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Kazemeini S, Nadeem-Tariq A, Shih R, Rafanan J, Ghani N, Vida TA. From Plaques to Pathways in Alzheimer's Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis. Int J Mol Sci 2024; 25:11720. [PMID: 39519272 PMCID: PMC11546801 DOI: 10.3390/ijms252111720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Alzheimer's disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent Aβ-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial-Neurovascular-Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood-brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide.
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Affiliation(s)
| | | | | | | | | | - Thomas A. Vida
- Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA; (S.K.); (A.N.-T.); (R.S.); (J.R.); (N.G.)
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Tran J, Parekh S, Rockcole J, Wilson D, Parmar MS. Repurposing antidiabetic drugs for Alzheimer's disease: A review of preclinical and clinical evidence and overcoming challenges. Life Sci 2024; 355:123001. [PMID: 39173996 DOI: 10.1016/j.lfs.2024.123001] [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: 07/05/2024] [Revised: 08/13/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Repurposing antidiabetic drugs for the treatment of Alzheimer's disease (AD) has emerged as a promising therapeutic strategy. This review examines the potential of repurposing antidiabetic drugs for AD treatment, focusing on preclinical evidence, clinical trials, and observational studies. In addition, the review aims to explore challenges and opportunities in repurposing antidiabetic drugs for AD, emphasizing the importance of well-designed clinical trials that consider patient selection criteria, refined outcome measures, adverse effects, and combination therapies to enhance therapeutic efficacy. Preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, metformin, thiazolidinediones, and sodium-glucose co-transporter-2 (SGLT2) inhibitors exhibit neuroprotective effects in AD preclinical models. In preclinical studies, antidiabetic drugs have demonstrated neuroprotective effects by reducing amyloid beta (Aβ) plaques, tau hyperphosphorylation, neuroinflammation, and cognitive impairment. Antidiabetic drug classes, notably GLP-1 analogs and SGLT2 inhibitors, and a reduced risk of dementia in patients with diabetes mellitus. While the evidence for DPP4 inhibitors is mixed, some studies suggest a potential protective effect. On the other hand, alpha-glucosidase inhibitors (AGIs) and sulfonylureas may potentially increase the risk, especially in those experiencing recurrent hypoglycemic events. Repurposing antidiabetic drugs for AD is a promising therapeutic strategy, but challenges such as disease heterogeneity, limited biomarkers, and benefits versus risk evaluation need to be addressed. Ongoing clinical trials in mild cognitive impairment (MCI) and early AD patients without diabetes will be crucial in determining the clinical efficacy and safety of the antidiabetic drugs, paving the way for potential treatments for AD.
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Affiliation(s)
- Jacky Tran
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA
| | - Sneh Parekh
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA
| | - Julia Rockcole
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA
| | - Danielle Wilson
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA
| | - Mayur S Parmar
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA.
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Pradhan SP, Sahu PK, Behera A. New insights toward molecular and nanotechnological approaches to antidiabetic agents for Alzheimer's disease. Mol Cell Biochem 2023; 478:2739-2762. [PMID: 36949264 DOI: 10.1007/s11010-023-04696-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 02/27/2023] [Indexed: 03/24/2023]
Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder affecting a major class of silver citizens. The disorder shares a mutual relationship on account of its cellular and molecular pathophysiology with type-II diabetes mellitus (DM). Chronic DM increases the risk for AD. Emerging evidence recommended that resistance in insulin production develops cognitive dysfunction, which generally leads to AD. Repurposing of antidiabetic drugs can be effective in preventing and treatment of the neurodegenerative disorder. Limitations of antidiabetic drugs restrict the repurposing of the drugs for other disorders. Therefore, nanotechnological intervention plays a significant role in the treatment of neurological disorders. In this review, we discuss the common cellular and molecular pathophysiologies between AD and type-II DM, the relevance of in vivo models of type II DM in the study of AD, and the repurposing of antidiabetic drugs and the nanodelivery systems of antidiabetic drugs against AD.
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Affiliation(s)
- Sweta Priyadarshini Pradhan
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Campus-II, Kalinga Nagar, Bhubaneswar, Odisha, India
| | - Pratap Kumar Sahu
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Campus-II, Kalinga Nagar, Bhubaneswar, Odisha, India
| | - Anindita Behera
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Campus-II, Kalinga Nagar, Bhubaneswar, Odisha, India.
