonina Azzolina
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90144 Palermo, Italy; (G.A.); (M.R.E.); (A.C.); (A.A.); (G.M.)
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90144 Palermo, Italy; (G.A.); (M.R.E.); (A.C.); (A.A.); (G.M.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA;
| | - Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), 90144 Palermo, Italy; (G.A.); (M.R.E.); (A.C.); (A.A.); (G.M.)
- Correspondence: ; Tel.: +39-091-6809-534
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Prati F, Buonfiglio R, Furlotti G, Cavarischia C, Mangano G, Picollo R, Oggianu L, di Matteo A, Olivieri S, Bovi G, Porceddu PF, Reggiani A, Garrone B, Di Giorgio FP, Ombrato R. Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and In Vivo Activity in a Mood Disorder Model. ACS Med Chem Lett 2020; 11:825-831. [PMID: 32435391 DOI: 10.1021/acsmedchemlett.9b00633] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β inhibitors with good in vivo efficacy and safety profile associated with high brain exposure is required. Accordingly, we have previously reported the selective indazole-based GSK-3 inhibitor 1, which showed excellent efficacy in a mouse model of mania. Despite the favorable preclinical profile, analog 1 suffered from activity at the hERG ion channel, which prevented its further progression. Herein, we describe our strategy to improve this off-target liability through modulation of physicochemical properties, such as lipophilicity and basicity. These efforts led to the potent inhibitor 14, which possessed reduced hERG affinity, promising in vitro ADME properties, and was very effective in a mood stabilizer in vivo model.
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Affiliation(s)
- Federica Prati
- Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy
| | | | - Guido Furlotti
- Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy
| | | | | | | | - Laura Oggianu
- Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy
| | - Anna di Matteo
- Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy
| | | | - Graziella Bovi
- Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy
| | - Pier Francesca Porceddu
- D3Validation Research Line, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
| | - Angelo Reggiani
- D3Validation Research Line, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
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Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches. Molecules 2020; 25:molecules25092163. [PMID: 32380735 PMCID: PMC7248956 DOI: 10.3390/molecules25092163] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 04/30/2020] [Accepted: 05/02/2020] [Indexed: 11/17/2022] Open
Abstract
The interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives 1-6, showing good GSK-3β inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability. Here, we describe the design, synthesis, and in vitro characterization of novel imidazo[1,5-a]pyridine-1-carboxamide (IMID 1) and imidazo[1,5-a]pyridine-3-carboxamide (IMID 2) compounds (7-18) to overcome such liability. In detail, structure-based approaches and fine-tuning of physicochemical properties guided the design of derivatives 7-18 resulting in ameliorated absorption, distribution, metabolism, and excretion (ADME) properties. A crystal structure of 16 in complex with GSK-3β enzyme (PDB entry 6Y9S) confirmed the in silico models. Despite the nanomolar inhibition activity, the new core compounds showed a reduction in potency with respect to INDZ derivatives 1-6. In this context, Molecular Dynamics (MD) and Quantum Mechanics (QM) based approaches along with NMR investigation helped to rationalize the observed structure activity relationship (SAR). With these findings, the key role of the acidic hydrogen of the central core for a tight interaction within the ATP pocket of the enzyme reflecting in good GSK-3β affinity was demonstrated.
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GSK-3β-Targeting Fisetin Promotes Melanogenesis in B16F10 Melanoma Cells and Zebrafish Larvae through β-Catenin Activation. Int J Mol Sci 2020; 21:ijms21010312. [PMID: 31906440 PMCID: PMC6982351 DOI: 10.3390/ijms21010312] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/24/2019] [Accepted: 12/30/2019] [Indexed: 01/01/2023] Open
Abstract
Fisetin is found in many fruits and plants such as grapes and onions, and exerts anti-inflammatory, anti-proliferative, and anticancer activity. However, whether fisetin regulates melanogenesis has been rarely studied. Therefore, we evaluated the effects of fisetin on melanogenesis in B16F10 melanoma cell and zebrafish larvae. The current study revealed that fisetin slightly suppressed in vitro mushroom tyrosinase activity; however, molecular docking data showed that fisetin did not directly bind to mushroom tyrosinase. Unexpectedly, fisetin significantly increased intracellular and extracellular melanin production in B16F10 melanoma cells regardless of the presence or absence of α-melanocyte stimulating hormone (α-MSH). We also found that the expression of melanogenesis-related genes such as tyrosinase and microphthalmia-associated transcription factor (MITF), were highly increased 48 h after fisetin treatment. Pigmentation of zebrafish larvae by fisetin treatment also increased at the concentrations up to 200 µM and then slightly decreased at 400 µM, with no alteration in the heart rates. Molecular docking data also revealed that fisetin binds to glycogen synthase kinase-3β (GSK-3β). Therefore, we evaluated whether fisetin negatively regulated GSK-3β, which subsequently activates β-catenin, resulting in melanogenesis. As expected, fisetin increased the expression of β-catenin, which was subsequently translocated into the nucleus. In the functional assay, FH535, a Wnt/β-catenin inhibitor, significantly inhibited fisetin-mediated melanogenesis in zebrafish larvae. Our data suggested that fisetin inhibits GSK-3β, which activates β-catenin, resulting in melanogenesis through the revitalization of MITF and tyrosinase.
