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1
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Mitochondrial dysfunction: A potential target for Alzheimer's disease intervention and treatment. Drug Discov Today 2021; 26:1991-2002. [PMID: 33962036 DOI: 10.1016/j.drudis.2021.04.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/05/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder which manifests as a progressive decline in cognitive function. Mitochondrial dysfunction plays a critical role in the early stages of AD, and advances the progression of this age-related neurodegenerative disorder. Therefore, it can be a potential target for interventions to treat AD. Several therapeutic strategies to target mitochondrial dysfunction have gained significant attention in the preclinical stage, but the clinical trials performed to date have shown little progress. Thus, we discuss the mechanisms and strategies of different therapeutic agents for targeting mitochondrial dysfunction in AD. We hope that this review will inspire and guide the development of efficient AD drugs in the future.
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2
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Exposure of Mesenchymal Stem Cells to an Alzheimer's Disease Environment Enhances Therapeutic Effects. Stem Cells Int 2021; 2021:6660186. [PMID: 33815510 PMCID: PMC7988745 DOI: 10.1155/2021/6660186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/07/2021] [Accepted: 02/19/2021] [Indexed: 01/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of Alzheimer's disease (AD). Previous studies suggested that the coculture of human MSCs with AD in an in vitro model reduced the expression of amyloid-beta 42 (Aβ42) in the medium as well as the overexpression of amyloid-beta- (Aβ-) degrading enzymes such as neprilysin (NEP). We focused on the role of primed MSCs (human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exposed to an AD cell line via a coculture system) in reducing the levels of Aβ and inhibiting cell death. We demonstrated that mouse groups treated with naïve MSCs and primed MSCs showed significant reductions in cell death, ubiquitin conjugate levels, and Aβ levels, but the effects were greater in primed MSCs. Also, mRNA sequencing data analysis indicated that high levels of TGF-β induced primed-MSCs. Furthermore, treatment with TGF-β reduced Aβ expression in an AD transgenic mouse model. These results highlighted AD environmental preconditioning is a promising strategy to reduce cell death and ubiquitin conjugate levels and maintain the stemness of MSCs. Further, these data suggest that human WJ-MSCs exposed to an AD environment may represent a promising and novel therapy for AD.
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3
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Uddin MS, Al Mamun A, Kabir MT, Ashraf GM, Bin-Jumah MN, Abdel-Daim MM. Multi-Target Drug Candidates for Multifactorial Alzheimer's Disease: AChE and NMDAR as Molecular Targets. Mol Neurobiol 2020; 58:281-303. [PMID: 32935230 DOI: 10.1007/s12035-020-02116-9] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/02/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer's symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
| | - Abdullah Al Mamun
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | | | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - May N Bin-Jumah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11474, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
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4
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Ge M, Zhang Y, Hao Q, Zhao Y, Dong B. Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer's disease: A systematic review and meta-analysis. Brain Behav 2018; 8:e00982. [PMID: 29877067 PMCID: PMC6043701 DOI: 10.1002/brb3.982] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 03/07/2018] [Accepted: 03/11/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a globally prevalent neurodegenerative disease, clinically characterized by progressive memory loss and gradual impairment of cognitive functions. Mesenchymal stem cells (MSCs) transplantation has been considered a possible therapeutic method for Alzheimer's disease (AD). However, no quantitative data synthesis of MSC therapy for AD exists. We conducted a systematic review and meta-analysis to study the effects of MSCs on cognitive deficits in animal models of AD. METHODS We identified eligible studies published from January 1980 to January 2017 by searching four electronic databases (PubMed, MEDLINE, EMBASE, CNKI). The endpoint was the effects of MSCs on cognitive performance evaluated by the Morris water maze (MWM) test including escape latency, and/or number of platform crossing, and/or time in the target quadrant. RESULTS Nine preclinical studies incorporating 225 animals with AD were included for the meta-analysis. The studies indicated that MSC-based treatment significantly improved the learning function through measurements of the escape latency (SMD = -0.99, 95% CI = -1.33 to -0.64, p < .00001). Additionally, we observed that transplantation of MSCs significantly increased the number of platform crossing in six experiments (SMD = 0.78, 95% CI = 0.43 to 1.13, p < .0001). What's more, the times in the target quadrant were increased in five studies indicated that transplantation of MSCs could ameliorate the cognitive impairments (SMD = 1.06, 95% CI = 0.46 to 1.67, p = .0005). CONCLUSIONS This study showed that MSC transplantation could reduce cognitive deficits in AD models. These findings support the further studies to translate MSCs in the treatment of AD in humans.