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Arbo BD, Schimith LE, Goulart dos Santos M, Hort MA. Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation. Eur J Pharmacol 2022; 919:174800. [DOI: 10.1016/j.ejphar.2022.174800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/18/2022] [Accepted: 02/02/2022] [Indexed: 11/03/2022]
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Glibenclamide ameliorates the expression of neurotrophic factors in sevoflurane anaesthesia-induced oxidative stress and cognitive impairment in hippocampal neurons of old rats. J Vet Res 2021; 65:527-538. [PMID: 35112009 PMCID: PMC8775723 DOI: 10.2478/jvetres-2021-0064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 11/19/2021] [Indexed: 11/28/2022] Open
Abstract
Introduction Several antidiabetic medications have been proposed as prospective treatments for cognitive impairments in type 2 diabetes patients, glibenclamide (GBC) among them. Our research aimed to evaluate the impact of GBC on hippocampal learning memory and inflammation due to enhanced neurotrophic signals induced by inhalation of sevoflurane. Material and Methods Rats (Sprague Dawley, both sexes) were assigned to four groups: a control (vehicle, p.o.), GBC (10 mg/kg b.w.; p.o.), low-dose sevoflurane and low-dose sevoflurane + GBC (10 mg/kg b.w.; p.o.) for 23 days. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining was performed to analyse the count of apoptotic cells and ELISA was conducted to assess the protein signals. A Western blot, a Y-maze test, and a Morris maze test were performed, and the results analysed. Blood and tissues were collected, and isolation of RNA was performed with qRT-PCR. Results The Morris maze test results revealed an improvement in the length of the escape latency on days 1 (P < 0.05), 2 (P < 0.01), 3, and 4 in the low-dose Sevo group. Time spent in the quadrant and crossing axis and the percentage of spontaneous alterations showed a substantial decrease in the low-dose Sevo group which received GBC at 10 mg/kg b.w. Significant increases were shown in IL-6 and TNF-α levels in the low-dose Sevo group, whereas a decrease was evident in the GBC group. Conclusion Our results indicate that glibenclamide may be a novel drug to prevent sevoflurane inhalation-induced impaired learning and reduce brain-derived neurotrophic factor release, which may be a vital target for the development of potential therapies for cognitive deficits and neurodegeneration.
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Rojas M, Chávez-Castillo M, Bautista J, Ortega Á, Nava M, Salazar J, Díaz-Camargo E, Medina O, Rojas-Quintero J, Bermúdez V. Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes 2021; 12:745-766. [PMID: 34168725 PMCID: PMC8192246 DOI: 10.4239/wjd.v12.i6.745] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/20/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD.
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Affiliation(s)
- Milagros Rojas
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Mervin Chávez-Castillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jordan Bautista
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Edgar Díaz-Camargo
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Oscar Medina
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Joselyn Rojas-Quintero
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, United States
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia
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Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review. Ageing Res Rev 2021; 67:101302. [PMID: 33609776 DOI: 10.1016/j.arr.2021.101302] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dementia is a debilitating syndrome that significantly impacts individuals over the age of 65 years. There are currently no disease-modifying treatments for dementia. Impairment of nutrient sensing pathways has been implicated in the pathogenesis of dementia, and may offer a novel treatment approach for dementia. AIMS This systematic review collates all available evidence for Food and Drug Administration (FDA)-approved therapeutics that modify nutrient sensing in the context of preventing cognitive decline or improving cognition in ageing, mild cognitive impairment (MCI), and dementia populations. METHODS PubMed, Embase and Web of Science databases were searched using key search terms focusing on available therapeutics such as 'metformin', 'GLP1', 'insulin' and the dementias including 'Alzheimer's disease' and 'Parkinson's disease'. Articles were screened using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). The risk of bias was assessed using the Cochrane Risk of Bias tool v 2.0 for human studies and SYRCLE's risk of bias tool for animal studies. RESULTS Out of 2619 articles, 114 were included describing 31 different 'modulation of nutrient sensing pathway' therapeutics, 13 of which specifically were utilized in human interventional trials for normal ageing or dementia. Growth hormone secretagogues improved cognitive outcomes in human mild cognitive impairment, and potentially normal ageing populations. In animals, all investigated therapeutic classes exhibited some cognitive benefits in dementia models. While the risk of bias was relatively low in human studies, this risk in animal studies was largely unclear. CONCLUSIONS Modulation of nutrient sensing pathway therapeutics, particularly growth hormone secretagogues, have the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.
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Insights into Potential Targets for Therapeutic Intervention in Epilepsy. Int J Mol Sci 2020; 21:ijms21228573. [PMID: 33202963 PMCID: PMC7697405 DOI: 10.3390/ijms21228573] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/04/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.
