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Radermacher J, Erhardt VKJ, Walzer O, Haas EC, Kuppler KN, Zügner JSR, Lauer AA, Hartmann T, Grimm HS, Grimm MOW. Influence of Ibuprofen on glycerophospholipids and sphingolipids in context of Alzheimer´s Disease. Biomed Pharmacother 2025; 185:117969. [PMID: 40073745 DOI: 10.1016/j.biopha.2025.117969] [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: 08/28/2024] [Revised: 02/21/2025] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Alzheimer's disease (AD) is a multifactorial disorder associated with neuroinflammation, elevated oxidative stress, lipid alterations as well as amyloid-deposits and the formation of neurofibrillary tangles. Ibuprofen, a globally used analgesic, is discussed to influence disease progression due to its anti-inflammatory effect. However, changes in lipid-homeostasis induced by Ibuprofen have not yet been analyzed. Here we investigate the effect of Ibuprofen on lipid classes known to be associated with AD. Ibuprofen treatment leads to a significant increase in phosphatidylcholine, sphingomyelin and triacylglyceride (TAG) species whereas plasmalogens, which are highly susceptible for oxidation, were significantly decreased. The observed alterations in phosphatidylcholine and sphingomyelin levels in presence of Ibuprofen might counteract the reduced phosphatidylcholine- and sphingomyelin-levels found in AD brain tissue with potential positive aspects on synaptic plasticity and ceramide-induced apoptotic effects. On the other hand, Ibuprofen leads to elevated TAG-level resulting in the formation of lipid droplets which are associated with neuroinflammation. Reduction of plasmalogen-levels might accelerate decreased plasmalogen-levels found in AD brains. Treatment of Ibuprofen in terms of lipid-homeostasis reveals both potentially positive and negative changes relevant to AD. Therefore, understanding the influence of Ibuprofen on lipid-homeostasis may help to understand the heterogeneous results of studies treating AD with Ibuprofen.
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Affiliation(s)
| | | | - Oliver Walzer
- Experimental Neurology, Saarland University, Homburg, Saar 66424, Germany.
| | | | | | | | - Anna Andrea Lauer
- Experimental Neurology, Saarland University, Homburg, Saar 66424, Germany; Nutrition Therapy and Counseling, Campus Rheinland, SRH University of Applied Health Sciences, Leverkusen 51377, Germany.
| | - Tobias Hartmann
- Experimental Neurology, Saarland University, Homburg, Saar 66424, Germany; Deutsches Institut für Demenzprävention (DIDP), Saarland University, Homburg, Saar 66424, Germany.
| | - Heike Sabine Grimm
- Experimental Neurology, Saarland University, Homburg, Saar 66424, Germany; Nutrition Therapy and Counseling, Campus Rheinland, SRH University of Applied Health Sciences, Leverkusen 51377, Germany; Deutsches Institut für Demenzprävention (DIDP), Saarland University, Homburg, Saar 66424, Germany.
| | - Marcus Otto Walter Grimm
- Experimental Neurology, Saarland University, Homburg, Saar 66424, Germany; Nutrition Therapy and Counseling, Campus Rheinland, SRH University of Applied Health Sciences, Leverkusen 51377, Germany; Deutsches Institut für Demenzprävention (DIDP), Saarland University, Homburg, Saar 66424, Germany.