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Affiliation(s)
- Meiling Ge
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Collaborative Innovation Center of Sichuan for Elderly Care and Health, Sichuan, China
| | - Yunxia Zhang
- Chengdu Medical College, Chengdu, Sichuan, China
| | - Qiukui Hao
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yunli Zhao
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Birong Dong
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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5
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Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer's disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis. Behav Brain Res 2016; 320:291-301. [PMID: 28007537 DOI: 10.1016/j.bbr.2016.12.021] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 12/12/2016] [Accepted: 12/16/2016] [Indexed: 12/17/2022]
Abstract
Stem cell transplantation represents a promising therapy for central nervous system injuries, but its application to Alzheimer's disease (AD) is still limited and the potential mechanism for cognition improvement remains to be elucidated. In the present study, we used Tg2576 mice which express AD-like pathological forms of amyloid precursor protein (APP) to investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) intravenous transplantation on AD mice. Interestingly, hUC-MSCs transplantation significantly ameliorated cognitive function of AD mice without altering Aβ levels in hippocampus. Remarkably, hUC-MSCs transplantation reduced oxidative stress in hippocampus of AD mice by decreasing the level of malondialdehyde (MDA), increasing the level of nitric oxide (NO), enhancing the activity of superoxide dismutase (SOD) and neuronal nitric oxide synthase (nNOS). The mechanisms underlying the improved cognitive function may be linked to hippocampal neurogenesis and an up-regulation of neuronal synaptic plasticity related proteins levels including silent information regulator 1 (Sirt1), brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN). Taken together, our findings suggest that hUC-MSCs can improve cognition of AD mice by decreasing oxidative stress and promoting hippocampal neurogenesis. These results suggest that modulating hUC-MSCs to generate excess neuroprotective factors could provide a viable therapy to treat AD.
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6
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Distribution of human umbilical cord blood-derived mesenchymal stem cells in the Alzheimer's disease transgenic mouse after a single intravenous injection. Neuroreport 2016; 27:235-41. [PMID: 26752148 DOI: 10.1097/wnr.0000000000000526] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The aim of this study was to track the migration of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) administered through a single intravenous injection and to observe the consequential therapeutic effects in a transgenic Alzheimer's disease mouse model. Ten-month-old APP/PS1 mice received a total injection of 1×10 cells through the lateral tail vein and were killed 1, 4, and 7 days after administration. On the basis of immunohistochemical analysis, hUCB-MSCs were not detected in the brain at any of the time points. Instead, most of the injected mesenchymal stem cells were found to be distributed in the lung, heart, and liver. In terms of the molecular effects, statistically significant differences in the amyloid β protein, neprilysin, and SOX2 levels were not observed among the groups. On the basis of the results from this study, we suggest that single intravenously administered hUCB-MSCs are not delivered to the brain and also do not have a significant influence on Alzheimer's disease pathology.
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7
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Porter T, Bharadwaj P, Groth D, Paxman A, Laws SM, Martins RN, Verdile G. The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity. J Alzheimers Dis 2016; 50:895-905. [PMID: 26836170 PMCID: PMC4927897 DOI: 10.3233/jad-150790] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.
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Affiliation(s)
- Tenielle Porter
- School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.,Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia
| | - Prashant Bharadwaj
- School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.,Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia
| | - David Groth
- School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.,School of Psychiatry and Clinical Neuroscience, University of Western Australia, Western Australia, Australia
| | - Adrian Paxman
- School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia
| | - Simon M Laws
- Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia
| | - Ralph N Martins
- Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.,School of Psychiatry and Clinical Neuroscience, University of Western Australia, Western Australia, Australia.,The Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Western Australia, Australia
| | - Giuseppe Verdile
- School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.,Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.,School of Psychiatry and Clinical Neuroscience, University of Western Australia, Western Australia, Australia.,The Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Western Australia, Australia
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8
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Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics. Future Med Chem 2016; 8:697-711. [DOI: 10.4155/fmc-2016-0003] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.
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9
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Irwin MH, Moos WH, Faller DV, Steliou K, Pinkert CA. Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases. Drug Dev Res 2016; 77:109-23. [PMID: 26899010 DOI: 10.1002/ddr.21294] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Michael H Irwin
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA
| | - Walter H Moos
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.,SRI Biosciences, A Division of SRI International, Menlo Park, CA, USA
| | - Douglas V Faller
- Cancer Research Center, Boston University School of Medicine, Boston, MA, USA
| | - Kosta Steliou
- Cancer Research Center, Boston University School of Medicine, Boston, MA, USA.,PhenoMatriX, Inc., Boston, MA, USA
| | - Carl A Pinkert
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.,Department of Biological Sciences, College of Arts and Sciences, The University of Alabama, Tuscaloosa, AL, USA
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10
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Kim DH, Lee D, Chang EH, Kim JH, Hwang JW, Kim JY, Kyung JW, Kim SH, Oh JS, Shim SM, Na DL, Oh W, Chang JW. GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model. Stem Cells Dev 2015; 24:2378-90. [PMID: 26154268 DOI: 10.1089/scd.2014.0487] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-β (Aβ) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Aβ42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.