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Suresh J, Khor IW, Kaur P, Heng HL, Torta F, Dawe GS, Tai ES, Tolwinski NS. Shared signaling pathways in Alzheimer’s and metabolic disease may point to new treatment approaches. FEBS J 2020; 288:3855-3873. [DOI: 10.1111/febs.15540] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/18/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022]
Affiliation(s)
| | - Ing Wei Khor
- Department of Medicine Yong Loo Lin School of MedicineNational University of Singapore
| | - Prameet Kaur
- Science Division Yale‐ NUS College Singapore Singapore
| | - Hui Li Heng
- Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore, and Neurobiology Programme
- Life Sciences Institute National University of Singapore Singapore
| | - Federico Torta
- Singapore Lipidomics Incubator Department of Biochemistry Yong Loo Lin School of MedicineNational University of Singapore Singapore
| | - Gavin S. Dawe
- Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore, and Neurobiology Programme
- Life Sciences Institute National University of Singapore Singapore
| | - E Shyong Tai
- Department of Medicine Yong Loo Lin School of MedicineNational University of Singapore
- Division of Endocrinology National University HospitalNational University Health System
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Zhou JB, Tang X, Han M, Yang J, Simó R. Impact of antidiabetic agents on dementia risk: A Bayesian network meta-analysis. Metabolism 2020; 109:154265. [PMID: 32446679 DOI: 10.1016/j.metabol.2020.154265] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/13/2020] [Accepted: 05/19/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND Dementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association. OBJECTIVE This study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus. METHODS Relevant studies were retrieved from the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. Nine antidiabetic agents were included in the search. Data were pooled via network meta-analysis and meta-analysis. RESULTS Nine studies were selected for the network meta-analysis with 530,355 individuals and 17 studies for the meta-analysis with 1,258,879 individuals. The analysis excluded glucagon-like peptide 1 (GLP-1) analogs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors due to the absence of relevant data. The use of dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, thiazolidinedione, and sulfonylurea was associated with a decreased risk of dementia in comparison to no treatment with antidiabetic agents (hazard ratio [HR] for DPP-4 inhibitors, 0.54; 95% confidence interval [CI], 0.38-0.74, HR for metformin, 0.75; 95% CI, 0.63-0.86; HR for sulfonylurea, 0.85; 95%CI, 0.73-0.98 and HR for thiazolidinedione, 0.70; 95% CI, 0.55-0.89, respectively). However, the node-splitting analysis showed the inconsistency of direct and indirect estimates in sulfonylurea (P = 0.042). DPP-4 inhibitors, metformin, thiazolidinedione, and sulfonylurea exhibited a significant impact on the risk of dementia in diabetics compared with insulin (HR, 0.35; 95%CI, 0.20-0.59, HR, 0.48; 95% CI, 0.30-0.77, HR, 0.45; 95% CI, 0.29-0.73 and HR, 0.55; 95% CI, 0.34-0.88, respectively). DPP-4 inhibitors also exhibited a protective effect on the risk of Alzheimer's dementia compared with the no treatment with antidiabetic agents (HR, 0.48; 95% CI, 0.25-0.92). The meta-analysis demonstrated a protective effect of using metformin and DPP-4 inhibitors on the risk of dementia (HR, 0.86; 95% CI, 0.74-1.00 and HR, 0.65; 95% CI, 0.55-0.76, respectively). Further analysis showed insulin was associated with an increased risk of Alzheimer's dementia (HR, 1.60; 95% CI, 1.13-2.26). Only two case-control studies mentioned GLP-1 analogs and SGLT-2 inhibitors, and the pooled ORs showed no evidence of an association with dementia (GLP-1 analogs: 0.71; 95% CI, 0.46-1.10 and SGLT-2 inhibitors: 0.74; 95% CI, 0.47-1.15). CONCLUSION This analysis indicated that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. For the increasing focus on the protective effect on dementia, further specific clinical studies are needed to evaluate the impact of GLP-1 analogs and SGLT-2 inhibitors on the risk of dementia.
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Affiliation(s)
- Jian-Bo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, China.
| | - Xingyao Tang
- Beijing Tongren Hospital, Capital Medical University, China
| | - Min Han
- Department of Nephrology, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Jinkui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, China
| | - Rafael Simó
- Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119, 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Ju YJ, Kim N, Gee MS, Jeon SH, Lee D, Do J, Ryu JS, Lee JK. Glibenclamide modulates microglial function and attenuates Aβ deposition in 5XFAD mice. Eur J Pharmacol 2020; 884:173416. [PMID: 32721448 DOI: 10.1016/j.ejphar.2020.173416] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/23/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022]
Abstract
Severe neuroinflammation is known as a main pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In these diseases, excessive microglial activation is one of the main causes of inflammation in the central nervous system. Therefore, inhibition of activated microglia may be suggested as a treatment for neuroinflammatory diseases. Glibenclamide, known as a therapeutics for type 2 diabetes in clinical trials has been shown to be effective in the inhibiting inflammatory conditions of various diseases. However, studies on the effects of glibenclamide for improving AD pathologies are little known. In this study, we tested glibenclamide on microglial cell line BV2 and 5XFAD mice. We found that glibenclamide significantly inhibited nitric oxide (NO) at 10 μM and 40 μM in BV2 cells induced by lipopolysaccharide (LPS) stimulation. In addition, we confirmed that 40 μM of glibenclamide reduced pro-inflammatory cytokines and proteins in the LPS-stimulated microglial cells. The anti-inflammatory effect of glibenclamide was further tested in APP/PS1 transgenic mouse. Although further analysis would be needed to confirm whether glibenclamide affects behavioral performance, our data suggests that glibenclamide may be a therapeutic option for AD treatment.