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2
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Sharma N, An SSA, Kim SY. Medication Exposure and Risk of Dementia and Alzheimer's Disease. Int J Mol Sci 2024; 25:12850. [PMID: 39684561 DOI: 10.3390/ijms252312850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Alzheimer's disease (AD), a complex neurodegenerative disease (ND), is the most predominant cause of dementia among the elderly. Generally, elderly people have multiple chronic health conditions, like hypertension, arthritis, diabetes, insomnia, bowel problems, and depression. Although prescribed medications have beneficial therapeutic compositions, some may have side effects that could hinder cognitive function or worsen cognitive decline. Hence, we should evaluate those medications to guarantee their safety. In the present mechanistic review, we discussed frequently used categories of medication (analgesics, anticholinergics, benzodiazepines, proton pump inhibitors, and statins), concerning their possible involvement in increasing AD and dementia risks. This review summarized the results of various observational studies, meta-analyses, randomized case-control studies, and systematic reviews. As the results were contradictory, it was difficult to ascertain the clear associations between medication usage and increased risks of dementia or AD. The blood-based biomarkers (BBMs) offer a low-cost and accessible alternative for early diagnosis of AD. Systematic reviews combined with meta-analysis would be crucial tools for accurately assessing and summarizing the efficacy of health interventions, yet randomized clinical trials have always been the best way to help with clinical care decisions. Thus, an open discussion is necessary to help individuals determine whether the advantages of utilizing medications outweigh the possible drawbacks.
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Affiliation(s)
- Niti Sharma
- Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujeong-gu, Seongnam-si 13120, Republic of Korea
| | - Seong Soo A An
- Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujeong-gu, Seongnam-si 13120, Republic of Korea
| | - Sang Yun Kim
- Department of Neurology, Seoul National University Bundang Hospital & Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si 13620, Republic of Korea
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3
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Shekho D, Mishra R, Kamal R, Bhatia R, Awasthi A. Breaking Barriers in Alzheimer's Disease: the Role of Advanced Drug Delivery Systems. AAPS PharmSciTech 2024; 25:207. [PMID: 39237748 DOI: 10.1208/s12249-024-02923-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/18/2024] [Indexed: 09/07/2024] Open
Abstract
Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.
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Affiliation(s)
- Devank Shekho
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Ritika Mishra
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Raj Kamal
- Department of Quality Assurance, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Rohit Bhatia
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ankit Awasthi
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
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4
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Serradas ML, Ding Y, Martorell PV, Kulińska I, Castro-Gomez S. Therapeutic Targets in Innate Immunity to Tackle Alzheimer's Disease. Cells 2024; 13:1426. [PMID: 39272998 PMCID: PMC11394242 DOI: 10.3390/cells13171426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer's disease (AD)-the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks of this disease-β-amyloid plaques and neurofibrillary tangles-failed, showed discrete clinical effects, or were accompanied by concerning side effects. There has been an ongoing search for novel therapeutic targets. Neuroinflammation, now widely recognized as a hallmark of all neurodegenerative diseases, has been proven to be a major contributor to AD pathology. Here, we summarize the role of neuroinflammation in the pathogenesis and progression of AD and discuss potential targets such as microglia, TREM2, the complement system, inflammasomes, and cytosolic DNA sensors. We also present an overview of ongoing studies targeting specific innate immune system components, highlighting the progress in this field of drug research while bringing attention to the delicate nature of innate immune modulations in AD.
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Affiliation(s)
- Maria L. Serradas
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
| | - Yingying Ding
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
| | - Paula V. Martorell
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Ida Kulińska
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
| | - Sergio Castro-Gomez
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
- Center for Neurology, Department of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, 53127 Bonn, Germany
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5
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Hiskens MI, Schneiders AG, Fenning AS. Selective COX-2 Inhibitors as Neuroprotective Agents in Traumatic Brain Injury. Biomedicines 2024; 12:1930. [PMID: 39200394 PMCID: PMC11352079 DOI: 10.3390/biomedicines12081930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/31/2024] [Accepted: 08/21/2024] [Indexed: 09/02/2024] Open
Abstract
Traumatic brain injury (TBI) is a significant contributor to mortality and morbidity in people, both young and old. There are currently no approved therapeutic interventions for TBI. Following TBI, cyclooxygenase (COX) enzymes generate prostaglandins and reactive oxygen species that perpetuate inflammation, with COX-1 and COX-2 isoforms providing differing responses. Selective COX-2 inhibitors have shown potential as neuroprotective agents. Results from animal models of TBI suggest potential treatment through the alleviation of secondary injury mechanisms involving neuroinflammation and neuronal cell death. Additionally, early clinical trials have shown that the use of celecoxib improves patient mortality and outcomes. This review aims to summarize the therapeutic effects of COX-2 inhibitors observed in TBI animal models, highlighting pertinent studies elucidating molecular pathways and expounding upon their mechanistic actions. We then investigated the current state of evidence for the utilization of COX-2 inhibitors for TBI patients.