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Affiliation(s)
- Dong Hyun Kim
- 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.,2 Department of Biotechnology and Bioengineering, Sungkyunkwan University , Suwon, Republic of Korea
| | - Dahm Lee
- 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea
| | - Eun Hyuk Chang
- 3 Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology , Samsung Electronics Co., Ltd., Seoul, Republic of Korea.,4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea
| | - Ji Hyun Kim
- 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.,4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea
| | - Jung Won Hwang
- 4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea.,5 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University , Seoul, Republic of Korea
| | - Ju-Yeon Kim
- 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea
| | - Jae Won Kyung
- 6 Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University , Seoul, Republic of Korea
| | - Sung Hyun Kim
- 6 Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University , Seoul, Republic of Korea
| | - Jeong Su Oh
- 2 Department of Biotechnology and Bioengineering, Sungkyunkwan University , Suwon, Republic of Korea
| | - Sang Mi Shim
- 7 Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul, Republic of Korea
| | - Duk Lyul Na
- 4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea
| | - Wonil Oh
- 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea
| | - Jong Wook Chang
- 5 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University , Seoul, Republic of Korea.,8 Stem Cell & Regenerative Medicine Center (SCRMC), Research Institute for Future Medicine , Samsung Medical Center, Seoul, Republic of Korea
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11
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Ustyugov A, Shevtsova E, Bachurin S. Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine). Mol Neurobiol 2015; 52:970-8. [DOI: 10.1007/s12035-015-9249-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Indexed: 12/14/2022]
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12
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Caldwell CC, Yao J, Brinton RD. Targeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities. Neurotherapeutics 2015; 12:66-80. [PMID: 25534394 PMCID: PMC4322082 DOI: 10.1007/s13311-014-0324-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.
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Affiliation(s)
- Charles C. Caldwell
- />Clinical and Experimental Therapeutics Program, School of Pharmacy, University of Southern California, Los Angeles, CA 90089 USA
| | - Jia Yao
- />Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089 USA
| | - Roberta Diaz Brinton
- />Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089 USA
- />Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089 USA
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13
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Egea J, Romero A, Parada E, León R, Dal-Cim T, López M. Neuroprotective effect of dimebon against ischemic neuronal damage. Neuroscience 2014; 267:11-21. [DOI: 10.1016/j.neuroscience.2014.02.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Accepted: 02/19/2014] [Indexed: 02/06/2023]
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14
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Multi-target Design Strategies in the Context of Alzheimer’s Disease: Acetylcholinesterase Inhibition and NMDA Receptor Antagonism as the Driving Forces. Neurochem Res 2014; 39:1914-23. [DOI: 10.1007/s11064-014-1250-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/23/2014] [Accepted: 01/24/2014] [Indexed: 01/08/2023]
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15
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Barnett JH, Hachinski V, Blackwell AD. Cognitive health begins at conception: addressing dementia as a lifelong and preventable condition. BMC Med 2013; 11:246. [PMID: 24252204 PMCID: PMC3832877 DOI: 10.1186/1741-7015-11-246] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 10/22/2013] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Dementia is a major public health problem that poses an increasing burden on the health and wealth of societies worldwide. Because the efficacy of current treatments is limited, increasing efforts are required to prevent the diseases that cause dementia. DISCUSSION We consider the evidence that lifelong prevention strategies may be an effective way to tackle the national burden of dementia in the absence of a cure. The links between lifestyle and cardiovascular disease are widely understood and accepted, but health professionals and patients remain unconvinced about the extent to which risk for dementia can be modified. However, there is strong evidence that at least half of risk for dementia is attributable to lifestyle factors such as diet, exercise and smoking. Moreover, the disease processes that result in dementia develop over several decades, implying that attempts to ameliorate them need to start early in life. Some modifiable risk factors for dementia act from the earliest stages of life, including in utero. SUMMARY Rebalancing efforts from the development of treatments to increased emphasis on prevention may be an alternative means to reducing the impact of dementia on society.
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Affiliation(s)
- Jennifer H Barnett
- Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 2QQ, UK.
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16
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Weisová P, Alvarez SP, Kilbride SM, Anilkumar U, Baumann B, Jordán J, Bernas T, Huber HJ, Düssmann H, Prehn JHM. Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability. Transl Psychiatry 2013; 3:e317. [PMID: 24150226 PMCID: PMC3818013 DOI: 10.1038/tp.2013.92] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/09/2013] [Indexed: 12/18/2022] Open
Abstract
Latrepirdine/Dimebon is a small-molecule compound with attributed neurocognitive-enhancing activities, which has recently been tested in clinical trials for the treatment of Alzheimer's and Huntington's disease. Latrepirdine has been suggested to be a neuroprotective agent that increases mitochondrial function, however the molecular mechanisms underlying these activities have remained elusive. We here demonstrate that latrepirdine, at (sub)nanomolar concentrations (0.1 nM), activates the energy sensor AMP-activated protein kinase (AMPK). Treatment of primary neurons with latrepirdine increased intracellular ATP levels and glucose transporter 3 translocation to the plasma membrane. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. Gene silencing of AMPKα or its upstream kinases, LKB1 and CaMKKβ, inhibited this effect. However, studies using the plasma membrane potential indicator DisBAC2(3) demonstrated that the effects of latrepirdine on TMRM uptake were largely mediated by plasma membrane hyperpolarization, precluding a purely 'mitochondrial' mechanism of action. In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca(2+) oscillations as well as glutamate-induced Ca(2+) increases in primary neurons, and protected neurons against glutamate toxicity. In conclusion, our experiments demonstrate that latrepirdine is a potent activator of AMPK, and suggest that one of the main pharmacological activities of latrepirdine is a reduction in neuronal excitability.