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Affiliation(s)
- Yeon-Joo Ju
- Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Namkwon Kim
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Min Sung Gee
- Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Seung Ho Jeon
- Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Danbi Lee
- Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Jimin Do
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Jong-Sik Ryu
- Exercise Metabolism Laboratory, Department of Physical Education, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, Republic of Korea
| | - Jong Kil Lee
- Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea; Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
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Esmaeili MH, Enayati M, Khabbaz Abkenar F, Ebrahimian F, Salari AA. Glibenclamide mitigates cognitive impairment and hippocampal neuroinflammation in rats with type 2 diabetes and sporadic Alzheimer-like disease. Behav Brain Res 2020; 379:112359. [PMID: 31733313 DOI: 10.1016/j.bbr.2019.112359] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 10/23/2019] [Accepted: 11/13/2019] [Indexed: 12/20/2022]
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Ohyagi Y, Miyoshi K, Nakamura N. Therapeutic Strategies for Alzheimer's Disease in the View of Diabetes Mellitus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1128:227-248. [PMID: 31062332 DOI: 10.1007/978-981-13-3540-2_11] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recently, Alzheimer's disease (AD) is understood as "diabetes of the brain" or "type 3 diabetes." Recent clinical trials of anti-amyloid β-protein (Aβ) therapies have not proved to be successful. Thus, glucose-insulin metabolism in the brain is thought to be an alternative therapeutic target. Various types of antidiabetic drugs such as insulin, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, biguanides, and others have been reported to be effective on cognitive impairment in animal models and patients with DM or AD. Here, recent reports are reviewed. While we identified apomorphine (APO) as a novel drug that promoted intracellular Aβ degradation and improved memory function in an AD mouse model, more recently, we have revealed that APO treatment improves neuronal insulin resistance and activates insulin-degrading enzyme (IDE), a major Aβ-degrading enzyme. In this context, recovery of impaired insulin signaling in AD neurons may be a promising therapeutic strategy for AD dementia.
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Affiliation(s)
- Yasumasa Ohyagi
- Department of Neurology and Geriatric Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
| | - Katsue Miyoshi
- Long-Term Care Health Facility Cosmos, Kushiro-mutsumi, Hokkaido, Japan
| | - Norimichi Nakamura
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Zheng R, Zhang ZH, Zhao YX, Chen C, Jia SZ, Cao XC, Shen LM, Ni JZ, Song GL. Transcriptomic Insights into the Response of the Olfactory Bulb to Selenium Treatment in a Mouse Model of Alzheimer's Disease. Int J Mol Sci 2019; 20:E2998. [PMID: 31248178 PMCID: PMC6627505 DOI: 10.3390/ijms20122998] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/05/2019] [Accepted: 06/17/2019] [Indexed: 01/08/2023] Open
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the presence of extracellular senile plaques primarily composed of Aβ peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins. Olfactory dysfunction is an early clinical phenotype in AD and was reported to be attributable to the presence of NFTs, senile Aβ plaques in the olfactory bulb (OB). Our previous research found that selenomethionine (Se-Met), a major form of selenium (Se) in organisms, effectively increased oxidation resistance as well as reduced the generation and deposition of Aβ and tau hyperphosphorylation in the olfactory bulb of a triple transgenic mouse model of AD (3×Tg-AD), thereby suggesting a potential therapeutic option for AD. In this study, we further investigated changes in the transcriptome data of olfactory bulb tissues of 7-month-old triple transgenic AD (3×Tg-AD) mice treated with Se-Met (6 µg/mL) for three months. Comparison of the gene expression profile between Se-Met-treated and control mice revealed 143 differentially expressed genes (DEGs). Among these genes, 21 DEGs were upregulated and 122 downregulated. The DEGs were then annotated against the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The results show that upregulated genes can be roughly classified into three types. Some of them mainly regulate the regeneration of nerves, such as Fabp7, Evt5 and Gal; some are involved in improving cognition and memory, such as Areg; and some are involved in anti-oxidative stress and anti-apoptosis, such as Adcyap1 and Scg2. The downregulated genes are mainly associated with inflammation and apoptosis, such as Lrg1, Scgb3a1 and Pglyrp1. The reliability of the transcriptomic data was validated by quantitative real time polymerase chain reaction (qRT-PCR) for the selected genes. These results were in line with our previous study, which indicated therapeutic effects of Se-Met on AD mice, providing a theoretical basis for further study of the treatment of AD by Se-Met.