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Affiliation(s)
- Matthew I. Hiskens
- Mackay Institute of Research and Innovation, Mackay Hospital and Health Service, Mackay, QLD 4740, Australia
| | - Anthony G. Schneiders
- School of Health, Medical and Applied Sciences, Central Queensland University, Rockhampton, QLD 4701, Australia (A.S.F.)
| | - Andrew S. Fenning
- School of Health, Medical and Applied Sciences, Central Queensland University, Rockhampton, QLD 4701, Australia (A.S.F.)
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6
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AmeliMojarad M, AmeliMojarad M. The neuroinflammatory role of microglia in Alzheimer's disease and their associated therapeutic targets. CNS Neurosci Ther 2024; 30:e14856. [PMID: 39031970 PMCID: PMC11259573 DOI: 10.1111/cns.14856] [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: 04/30/2024] [Revised: 06/17/2024] [Accepted: 07/02/2024] [Indexed: 07/22/2024] Open
Abstract
INTRODUCTION Alzheimer's disease (AD), the main cause of dementia, is characterized by synaptic loss and neurodegeneration. Amyloid-β (Aβ) accumulation, hyperphosphorylation of tau protein, and neurofibrillary tangles (NFTs) in the brain are considered to be the initiating factors of AD. However, this hypothesis falls short of explaining many aspects of AD pathogenesis. Recently, there has been mounting evidence that neuroinflammation plays a key role in the pathophysiology of AD and causes neurodegeneration by over-activating microglia and releasing inflammatory mediators. METHODS PubMed, Web of Science, EMBASE, and MEDLINE were used for searching and summarizing all the recent publications related to inflammation and its association with Alzheimer's disease. RESULTS Our review shows how inflammatory dysregulation influences AD pathology as well as the roles of microglia in neuroinflammation, the possible microglia-associated therapeutic targets, top neuroinflammatory biomarkers, and anti-inflammatory drugs that combat inflammation. CONCLUSION In conclusion, microglial inflammatory reactions are important factors in AD pathogenesis and need to be discussed in more detail for promising therapeutic strategies.
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Affiliation(s)
- Melika AmeliMojarad
- Department of Bioprocess Engineering, Institute of Industrial and Environmental BiotechnologyNational Institute of Genetic Engineering and BiotechnologyTehranIran
| | - Mandana AmeliMojarad
- Department of Bioprocess Engineering, Institute of Industrial and Environmental BiotechnologyNational Institute of Genetic Engineering and BiotechnologyTehranIran
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7
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Mushtaq U. EP1 receptor: Devil in emperors coat. J Cell Biochem 2023; 124:1105-1114. [PMID: 37450673 DOI: 10.1002/jcb.30436] [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: 01/23/2023] [Revised: 05/20/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023]
Abstract
EP1 receptor belongs to prostanoid receptors and is activated by prostaglandin E2. The receptor performs contrasting functions in central nervous system (CNS) and other tissues. Although the receptor is neurotoxic and proapoptotic in CNS, it has also been reported to act in an antiapoptotic manner by modulating cell survival, proliferation, invasion, and migration in different types of cancers. The receptor mediates its neurotoxic effects by increasing cytosolic Ca2+ levels, leading to the activation of its downstream target, protein kinase C, in different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and epilepsy. Antagonists ONO-8713, SC51089, and SC51322 against EP1 receptor ameliorate the neurotoxic effect by attenuating the neuroinflammation. The receptor also shows increased expression in different types of cancers and has been found to activate different signaling pathways, which lead to the development, progression, and metastasis of different cancers. The receptor stimulates the cell survival pathway by phosphorylating the AKT and PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways. Although there are limited studies about this receptor and not a single clinical trial has been targeting the EP1 receptor for different neurological disorders or cancer, the receptor is appearing as a potential candidate for therapeutic targets. The aim of this article is to review the recent progress in understanding the pathogenic roles of EP1 receptors in different pathological conditions.