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Affiliation(s)
- P Weisová
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland,Max F. Perutz Laboratories, University of Vienna, Vienna, Austria
| | - S P Alvarez
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland,Dpto Ciencias Médicas-Farmacología, Faculdad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain
| | - S M Kilbride
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - U Anilkumar
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - B Baumann
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - J Jordán
- Dpto Ciencias Médicas-Farmacología, Faculdad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain
| | - T Bernas
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland,Institute of Experimental Biology PAS, Warsaw, Poland
| | - H J Huber
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - H Düssmann
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - J H M Prehn
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland,Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin, 2, Ireland. E-mail:
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17
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Bharadwaj PR, Verdile G, Barr RK, Gupta V, Steele JW, Lachenmayer ML, Yue Z, Ehrlich ME, Petsko G, Ju S, Ringe D, Sankovich SE, Caine JM, Macreadie IG, Gandy S, Martins RN. Latrepirdine (dimebon) enhances autophagy and reduces intracellular GFP-Aβ42 levels in yeast. J Alzheimers Dis 2013; 32:949-67. [PMID: 22903131 DOI: 10.3233/jad-2012-120178] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Latrepirdine (Dimebon), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer's disease (AD) and has been shown to promote the removal of α-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether latrepirdine can enhance autophagy and reduce levels of amyloid-β (Aβ)42 aggregates. Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged Aβ yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-Aβ42. GFP-Aβ42 was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-Aβ42 (19:34), which does not aggregate. In the autophagy deficient mutant (Atg8Δ), GFP-Aβ42 showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-Aβ42. Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-Aβ42 in wild-type compared to the Atg8Δ mutant. Further, latrepirdine treatment attenuated Aβ42-induced toxicity in wild-type cells but not in the Atg8Δ mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-Aβ42.
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Affiliation(s)
- Prashant R Bharadwaj
- Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, WA, Australia
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18
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Steele JW, Ju S, Lachenmayer ML, Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol Psychiatry 2013; 18:882-8. [PMID: 22869031 PMCID: PMC3523214 DOI: 10.1038/mp.2012.115] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 06/04/2012] [Accepted: 06/12/2012] [Indexed: 11/29/2022]
Abstract
Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.
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Affiliation(s)
- John W. Steele
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Psychiatry and Mount Sinai Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York NY 10029,Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York NY 10065
| | - Shulin Ju
- Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham MA 02453
| | - M. Lenard Lachenmayer
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Neurology, University of Bonn, Bonn, Germany
| | - Jessica Liken
- Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham MA 02453
| | - Aryeh Stock
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Psychiatry and Mount Sinai Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York NY 10029
| | - Soong Ho Kim
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Psychiatry and Mount Sinai Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York NY 10029
| | | | | | - Sebastian Bernales
- Fundación Ciencia Para La Vida, Santiago, Chile,Medivation, Inc., San Francisco, CA 94105 USA
| | - Giuseppe Verdile
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia, 6027
| | - Prashant Bharadwaj
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia, 6027
| | - Veer Gupta
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia, 6027
| | - Renae Barr
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia, 6027
| | - Amy Friss
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York NY 10029
| | - Georgia Dolios
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York NY 10029
| | - Rong Wang
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York NY 10029
| | - Dagmar Ringe
- Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham MA 02453
| | | | - Ralph N. Martins
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia, 6027,School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia,Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia
| | - Michelle E. Ehrlich
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York NY 10029,Department of Pediatrics, Mount Sinai School of Medicine, New York NY 10029
| | - Zhenyu Yue
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Neuroscience, Mount Sinai School of Medicine, New York NY 10029
| | - Gregory A. Petsko
- Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham MA 02453
| | - Sam Gandy
- Department of Neurology, Mount Sinai School of Medicine, New York NY 10029,Department of Psychiatry and Mount Sinai Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York NY 10029,James J Peters VA Medical Center, Bronx NY 10468,To whom correspondence should be addressed: Sam Gandy, M.D., Ph.D., Departments of Neurology and Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1137, New York, NY 10029 USA or
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19
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Trillo L, Das D, Hsieh W, Medina B, Moghadam S, Lin B, Dang V, Sanchez MM, De Miguel Z, Ashford JW, Salehi A. Ascending monoaminergic systems alterations in Alzheimer's disease. translating basic science into clinical care. Neurosci Biobehav Rev 2013; 37:1363-79. [PMID: 23707776 DOI: 10.1016/j.neubiorev.2013.05.008] [Citation(s) in RCA: 162] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 05/13/2013] [Accepted: 05/16/2013] [Indexed: 01/23/2023]
Abstract
Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD.
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Affiliation(s)
- Ludwig Trillo
- Department of Physiology, School of Medicine, National University of San Agustin, Arequipa, Peru
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20
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Kim JY, Kim DH, Kim JH, Yang YS, Oh W, Lee EH, Chang JW. Umbilical cord blood mesenchymal stem cells protect amyloid-β42 neurotoxicity via paracrine. World J Stem Cells 2012; 4:110-116. [PMID: 23293711 PMCID: PMC3536832 DOI: 10.4252/wjsc.v4.i11.110] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 12/04/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To understand the neuroprotective mechanism of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) against amyloid-β42 (Aβ42) exposed rat primary neurons.