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Affiliation(s)
- Rui Zheng
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Zhong-Hao Zhang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Yu-Xi Zhao
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Chen Chen
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Shi-Zheng Jia
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Xian-Chun Cao
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Li-Ming Shen
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Jia-Zuan Ni
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
| | - Guo-Li Song
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
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15
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Salgado-Puga K, Rodríguez-Colorado J, Prado-Alcalá RA, Peña-Ortega F. Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β. J Alzheimers Dis 2018; 57:205-226. [PMID: 28222502 DOI: 10.3233/jad-160543] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.
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Affiliation(s)
- Karla Salgado-Puga
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, QRO, México
| | - Javier Rodríguez-Colorado
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, QRO, México
| | - Roberto A Prado-Alcalá
- Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, QRO, México
| | - Fernando Peña-Ortega
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, QRO, México
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16
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Alford S, Patel D, Perakakis N, Mantzoros CS. Obesity as a risk factor for Alzheimer's disease: weighing the evidence. Obes Rev 2018; 19:269-280. [PMID: 29024348 DOI: 10.1111/obr.12629] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 09/03/2017] [Accepted: 09/04/2017] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is the sixth leading cause of death in the USA today; therefore, it is imperative that public health initiatives and clinical strategies are developed to prevent and effectively treat AD. Despite the enormous impact that AD has on individuals, families, society, and the health care system, there are no biomarkers to clearly identify those at risk for AD, public health prevention strategies in place, or treatments to address the underlying pathology or stop the progression of AD. There is ample scientific as well as empirical evidence that obesity and its metabolic and vascular comorbidities are related to AD and likely in the causative pathway. Obesity prevention and treatment could prove to be an efficacious and safe approach to preventing AD, a serious and daunting epidemic disease. In this review, we present the current pathophysiological and clinical evidence linking obesity and obesity-related comorbidities (eg, insulin resistance, hyperglycaemia, and type 2 diabetes) with AD. Additionally, we discuss which population to target and when to consider treatment for AD. Finally, we summarize the current evidence regarding the efficacy of anti-obesity and anti-diabetic pharmacotherapeutic agents for the treatment of AD.
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Affiliation(s)
| | - D Patel
- MCPHS University, Boston, MA, USA.,VA Boston Healthcare System, Boston, MA, USA
| | - N Perakakis
- Mantzoros Lab, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - C S Mantzoros
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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17
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ATP-sensitive potassium-channel inhibitor glibenclamide attenuates HPA axis hyperactivity, depression- and anxiety-related symptoms in a rat model of Alzheimer's disease. Brain Res Bull 2018; 137:265-276. [PMID: 29307659 DOI: 10.1016/j.brainresbull.2018.01.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 12/13/2017] [Accepted: 01/03/2018] [Indexed: 12/17/2022]
Abstract
Affective disorders including depression and anxiety are among the most prevalent behavioral abnormalities in patients with Alzheimer's disease (AD), which affect the quality of life and progression of the disease. Dysregulation of the hypothalamic-pituitary-adrenal-(HPA) axis has been reported in affective disorders and AD. Recent studies revealed that current antidepressant drugs are not completely effective for treating anxiety- and depression-related disorders in people with dementia. ATP-sensitive-potassium-(KATP) channels are well-known to be involved in AD pathophysiology, HPA axis function and the pathogenesis of depression and anxiety-related behaviors. Thus, targeting of KATP channel may be a potential therapeutic strategy in AD. Hence, we investigated the effects of intracerebroventricular injection of Aβ25-35 alone or in combination with glibenclamide, KATP channel inhibitor on depression- and anxiety-related behaviors as well as HPA axis response to stress in rats. To do this, non-Aβ25-35- and Aβ25-35-treated rats were orally treated with glibenclamide, then the behavioral consequences were assessed using sucrose preference, forced swim, light-dark box and plus maze tests. Stress-induced corticosterone levels following forced swim and plus maze tests were also evaluated as indicative of abnormal HPA-axis-function. Aβ25-35 induced HPA axis hyperreactivity and increased depression- and anxiety-related symptoms in rats. Our results showed that blockade of KATP channels with glibenclamide decreased depression- and anxiety-related behaviors by normalizing HPA axis activity in Aβ25-35-treated rats. This study provides additional evidence that Aβ administration can induce depression- and anxiety-like symptoms in rodents, and suggests that KATP channel inhibitors may be a plausible therapeutic strategy for treating affective disorders in AD patients.