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Affiliation(s)
- Umar Mushtaq
- Department of Biotechnology, Central University of Kashmir, Ganderbal, India
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8
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Gorthi SP, Gupta D. Alzheimer's Disease: Treatment Today and Tomorrow. Ann Indian Acad Neurol 2023; 26:326-333. [PMID: 37970257 PMCID: PMC10645267 DOI: 10.4103/aian.aian_254_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 11/17/2023] Open
Abstract
Background and Aims The scope of treatment in Alzheimer's Disease has widened in recent times with FDA approval of new drugs. This review looks at established treatments in AD as well as critically analyses the newer drugs available. Methods Data in this review was gathered from PubMed; Google Scholar and MEDLINE from January-March 2023. Search words used were 'Alzheimer's Disease treatment' and 'Dementia treatment'. Results Older time tested drugs like Acetyl Choline Receptor Inhibitors and NMDA Receptor antagonists remain the mainstay of pharmacological treatment in AD. Despite a lot of excitement about newer FDA approved drugs; we have to be cautious in their use. Aducanumab showed good reduction in CSF amyloid levels (biomarker of AD); but this did not necessarily translate into better clinical outcomes of patients. Conclusion Despite the recent advances and approval of drugs in treatment of AD, we have to exhibit caution while prescribing these drugs. Even with a sound mechanism of action, these drugs do not always show improvement in clinical outcomes. More clinical trials are required for development of drugs in treatment of AD which explore various different mechanisms of action.
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Affiliation(s)
- Sankar P. Gorthi
- Department of Neurology, Bharati Vidyapeeth Medical College (DTU) and Hospital, Pune, Maharashtra, India
| | - Dulari Gupta
- Department of Neurology, Bharati Vidyapeeth Medical College (DTU) and Hospital, Pune, Maharashtra, India
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9
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Nango H, Tsuruta K, Miyagishi H, Aono Y, Saigusa T, Kosuge Y. Update on the pathological roles of prostaglandin E 2 in neurodegeneration in amyotrophic lateral sclerosis. Transl Neurodegener 2023; 12:32. [PMID: 37337289 DOI: 10.1186/s40035-023-00366-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 06/07/2023] [Indexed: 06/21/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.
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Affiliation(s)
- Hiroshi Nango
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-Shi, Chiba, 274-8555, Japan
| | - Komugi Tsuruta
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-Shi, Chiba, 274-8555, Japan
| | - Hiroko Miyagishi
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-Shi, Chiba, 274-8555, Japan
| | - Yuri Aono
- Department of Pharmacology, School of Dentistry at Matsudo, Nihon University, 2-870-1 Sakaechonishi, Matsudo-Shi, Chiba, 271-8587, Japan
| | - Tadashi Saigusa
- Department of Pharmacology, School of Dentistry at Matsudo, Nihon University, 2-870-1 Sakaechonishi, Matsudo-Shi, Chiba, 271-8587, Japan
| | - Yasuhiro Kosuge
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-Shi, Chiba, 274-8555, Japan.
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10
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Walker KA, Le Page LM, Terrando N, Duggan MR, Heneka MT, Bettcher BM. The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap. Mol Neurodegener 2023; 18:37. [PMID: 37277738 PMCID: PMC10240487 DOI: 10.1186/s13024-023-00627-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 05/24/2023] [Indexed: 06/07/2023] Open
Abstract
Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer's disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood-brain barrier and other components of the neuro-immune axis in Alzheimer's disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer's disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology.