METHODS: To evaluate the neuroprotective effect of hUCB-MSCs, the cells were co-cultured with Aβ42-exposed rat primary neuronal cells in a Transwell apparatus. To assess the involvement of soluble factors released from hUCB-MSCs in neuroprotection, an antibody-based array using co-cultured media was conducted. The neuroprotective roles of the identified hUCB-MSC proteins was assessed by treating recombinant proteins or specific small interfering RNAs (siRNAs) for each candidate protein in a co-culture system.
RESULTS: The hUCB-MSCs secreted elevated levels of decorin and progranulin when co-cultured with rat primary neuronal cells exposed to Aβ42. Treatment with recombinant decorin and progranulin protected from Aβ42-neurotoxicity in vitro. In addition, siRNA-mediated knock-down of decorin and progranulin production in hUCB-MSCs reduced the anti-apoptotic effects of hUCB-MSC in the co-culture system.
CONCLUSION: Decorin and progranulin may be involved in anti-apoptotic activity of hUCB-MSCs exposed to Aβ42.
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21
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Hamley IW. The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization. Chem Rev 2012; 112:5147-92. [DOI: 10.1021/cr3000994] [Citation(s) in RCA: 709] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- I. W. Hamley
- Department
of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD,
U.K
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22
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Zhao Y, Wang J, Wang Y, Huang J. A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse. J Clin Bioinforma 2012; 2:10. [PMID: 22548699 PMCID: PMC3413526 DOI: 10.1186/2043-9113-2-10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 05/01/2012] [Indexed: 12/12/2022] Open
Abstract
Background Mouse is widely used in animal testing of cardiovascular disease. However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human. Methods In this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations. In addition, we also measured the level of conservation of gene expression patterns of the drug targets and their interacting partners by analyzing the microarray data. Results The results show that target proteins of withdrawn cardiovascular drugs are functionally conserved between human and mouse. However, all the binding patterns of withdrawn drugs we retrieved show striking difference due to sequence divergence in drug-binding pocket, mainly through loss or gain of hydrogen bond donors and distinct drug-binding pockets. The binding affinities of withdrawn drugs to their receptors tend to be reduced from mouse to human. In contrast, the FDA-approved and best-selling drugs are little affected. Conclusions Our analysis suggests that sequence divergence in drug-binding pocket may be a reasonable explanation for the discrepancy of drug effects between animal models and human.
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Affiliation(s)
- Yuqi Zhao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32, Eastern Jiaochang Road, Kunming, Yunnan, 650223, China.
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23
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Wendler A, Wehling M. Translatability scoring in drug development: eight case studies. J Transl Med 2012; 10:39. [PMID: 22397594 PMCID: PMC3330010 DOI: 10.1186/1479-5876-10-39] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 03/07/2012] [Indexed: 11/29/2022] Open
Abstract
Translational medicine describes the transfer of basic in vitro and in vivo data into human applications. In the light of low rates of market approvals for new medical entities, better strategies to predict the risk of drug development should be used to increase output and reduce costs. Recently, a scoring system to assess the translatability of early drug projects has been proposed. Here eight drugs from different therapeutic areas have been subjected to a retrospective test-run in this system fictively located at the phase II-III transition. The scores gained here underline the importance of biomarker quality which is pivotal to decrease the risk of the project in all cases. This is particularly evident for gefitinib. The EGFR mutation status is a breakthrough biomarker to predict therapeutic success which made this compound clinically acceptable, and this is plausibly reflected by a considerable increase of the translatability score. For psychiatric and Alzheimer's drugs, and for a CETP-inhibitor, the lack of suitable biomarkers and animal models is reflected by a low translatability score, well correlating with the excessive translational risk in these areas. These case studies document the apparent utility of the scoring system, at least under retrospective conditions, as the scores correlate with the outcomes at the level of market approval. Prospective validation is still missing, but these case studies are encouraging.
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Affiliation(s)
- Alexandra Wendler
- Institute of Experimental and Clinical Pharmacology and Toxicology Clinical Pharmacology Mannheim, Faculty of Medicine Mannheim, Ruprecht-Karls-University of Heidelberg, Maybachstr,14, D-68169 Mannheim, Germany
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24
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Kim JY, Kim DH, Kim JH, Lee D, Jeon HB, Kwon SJ, Kim SM, Yoo YJ, Lee EH, Choi SJ, Seo SW, Lee JI, Na DL, Yang YS, Oh W, Chang JW. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-β plaques. Cell Death Differ 2011; 19:680-91. [PMID: 22015609 PMCID: PMC3307982 DOI: 10.1038/cdd.2011.140] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Presently, co-culture of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) with BV2 microglia under amyloid-β42 (Aβ42) exposure induced a reduction of Aβ42 in the medium as well as an overexpression of the Aβ-degrading enzyme neprilysin (NEP) in microglia. Cytokine array examinations of co-cultured media revealed elevated release of soluble intracellular adhesion molecule-1 (sICAM-1) from hUCB-MSCs. Administration of human recombinant ICAM-1 in BV2 cells and wild-type mice brains induced NEP expression in time- and dose-dependent manners. In co-culturing with BV2 cells under Aβ42 exposure, knockdown of ICAM-1 expression on hUCB-MSCs by small interfering RNA (siRNA) abolished the induction of NEP in BV2 cells as well as reduction of added Aβ42 in the co-cultured media. By contrast, siRNA-mediated inhibition of the sICAM-1 receptor, lymphocyte function-associated antigen-1 (LFA-1), on BV2 cells reduced NEP expression by ICAM-1 exposure. When hUCB-MSCs were transplanted into the hippocampus of a 10-month-old transgenic mouse model of Alzheimer's disease for 10, 20, or 40 days, NEP expression was increased in the mice brains. Moreover, Aβ42 plaques in the hippocampus and other regions were decreased by active migration of hUCB-MSCs toward Aβ deposits. These data suggest that hUCB-MSC-derived sICAM-1 decreases Aβ plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway.