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Hintermayer MA, Volkening K, Moszczynski AJ, Donison N, Strong MJ. Tau protein phosphorylation at Thr 175 initiates fibril formation via accessibility of the N-terminal phosphatase-activating domain. J Neurochem 2019; 155:313-326. [PMID: 31853971 DOI: 10.1111/jnc.14942] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 12/10/2019] [Accepted: 12/13/2019] [Indexed: 01/21/2023]
Abstract
One of the neuropathological hallmarks of the tauopathies is the formation of neuronal cytoplasmic inclusions and fibrils of microtubule-associated tau protein (tau). The phosphorylation of Thr175 of tau (pThr175 tau) appears to be sufficient for fibril formation in vitro and in vivo, but the mechanism by which this initiates fibril formation is unknown. Using transient transfections of tau mutants into HEK293T cells, we determined that the phosphorylation of Thr175 leads to exposure of the tau N-terminal phosphatase-activating domain (PAD). The exposed PAD is known to interact with protein phosphatase-1 (PP1) resulting in glycogen synthase kinase 3β (GSK3β) activation. In vivo, a single traumatic controlled cortical injury in rats also resulted in the phosphorylation of Thr175 and increased exposure of tau PAD followed by pathological tau fibril formation. Taken together, these data suggest that neurotoxicity may be precipitated by phosphorylation at Thr175 and subsequent tau PAD exposure, GSK3β activation and tau fibril formation. Cover Image for this issue: doi: 10.1111/jnc.14767.
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Affiliation(s)
- Matthew A Hintermayer
- Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
| | - Kathryn Volkening
- Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.,Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Alexander J Moszczynski
- Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
| | - Neil Donison
- Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
| | - Michael J Strong
- Molecular Brain Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.,Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
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The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents. Sci Rep 2019; 9:18045. [PMID: 31792284 PMCID: PMC6888874 DOI: 10.1038/s41598-019-54557-5] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 11/15/2019] [Indexed: 12/20/2022] Open
Abstract
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25–35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25–35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
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Bernard-Gauthier V, Mossine AV, Knight A, Patnaik D, Zhao WN, Cheng C, Krishnan HS, Xuan LL, Chindavong PS, Reis SA, Chen JM, Shao X, Stauff J, Arteaga J, Sherman P, Salem N, Bonsall D, Amaral B, Varlow C, Wells L, Martarello L, Patel S, Liang SH, Kurumbail RG, Haggarty SJ, Scott PJH, Vasdev N. Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery. J Med Chem 2019; 62:9600-9617. [PMID: 31535859 PMCID: PMC6883410 DOI: 10.1021/acs.jmedchem.9b01030] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
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Affiliation(s)
- Vadim Bernard-Gauthier
- Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada
- Department of Psychiatry/Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 1R8, Canada
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Andrew V. Mossine
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Ashley Knight
- Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada
- Department of Psychiatry/Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 1R8, Canada
- Eisai AiM Institute, Boston, Massachusetts 01810, United States
| | - Debasis Patnaik
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Wen-Ning Zhao
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Chialin Cheng
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Hema S. Krishnan
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Lucius L. Xuan
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Peter S. Chindavong
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Surya A. Reis
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Jinshan Michael Chen
- Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Xia Shao
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Jenelle Stauff
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Janna Arteaga
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Phillip Sherman
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Nicolas Salem
- Biogen, Research and Early Development Imaging, Cambridge, Massachusetts 02142, United States
| | | | - Brenda Amaral
- Biogen, Research and Early Development Imaging, Cambridge, Massachusetts 02142, United States
| | - Cassis Varlow
- Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada
| | | | - Laurent Martarello
- Biogen, Research and Early Development Imaging, Cambridge, Massachusetts 02142, United States
| | - Shil Patel
- Eisai AiM Institute, Boston, Massachusetts 01810, United States
| | - Steven H. Liang
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Ravi G. Kurumbail
- Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Stephen J. Haggarty
- Chemical Neurobiology Laboratory, Massachusetts General Hospital, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Harvard Medical School, Boston, Massachusetts 02114, United States
| | - Peter J. H. Scott
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
- The Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Neil Vasdev
- Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada
- Department of Psychiatry/Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 1R8, Canada
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States
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Ko HJ, Chiou SJ, Wong YH, Wang YH, Lai Y, Chou CH, Wang C, Loh JK, Lieu AS, Cheng JT, Lin YT, Lu PJ, Fann MJ, Huang CYF, Hong YR. GSKIP-Mediated Anchoring Increases Phosphorylation of Tau by PKA but Not by GSK3beta via cAMP/PKA/GSKIP/GSK3/Tau Axis Signaling in Cerebrospinal Fluid and iPS Cells in Alzheimer Disease. J Clin Med 2019; 8:1751. [PMID: 31640277 PMCID: PMC6832502 DOI: 10.3390/jcm8101751] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 11/17/2022] Open
Abstract
Based on the protein kinase A (PKA)/GSK3β interaction protein (GSKIP)/glycogen synthase kinase 3β (GSK3β) axis, we hypothesized that these might play a role in Tau phosphorylation. Here, we report that the phosphorylation of Tau Ser409 in SHSY5Y cells was increased by overexpression of GSKIP WT more than by PKA- and GSK3β-binding defective mutants (V41/L45 and L130, respectively). We conducted in vitro assays of various kinase combinations to show that a combination of GSK3β with PKA but not Ca2+/calmodulin-dependent protein kinase II (CaMK II) might provide a conformational shelter to harbor Tau Ser409. Cerebrospinal fluid (CSF) was evaluated to extend the clinical significance of Tau phosphorylation status in Alzheimer's disease (AD), neurological disorders (NAD), and mild cognitive impairment (MCI). We found higher levels of different PKA-Tau phosphorylation sites (Ser214, Ser262, and Ser409) in AD than in NAD, MCI, and normal groups. Moreover, we used the CRISPR/Cas9 system to produce amyloid precursor protein (APPWT/D678H) isogenic mutants. These results demonstrated an enhanced level of phosphorylation by PKA but not by the control. This study is the first to demonstrate a transient increase in phosphor-Tau caused by PKA, but not GSK3β, in the CSF and induced pluripotent stem cells (iPSCs) of AD, implying that both GSKIP and GSK3β function as anchoring proteins to strengthen the cAMP/PKA/Tau axis signaling during AD pathogenesis.