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Affiliation(s)
- Keenan A Walker
- Laboratory of Behavioral Neuroscience, National Institute On Aging. Baltimore, Baltimore, MD, USA.
| | - Lydia M Le Page
- Departments of Physical Therapy and Rehabilitation Science, and Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Niccolò Terrando
- Department of Anesthesiology, Cell Biology and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Michael R Duggan
- Laboratory of Behavioral Neuroscience, National Institute On Aging. Baltimore, Baltimore, MD, USA
| | - Michael T Heneka
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
| | - Brianne M Bettcher
- Behavioral Neurology Section, Department of Neurology, University of Colorado Alzheimer's and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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11
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Dimiza F, Barmpa A, Chronakis A, Hatzidimitriou AG, Sanakis Y, Papadopoulos AN, Psomas G. Iron(III) Complexes with Non-Steroidal Anti-Inflammatory Drugs: Structure, Antioxidant and Anticholinergic Activity, and Interaction with Biomolecules. Int J Mol Sci 2023; 24:ijms24076391. [PMID: 37047364 PMCID: PMC10094617 DOI: 10.3390/ijms24076391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
One the main research goals of bioinorganic chemists is the synthesis of novel coordination compounds possessing biological potency. Within this context, three novel iron(III) complexes with the non-steroidal anti-inflammatory drugs diflunisal and diclofenac in the presence or absence of the nitrogen donors 1,10-phenanthroline or pyridine were isolated and characterized by diverse techniques. The complexes were evaluated for their ability to scavenge in vitro free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals, revealing their selective potency towards hydroxyl radicals. The in vitro inhibitory activity of the complexes towards the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated, and their potential to achieve neuroprotection appeared promising. The interaction of the complexes with calf-thymus DNA was examined in vitro, revealing their ability to intercalate in-between DNA nucleobases. The affinity of the complexes for serum albumins was evaluated in vitro and revealed their tight and reversible binding.
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12
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Thönnißen V, Atodiresei IL, Patureau FW. Atroposelective Nenitzescu Indole Synthesis. Chemistry 2023; 29:e202300279. [PMID: 36725685 DOI: 10.1002/chem.202300279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/03/2023]
Abstract
In the past decade, compounds bearing a stereogenic C-N axis have gained significant attention in fields ranging from ligand to drug design. Yet, the atroposelective synthesis of these molecules remains a considerable challenge. In contrast to recent methods using more advanced chiral catalysts, a very simply accessed Jacobsen-type chromium(III)-salen complex was used here as a chiral enantiopure Lewis acid catalyst for a highly atroposelective Nenitzescu indole synthesis. Mild reaction conditions afforded various 5-hydroxybenzo[g]indoles in up to 97 % yield. Moreover, through a simple work-up, very high enantiomeric excesses of up to 99 % could be obtained.
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Affiliation(s)
- Vinzenz Thönnißen
- Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany
| | - Iuliana L Atodiresei
- Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany
| | - Frederic W Patureau
- Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany
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13
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Rajah Kumaran K, Yunusa S, Perimal E, Wahab H, Müller CP, Hassan Z. Insights into the Pathophysiology of Alzheimer's Disease and Potential Therapeutic Targets: A Current Perspective. J Alzheimers Dis 2023; 91:507-530. [PMID: 36502321 DOI: 10.3233/jad-220666] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aging population increases steadily because of a healthy lifestyle and medical advancements in healthcare. However, Alzheimer's disease (AD) is becoming more common and problematic among older adults. AD-related cases show an increasing trend annually, and the younger age population may also be at risk of developing this disorder. AD constitutes a primary form of dementia, an irreversible and progressive brain disorder that steadily damages cognitive functions and the ability to perform daily tasks. Later in life, AD leads to death as a result of the degeneration of specific brain areas. Currently, the cause of AD is poorly understood, and there is no safe and effective therapeutic agent to cure or slow down its progression. The condition is entirely preventable, and no study has yet demonstrated encouraging findings in terms of treatment. Identifying this disease's pathophysiology can help researchers develop safe and efficient therapeutic strategies to treat this ailment. This review outlines and discusses the pathophysiology that resulted in the development of AD including amyloid-β plaques, tau neurofibrillary tangles, neuroinflammation, oxidative stress, cholinergic dysfunction, glutamate excitotoxicity, and changes in neurotrophins level may sound better based on the literature search from Scopus, PubMed, ScienceDirect, and Google Scholar. Potential therapeutic strategies are discussed to provide more insights into AD mechanisms by developing some possible pharmacological agents for its treatment.