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Affiliation(s)
- J-Y Kim
- Biomedical Research Institute, MEDIPOST Co. Ltd., Seoul 137-874, Republic of Korea
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25
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Terry AV, Callahan PM, Hall B, Webster SJ. Alzheimer's disease and age-related memory decline (preclinical). Pharmacol Biochem Behav 2011; 99:190-210. [PMID: 21315756 PMCID: PMC3113643 DOI: 10.1016/j.pbb.2011.02.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 01/21/2011] [Accepted: 02/01/2011] [Indexed: 01/05/2023]
Abstract
An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.
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Affiliation(s)
- Alvin V Terry
- Department of Pharmacology and Toxicology and Small Animal Behavior Core, Medical College of Georgia, Augusta, GA 30912, USA.
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26
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Latrepirdine increases cerebral glucose utilization in aged mice as measured by [18F]-fluorodeoxyglucose positron emission tomography. Neuroscience 2011; 189:299-304. [PMID: 21619913 DOI: 10.1016/j.neuroscience.2011.05.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Revised: 05/10/2011] [Accepted: 05/12/2011] [Indexed: 11/22/2022]
Abstract
Latrepirdine is hypothesized to exert a unique mechanism of action involving stabilization of mitochondria that may have utility in treating Alzheimer's disease. However, the ability of latrepirdine to improve cognition in Alzheimer's disease (AD) is controversial due to a discrepancy between the positive signal reported in the multi-site phase II clinical trial where latrepirdine met all primary and secondary endpoints [Doody et al. (2008) Lancet 372:207-215], and the subsequent null effect observed in a multicenter, phase III trial. While dysfunction of mitochondria and abnormal energy metabolism has been linked to AD pathology, no studies have been reported that investigate latrepirdine's effect on cerebral glucose utilization (CGU). Glucose metabolism, following acute latrepirdine administration, can be used to help dose selection in Phase I dose-ranging studies. The aim of the current study was to assess changes in CGU in young and aged mice in vivo using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) after acute treatment with latrepirdine. Two ages of B6SJLF2 mice (5 and 20 months old) were tested. Three test-retest FDG-PET baseline scans were assessed across all subjects. As CGU was heterogeneous in aged mice, compared to young mice, aged subjects were rank ordered and then counterbalanced into two CGU homogenous groups. In Studies 1 and 2, latrepirdine (1.0 mg/kg) significantly enhanced CGU in aged mice. In contrast, Study 3 revealed that latrepirdine did not modulate CGU in young mice. Monitoring changes in CGU in response to acute drug administration may represent an imaging biomarker for dose selection in AD. Further studies that would establish the translation from mice to non-human primates to humans need to be investigated to confirm the utility of FDG-PET in dose-selection for mitochondrial modulators.
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27
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Wilcox JT, Lai JKY, Semple E, Brisson BA, Gartley C, Armstrong JN, Betts DH. Synaptically-competent neurons derived from canine embryonic stem cells by lineage selection with EGF and Noggin. PLoS One 2011; 6:e19768. [PMID: 21611190 PMCID: PMC3096636 DOI: 10.1371/journal.pone.0019768] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Accepted: 04/04/2011] [Indexed: 12/23/2022] Open
Abstract
Pluripotent stem cell lines have been generated in several domestic animal species; however, these lines traditionally show poor self-renewal and differentiation. Using canine embryonic stem cell (cESC) lines previously shown to have sufficient self-renewal capacity and potency, we generated and compared canine neural stem cell (cNSC) lines derived by lineage selection with epidermal growth factor (EGF) or Noggin along the neural default differentiation pathway, or by directed differentiation with retinoic acid (RA)-induced floating sphere assay. Lineage selection produced large populations of SOX2+ neural stem/progenitor cell populations and neuronal derivatives while directed differentiation produced few and improper neuronal derivatives. Primary canine neural lines were generated from fetal tissue and used as a positive control for differentiation and electrophysiology. Differentiation of EGF- and Noggin-directed cNSC lines in N2B27 with low-dose growth factors (BDNF/NT-3 or PDGFαα) produced phenotypes equivalent to primary canine neural cells including 3CB2+ radial progenitors, MOSP+ glia restricted precursors, VIM+/GFAP+ astrocytes, and TUBB3+/MAP2+/NFH+/SYN+ neurons. Conversely, induction with RA and neuronal differentiation produced inadequate putative neurons for further study, even though appropriate neuronal gene expression profiles were observed by RT-PCR (including Nestin, TUBB3, PSD95, STX1A, SYNPR, MAP2). Co-culture of cESC-derived neurons with primary canine fetal cells on canine astrocytes was used to test functional maturity of putative neurons. Canine ESC-derived neurons received functional GABAA- and AMPA-receptor mediated synaptic input, but only when co-cultured with primary neurons. This study presents established neural stem/progenitor cell populations and functional neural derivatives in the dog, providing the proof-of-concept required to translate stem cell transplantation strategies into a clinically relevant animal model.