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Affiliation(s)
- Huey-Jiun Ko
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Shean-Jaw Chiou
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Yu-Hui Wong
- Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Yin-Hsuan Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - YunLing Lai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Chia-Hua Chou
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Chihuei Wang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Joon-Khim Loh
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Ann-Shung Lieu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Jiin-Tsuey Cheng
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
| | - Yu-Te Lin
- Section of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
| | - Pei-Jung Lu
- Institute of Clinical Medicine, School of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
| | - Ming-Ji Fann
- Department of Life Sciences and Institute of Genome Sciences and Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Chi-Ying F Huang
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
| | - Yi-Ren Hong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
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p53-Mediated Oxidative Stress Enhances Indirubin-3'-Monoxime-Induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-Related Apoptosis-Inducing Ligand Expression. Antioxidants (Basel) 2019; 8:antiox8100423. [PMID: 31546731 PMCID: PMC6826553 DOI: 10.3390/antiox8100423] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 01/02/2023] Open
Abstract
Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53−/− cells were insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis was promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulted in endoplasmic reticulum (ER) stress-mediated DR5 expression, which was upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with I3M and TRAIL enhanced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53−/− cells were less sensitive to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells. Additionally, this study also revealed that I3M sensitizes colorectal cancer cells such as HT29 and SW480 to TRAIL-mediated apoptosis.
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Das TK, Jana P, Chakrabarti SK, Abdul Hamid MRW. Curcumin Downregulates GSK3 and Cdk5 in Scopolamine-Induced Alzheimer's Disease Rats Abrogating Aβ 40/42 and Tau Hyperphosphorylation. J Alzheimers Dis Rep 2019; 3:257-267. [PMID: 31754658 PMCID: PMC6839535 DOI: 10.3233/adr-190135] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia. Extracellular amyloid-β (Aβ) aggregation and tau hyperphosphorylation are the key drivers of AD. Glycogen synthase kinase 3 (GSK3) and cyclin dependent kinase 5 (Cdk5) have been known as leading applicants arbitrating abnormal tau hyperphosphorylation. Thus, we evaluated the efficacy and underlying mechanism of action of curcumin in scopolamine-induced AD rats in our study. We found that curcumin-treated AD rats markedly reduced the levels of Aβ40 and Aβ42 in the brain and in the plasma in comparison to untreated AD rats. Moreover, the levels of phosphorylated tau at Ser396 (PHF13), Ser202/Thr205 (AT8), and Aβ40/42 (MOAB2) were decreased significantly in AD rats treated with curcumin. Phospho-GSK3β (Tyr216), the active form of GSK3β, and total GSK3β were significantly decreased in AD rats treated with curcumin. Furthermore, Cdk5 and its activators p35 and p25 were significantly decreased in curcumin-treated AD rats. The reduced levels of Cdk5, p35, p25, and GSK3β in curcumin-treated AD rats may result decreased Aβ aggregation and tau hyperphosphorylation, thus ameliorating AD. Impaired spatial memory and locomotor activity in AD rats were partially reversed by curcumin. Therefore, curcumin, as a natural compound present in turmeric, may be a more effective therapeutic agent in the treatment of AD in humans.
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Affiliation(s)
- Tushar Kanti Das
- Universiti Brunei Darussalam, PAPRSB Institute of Health Sciences, Jalan Tungku Link, Gadong, Brunei Darussalam.,Institute of Reproductive Medicine, Salt Lake, Kolkata, India
| | - Piyali Jana
- Department of Microbiology, Vidyasagar University, India
| | | | - Mas R W Abdul Hamid
- Universiti Brunei Darussalam, PAPRSB Institute of Health Sciences, Jalan Tungku Link, Gadong, Brunei Darussalam
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