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18
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Li J, Cesari M, Liu F, Dong B, Vellas B. Effects of Diabetes Mellitus on Cognitive Decline in Patients with Alzheimer Disease: A Systematic Review. Can J Diabetes 2016; 41:114-119. [PMID: 27614804 DOI: 10.1016/j.jcjd.2016.07.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 06/26/2016] [Accepted: 07/14/2016] [Indexed: 02/05/2023]
Abstract
Basic and clinical research support a link between diabetes mellitus and Alzheimer disease (AD). However, the relationship with AD progression is unclear. This review focuses on the association between diabetes and cognitive decline in patients with AD. The literature published through May 2015 was searched in 3 databases: PubMed, Embase and Cochrane. Studies evaluating the effects of diabetes on patients with AD or cognitive decline were included, and extracted data were analyzed. A total of 10 articles met the inclusion criteria for review. The results of these studies were inconsistent in terms of the association between diabetes and cognitive decline. Only 2 studies demonstrated that the presence of diabetes was independently related to the progression of cognitive decline in the patients with AD, and 3 studies suggested that histories of diabetes were not correlated with the changes in cognitive function in patients with AD. Half of the included studies even indicated that histories of diabetes were associated with lesser declines in cognitive function in patients with AD. Current evidence indicates that the link between diabetes and cognitive decline in patients with AD is uncertain. Further clinical studies are needed, with larger samples, long-term follow up and an extended battery of cognitive assessments.
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Affiliation(s)
- Jun Li
- The Center of Gerontology and Geriatrics, West China Medical School/West China Hospital, Sichuan University, Chengdu, Sichuan, China; Institut du Vieillissement, Gérontopôle, Université Toulouse III-Paul Sabatier, Toulouse, France.
| | - Matteo Cesari
- Institut du Vieillissement, Gérontopôle, Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Fei Liu
- Department of Nephrology, West China Medical School/West China Hospital, Sichuan University, Chengdu, Sichuan,China
| | - Birong Dong
- The Center of Gerontology and Geriatrics, West China Medical School/West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bruno Vellas
- Institut du Vieillissement, Gérontopôle, Université Toulouse III-Paul Sabatier, Toulouse, France
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19
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Chen F, Dong RR, Zhong KL, Ghosh A, Tang SS, Long Y, Hu M, Miao MX, Liao JM, Sun HB, Kong LY, Hong H. Antidiabetic drugs restore abnormal transport of amyloid-β across the blood-brain barrier and memory impairment in db/db mice. Neuropharmacology 2015. [PMID: 26211973 DOI: 10.1016/j.neuropharm.2015.07.023] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Previous studies have shown significant changes in amyloid-β (Aβ) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in Aβ transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in Aβ transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased Aβ influx across the BBB determined by intra-arterial infusion of (125)I-Aβ(1-40), and expression of the receptor for advanced glycation end products (RAGE) participating in Aβ influx. Insulin glargine, but not, metformin or glibenclamide increased Aβ efflux across the BBB determined by stereotaxic intra-cerebral infusion of (125)I-Aβ(1-40), and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in Aβ efflux. Moreover, treatment with these drugs significantly decreased hippocampal Aβ(1-40) or Aβ(1-42) and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal Aβ transport across the BBB and memory impairment under diabetic context.
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Affiliation(s)
- Fang Chen
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Rong Rong Dong
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Kai Long Zhong
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Arijit Ghosh
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Su Su Tang
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Yan Long
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Mei Hu
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Ming Xing Miao
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Jian Min Liao
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Hong Bing Sun
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Ling Yi Kong
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Hao Hong
- Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
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20
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The role of type 2 diabetes in neurodegeneration. Neurobiol Dis 2015; 84:22-38. [PMID: 25926349 DOI: 10.1016/j.nbd.2015.04.008] [Citation(s) in RCA: 197] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/18/2015] [Accepted: 04/21/2015] [Indexed: 02/07/2023] Open
Abstract
A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular beta amyloid (Aβ) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Aβ may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed.
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21
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Lang R, Gundlach AL, Holmes FE, Hobson SA, Wynick D, Hökfelt T, Kofler B. Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity. Pharmacol Rev 2015; 67:118-75. [PMID: 25428932 DOI: 10.1124/pr.112.006536] [Citation(s) in RCA: 238] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Galanin was first identified 30 years ago as a "classic neuropeptide," with actions primarily as a modulator of neurotransmission in the brain and peripheral nervous system. Other structurally-related peptides-galanin-like peptide and alarin-with diverse biologic actions in brain and other tissues have since been identified, although, unlike galanin, their cognate receptors are currently unknown. Over the last two decades, in addition to many neuronal actions, a number of nonneuronal actions of galanin and other galanin family peptides have been described. These include actions associated with neural stem cells, nonneuronal cells in the brain such as glia, endocrine functions, effects on metabolism, energy homeostasis, and paracrine effects in bone. Substantial new data also indicate an emerging role for galanin in innate immunity, inflammation, and cancer. Galanin has been shown to regulate its numerous physiologic and pathophysiological processes through interactions with three G protein-coupled receptors, GAL1, GAL2, and GAL3, and signaling via multiple transduction pathways, including inhibition of cAMP/PKA (GAL1, GAL3) and stimulation of phospholipase C (GAL2). In this review, we emphasize the importance of novel galanin receptor-specific agonists and antagonists. Also, other approaches, including new transgenic mouse lines (such as a recently characterized GAL3 knockout mouse) represent, in combination with viral-based techniques, critical tools required to better evaluate galanin system physiology. These in turn will help identify potential targets of the galanin/galanin-receptor systems in a diverse range of human diseases, including pain, mood disorders, epilepsy, neurodegenerative conditions, diabetes, and cancer.