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Affiliation(s)
- Jared T. Wilcox
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- * E-mail: (JTW); (DHB)
| | - Jonathan K. Y. Lai
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Esther Semple
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Brigitte A. Brisson
- Department of Clinical Studies, Ontario Veterinary College, Guelph, Ontario, Canada
| | - Cathy Gartley
- Department of Population Medicine, Ontario Veterinary College, Guelph, Ontario, Canada
| | - John N. Armstrong
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Dean H. Betts
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
- * E-mail: (JTW); (DHB)
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George DR, Whitehouse PJ. Marketplace of memory: what the brain fitness technology industry says about us and how we can do better. THE GERONTOLOGIST 2011; 51:590-6. [PMID: 21572161 DOI: 10.1093/geront/gnr042] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In the therapeutic void created by over 20 failed Alzheimer's disease drugs during the past decade, a new marketplace of "brain fitness" technology products has emerged. Ranging from video games and computer software to mobile phone apps and hand-held devices, these commercial products promise to maintain and enhance the memory, concentration, visual and spatial skills, verbal recall, and executive functions of individual users. It is instructive to view these products as sociocultural objects deeply imbued with the values and ideologies of our age; consequently, this article offers a critique of the brain fitness technology marketplace while identifying limitations in the capacity of commercial products to realistically improve cognitive health. A broader conception of brain health is presented, going beyond the reductionism of the commercial brain fitness marketplace and asking how our most proximate relationships and local communities can play a role in supporting cognitive and psychosocial well-being. This vision is grounded in recent experiences at The Intergenerational School in Cleveland, OH, a multigenerational community-oriented learning environment that is implementing brain fitness technology in novel ways.
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Affiliation(s)
- Daniel R George
- Department of Humanities, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
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29
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Wu TY, Chen CP, Jinn TR. Alzheimer's disease: aging, insomnia and epigenetics. Taiwan J Obstet Gynecol 2011; 49:468-72. [PMID: 21199749 DOI: 10.1016/s1028-4559(10)60099-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2010] [Indexed: 12/11/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia. Severe memory loss, confusion, and impaired cognitive abilities characterize AD. It was only a century after Alzheimer's discovery that scientists were able to shed light on the mystery of its cause, but AD has also become a globally important health issue and the treatment of AD is a challenge for modern medicine. At present, there are five drugs approved in the United States for the treatment of AD, namely, donepezil, galantamine, rivastigmine, and tacrine (which are all cholinesterase inhibitors); and memantine (which is a glutamate receptor antagonist). However, these drugs show only modest effects on AD patients. Thus, new investigations are necessary for pharmacological development in AD. This brief review focuses on new studies that demonstrate the link between epigenetics and AD, and explores the possibility that insomnia may be one factor that effects AD.
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Affiliation(s)
- Tzong Yuan Wu
- Department of Bioscience Technology, Chung Yuan Christian University, Chung Li, Taipei, Taichung, Taiwan.
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30
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Vignisse J, Steinbusch HWM, Bolkunov A, Nunes J, Santos AI, Grandfils C, Bachurin S, Strekalova T. Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:510-22. [PMID: 21163318 DOI: 10.1016/j.pnpbp.2010.12.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Revised: 12/07/2010] [Accepted: 12/08/2010] [Indexed: 11/25/2022]
Abstract
Pre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.
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Affiliation(s)
- Julie Vignisse
- School for Mental Health and Neuroscience, Department of Neuroscience, Maastricht University, Universiteitssingel 50, NL 6229 ER Maastricht, The Netherlands
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31
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Naga KK, Geddes JW. Dimebon inhibits calcium-induced swelling of rat brain mitochondria but does not alter calcium retention or cytochrome C release. Neuromolecular Med 2011; 13:31-6. [PMID: 20625939 PMCID: PMC3388507 DOI: 10.1007/s12017-010-8130-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Accepted: 06/26/2010] [Indexed: 01/21/2023]
Abstract
Dimebon was originally introduced as an antihistamine and subsequently investigated as a possible therapeutic for a variety of disorders, including Alzheimer's disease. One putative mechanism underlying the neuroprotective properties of Dimebon is inhibition of mitochondrial permeability transition, based on the observation that Dimebon inhibited the swelling of rat liver mitochondria induced by calcium and other agents that induce permeability transition. Because liver and brain mitochondria differ substantially in their properties and response to conditions associated with opening of the permeability transition pore, we sought to determine whether Dimebon inhibited permeability transition in brain mitochondria. Dimebon reduced calcium-induced mitochondrial swelling but did not enhance the calcium retention capacity or impair calcium-induced cytochrome C release from non-synaptic mitochondria isolated from rat brain cerebral cortex. These findings indicate that Dimebon does not inhibit mitochondrial permeability transition, induced by excessive calcium uptake, in brain mitochondria.