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Affiliation(s)
- Roland Lang
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
| | - Andrew L Gundlach
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
| | - Fiona E Holmes
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
| | - Sally A Hobson
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
| | - David Wynick
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
| | - Tomas Hökfelt
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
| | - Barbara Kofler
- Department of Dermatology (R.L.) and Laura Bassi Centre of Expertise, Department of Pediatrics (B.K.), Paracelsus Private Medical University, Salzburg, Austria; The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia (A.L.G.); Schools of Physiology and Pharmacology and Clinical Sciences, Bristol University, Bristol, United Kingdom (F.E.H., S.A.H., D.W.); and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.H.)
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Domínguez R, Pagano M, Marschoff E, González S, Repetto M, Serra J. Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis. NEUROLOGÍA (ENGLISH EDITION) 2014. [DOI: 10.1016/j.nrleng.2014.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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23
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Sripetchwandee J, Pipatpiboon N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. DPP-4 Inhibitor and PPARγ Agonist Restore the Loss of CA1 Dendritic Spines in Obese Insulin-resistant Rats. Arch Med Res 2014; 45:547-52. [DOI: 10.1016/j.arcmed.2014.09.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 09/12/2014] [Indexed: 02/07/2023]
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24
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Qiu WQ, Zhu H. Amylin and its analogs: a friend or foe for the treatment of Alzheimer's disease? Front Aging Neurosci 2014; 6:186. [PMID: 25120481 PMCID: PMC4114192 DOI: 10.3389/fnagi.2014.00186] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 07/09/2014] [Indexed: 12/20/2022] Open
Abstract
Amylin, a gut-brain axis hormone, and amyloid-beta peptides (Aβ), a major component of the Alzheimer's disease (AD) brain, share several features, including similar β-sheet secondary structures, binding to the same receptor and being degraded by the same protease, insulin degrading enzyme (IDE). However, while amylin readily crosses the blood brain barrier (BBB) and mediates several activities including improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reaction and perhaps enhancing neural regeneration, Aβ has no known physiological functions. Thus, abundant Aβ in the AD brain could block or interfere with the binding of amylin to its receptor and hinder its functions. Recent studies using animal models for AD demonstrate that amylin and its analog reduce the AD pathology in the brain and improve cognitive impairment in AD. Given that, in addition to amyloid plaques and neurofibrillary tangles, perturbed cerebral glucose metabolism and cerebrovascular damage are the hallmarks of the AD brain, we propose that giving exogenous amylin type peptides have the potential to become a new avenue for the diagnosis and therapeutic of AD. Although amylin's property of self-aggregation may be a limitation to developing it as a therapeutic for AD, its clinical analog, pramlintide containing 3 amino acid differences from amylin, does not aggregate like human amylin, but more potently mediates amylin's activities in the brain. Pramlintide is an effective drug for diabetes with a favorable profile of safety. Thus a randomized, double-blind, placebo-controlled clinical trial should be conducted to examine the efficacy of pramlintide for AD. This review summarizes the knowledge and findings on amylin type peptides and discuss pros and cons for their potential for AD.
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Affiliation(s)
- Wei Qiao Qiu
- Department of Psychiatry, Boston University School of Medicine Boston, MA, USA ; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine Boston, MA, USA ; Alzheimer's Disease Center, Boston University School of Medicine Boston, MA, USA
| | - Haihao Zhu
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine Boston, MA, USA
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Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim Biophys Acta Mol Basis Dis 2014; 1842:1693-706. [PMID: 24949886 DOI: 10.1016/j.bbadis.2014.06.010] [Citation(s) in RCA: 284] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 06/05/2014] [Accepted: 06/09/2014] [Indexed: 12/23/2022]
Abstract
Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data interpreted from the point of view of oxidative stress with the aim of highlighting progresses in this field.