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Affiliation(s)
- Kranthi Kumari Naga
- Spinal Cord and Brain Injury Research Center, Department of Anatomy and Neurobiology, University of Kentucky, 741. S. Limestone Street, Lexington, KY 40536-0509, USA
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32
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MacMillan KS, Naidoo J, Liang J, Melito L, Williams NS, Morlock L, Huntington PJ, Estill SJ, Longgood J, Becker GL, McKnight SL, Pieper AA, De Brabander JK, Ready JM. Development of proneurogenic, neuroprotective small molecules. J Am Chem Soc 2011; 133:1428-37. [PMID: 21210688 PMCID: PMC3033481 DOI: 10.1021/ja108211m] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.
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33
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Swerdlow RH. Role and treatment of mitochondrial DNA-related mitochondrial dysfunction in sporadic neurodegenerative diseases. Curr Pharm Des 2011; 17:3356-73. [PMID: 21902672 PMCID: PMC3351798 DOI: 10.2174/138161211798072535] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 08/26/2011] [Indexed: 12/12/2022]
Abstract
Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed.
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Affiliation(s)
- Russell H Swerdlow
- Department of Neurology, University of Kansas School of Medicine, Kansas City, 66160, USA.
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Ludwig J, Höffle-Maas A, Samochocki M, Luttmann E, Albuquerque EX, Fels G, Maelicke A. Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain. J Recept Signal Transduct Res 2010; 30:469-83. [PMID: 21062106 DOI: 10.3109/10799893.2010.505239] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Galantamine is an approved drug treatment for Alzheimer's disease. Initially identified as a weak cholinesterase inhibitor, we have established that galantamine mainly acts as an 'allosterically potentiating ligand (APL)' of nicotinic acetylcholine receptors (nAChR). Meanwhile other 'positive allosteric modulators (PAM)' of nAChR channel activity have been discovered, and for one of them a binding site within the transmembrane domain has been proposed. Here we show, by performing site-directed mutagenesis studies of ectopically expressed chimeric chicken α7/mouse 5-hydroxytryptamine 3 receptor-channel complex, in combination with whole-cell current measurements, in the presence and absence of galantamine, that the APL binding site is different from the proposed PAM binding site. We demonstrate that residues T197, I196, and F198 of ß-strand 10 represent major elements of the galantamine binding site. Residue K123, earlier suggested as being 'close to' the APL binding site, is not part of this site but rather appears to play a role in coupling of agonist binding to channel opening and closing. Our data confirm our earlier results that the galantamine binding site is different from the ACh binding site. Both sites are in close proximity and hence may influence each other in a synergistic fashion. Other interesting areas identified in the present study are a 'hinge' region around and containing residues F122, K123, and K143 possibly being involved in relaying the signal of agonist binding to gating of the transmembrane channel, and a 'folding centre', with P119 as the dominating residue, that crucially positions the agonist binding site with respect to the hinge region.
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35
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Becker RE, Greig NH. Why so few drugs for Alzheimer's disease? Are methods failing drugs? Curr Alzheimer Res 2010; 7:642-51. [PMID: 20704560 PMCID: PMC3010269 DOI: 10.2174/156720510793499075] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 06/02/2010] [Indexed: 11/22/2022]
Abstract
Recent studies of Alzheimer's disease (AD) and other neuropsychiatric drug developments raise questions whether failures of some drugs occur due to flaws in methods. In three case studies of recent AD drug development failures with phenserine, metrifonate, and tarenflurbil we identified methodological lapses able to account for the failures. Errors in complex systems such as drug developments are both almost inescapable due to human mistakes and most frequently hidden at the time of occurrence and thereafter. We propose preemptive error management as a preventive strategy to exclude or control error intrusions into neuropsychiatric drug developments. We illustrate the functions we anticipate for a preemptive error management preventive strategy with a checklist and identify the limitations of this aspect of the proposal with three drug examples. This strategy applies core scientific practices to insure the quality of data within the current context of AD drug development practices.
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Affiliation(s)
- Robert E. Becker
- Aristea Translational Medicine Corporation, Freeport, ME 04078; USA
- Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Nigel H. Greig
- Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
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36
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37
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Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL. Discovery of a proneurogenic, neuroprotective chemical. Cell 2010; 142:39-51. [PMID: 20603013 PMCID: PMC2930815 DOI: 10.1016/j.cell.2010.06.018] [Citation(s) in RCA: 292] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2010] [Revised: 06/04/2010] [Accepted: 06/10/2010] [Indexed: 11/29/2022]
Abstract
An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:
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Affiliation(s)
- Andrew A. Pieper
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | | | | | | | - Jeannie Zhong
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | | | - Ginger L. Becker
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | - Paula Huntington
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | - Shauna E. Goldman
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | | | - Maria Capota
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | - Jeremiah K. Britt
- Department of Biochemistry, Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
| | | | | | - Daniel J. Brat
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30332
| | | | | | | | | | - Jenny Hsieh
- Department of Molecular Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9152
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