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Domínguez RO, Pagano MA, Marschoff ER, González SE, Repetto MG, Serra JA. Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis. Neurologia 2013; 29:567-72. [PMID: 24140159 DOI: 10.1016/j.nrl.2013.05.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 05/05/2013] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased risk of developing Alzheimer disease, but the relationship between the 2 entities is not clear. DEVELOPMENT Both diseases exhibit similar metabolic abnormalities: disordered glucose metabolism, abnormal insulin receptor signalling and insulin resistance, oxidative stress, and structural abnormalities in proteins and β-amyloid deposits. Different hypotheses have emerged from experimental work in the last two decades. One of the most comprehensive relates the microvascular damage in diabetic polyneuritis with the central nervous system changes occurring in Alzheimer disease. Another hypothesis considers that cognitive impairment in both diabetes and Alzheimer disease is linked to a state of systemic oxidative stress. Recently, attenuation of cognitive impairment and normalisation of values in biochemical markers for oxidative stress were found in patients with Alzheimer disease and concomitant diabetes. Antidiabetic drugs may have a beneficial effect on glycolysis and its end products, and on other metabolic alterations. CONCLUSIONS Diabetic patients are at increased risk for developing Alzheimer disease, but paradoxically, their biochemical alterations and cognitive impairment are less pronounced than in groups of dementia patients without diabetes. A deeper understanding of interactions between the pathogenic processes of both entities may lead to new therapeutic strategies that would slow or halt the progression of impairment.
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Affiliation(s)
- R O Domínguez
- Departamento de Neurología, Hospital Sirio Libanés, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
| | - M A Pagano
- Departamento de Neurología, Hospital Juan A. Fernández, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - E R Marschoff
- Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - S E González
- Departamento de Neurología, Hospital Sirio Libanés, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - M G Repetto
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - J A Serra
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Bioquímica y Medicina Molecular (IBIMOL, UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
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Domínguez RO, Marschoff ER, González SE, Repetto MG, Serra JA. Type 2 diabetes and/or its treatment leads to less cognitive impairment in Alzheimer's disease patients. Diabetes Res Clin Pract 2012; 98:68-74. [PMID: 22658669 DOI: 10.1016/j.diabres.2012.05.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 05/08/2012] [Accepted: 05/10/2012] [Indexed: 12/21/2022]
Abstract
AIM To evaluate the cognitive performance of a homogeneous population of Alzheimer's disease (AD), non-demented Type 2 Diabetes Mellitus (DIAB), demented with concomitant diseases (AD+DIAB) and healthy control subjects. AD is a progressive dementia disorder characterized clinically by impairment of memory, cognition and behavior. Recently, a major research interest in AD has been placed on early evaluation. Diabetes is one of the clinical conditions that represent the greatest risk of developing oxidative stress and dementia. Glucose overload, leading to the development of impaired-induced insulin secretion in DIAB and has been suggested to slow or deter AD pathogenesis. METHODS The degree of cognitive impairment was determined on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) and the Folstein's Mini Mental State Examination (MMSE); the severity of dementia was quantified applying the Clinical Dementia Rating (CDR) test; the Hamilton test was employed to evaluate depressive conditions; the final population studied was 101 subjects. RESULTS The cognitive deterioration is statistically significantly lower (p<0.05) in AD+DIAB patients as compared with AD patients. CONCLUSIONS In this longitudinal study the superimposed diabetic condition was associated with a lower rate of cognitive decline, while diabetic non-demented patients and controls present normal scores.
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Affiliation(s)
- Raúl O Domínguez
- Sirio-Libanés Hospital, Department of Neurology, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina
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Improvement in long term and visuo-spatial memory following chronic pioglitazone in mouse model of Alzheimer's disease. Pharmacol Biochem Behav 2012; 102:184-90. [PMID: 22503969 DOI: 10.1016/j.pbb.2012.03.028] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Revised: 03/06/2012] [Accepted: 03/28/2012] [Indexed: 12/11/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists (thiazolidinediones) are widely prescribed for the treatment of type-II diabetes mellitus. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in a mouse model of Alzheimer's disease induced by scopolamine. Scopolamine was administered in a dose of 1mg/kg intraperitoneally (i.p.). Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and escape latency in Morris water maze test. Pioglitazone was also investigated for its effects on parameters of oxidative stress by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels in the brain. Scopolamine produced significant reduction in SDL and prolongation of escape latency indicating cognitive impairment in mice. Pioglitazone (20 and 40 mg/kg, i.p.), administered for 21 days, showed significant dose-dependent improvement in scopolamine-induced dysfunctions in long-term and visuo-spatial memory in passive avoidance and Morris water maze tests, respectively. Furthermore, pioglitazone significantly prevented the fall in GSH levels and elevation in brain MDA levels induced by scopolamine. These results demonstrate that pioglitazone offers protection against scopolamine-induced dysfunctions in long-term and visuo-spatial memory, possibly due to its antioxidant action, and therefore, could have a therapeutic potential in Alzheimer's disease.
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