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Affiliation(s)
- Kesevan Rajah Kumaran
- Malaysian Institute of Pharmaceuticals and Nutraceuticals, National Institutes of Biotechnology Malaysia, Halaman Bukit Gambir, Gelugor, Pulau Pinang, Malaysia
| | - Suleiman Yunusa
- Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia.,Department of Pharmacology, Bauchi State University Gadau, Bauchi State, Nigeria
| | - Enoch Perimal
- Curtin Medical School, Curtin University, Bentley, Western Australia, Australia.,Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Habibah Wahab
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
| | - Christian P Müller
- Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia.,Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Zurina Hassan
- Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia.,Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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Andronie-Cioara FL, Ardelean AI, Nistor-Cseppento CD, Jurcau A, Jurcau MC, Pascalau N, Marcu F. Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression. Int J Mol Sci 2023; 24:ijms24031869. [PMID: 36768235 PMCID: PMC9915182 DOI: 10.3390/ijms24031869] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/01/2023] [Accepted: 01/11/2023] [Indexed: 01/20/2023] Open
Abstract
Aging is the most prominent risk factor for late-onset Alzheimer's disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimer's disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimer's disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.
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Affiliation(s)
- Felicia Liana Andronie-Cioara
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Adriana Ioana Ardelean
- Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Carmen Delia Nistor-Cseppento
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
- Correspondence: (C.D.N.-C.); (N.P.)
| | - Anamaria Jurcau
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | | | - Nicoleta Pascalau
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
- Correspondence: (C.D.N.-C.); (N.P.)
| | - Florin Marcu
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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15
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Sharif N. Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors. Neural Regen Res 2023; 18:5-17. [PMID: 35799502 PMCID: PMC9241399 DOI: 10.4103/1673-5374.343887] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and thromboxane-A2 interact with five major receptors (and their sub-types) to elicit specific downstream cellular and tissue actions. In general, prostaglandins have been associated with pain, inflammation, and edema when they are present at high local concentrations and involved on a chronic basis. However, in acute settings, certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation, providing cellular protection, regulating sleep, and enhancing blood flow, to lowering intraocular pressure to prevent the development of glaucoma, a blinding disease. Several classes of prostaglandins are implicated (or are considered beneficial) in certain central nervous system dysfunctions (e.g., Alzheimer’s, Parkinson’s, and Huntington’s diseases; amyotrophic lateral sclerosis and multiple sclerosis; stroke, traumatic brain injuries and pain) and in ocular disorders (e.g., ocular hypertension and glaucoma; allergy and inflammation; edematous retinal disorders). This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease, and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists, polyunsaturated fatty acids, and cyclooxygenase inhibitors.
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16
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Kim J, Kim YK. Molecular Imaging of Neuroinflammation in Alzheimer's Disease and Mild Cognitive Impairment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:301-326. [PMID: 36949316 DOI: 10.1007/978-981-19-7376-5_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Alzheimer's disease (AD) is the most prevalent neurocognitive disorder. Due to the ineffectiveness of treatments targeting the amyloid cascade, molecular biomarkers for neuroinflammation are attracting attention with increasing knowledge about the role of neuroinflammation in the pathogenesis of AD. This chapter will explore the results of studies using molecular imaging for diagnosing AD and mild cognitive impairment (MCI). Because it is critical to interpreting the data to understand which substances are targeted in molecular imaging, this chapter will discuss the two most significant targets, microglia and astrocytes, as well as the best-known radioligands for each. Then, neuroimaging results with PET neuroinflammation imaging will be reviewed for AD and MCI. Although a growing body of evidence has suggested that these molecular imaging biomarkers for neuroinflammation may have a role in the diagnosis of AD and MCI, the findings are inconsistent or cross-sectional, which indicates that it is difficult to apply the contents in practice due to the need for additional study. In particular, because the results of multiple interventions targeting neuroinflammation were inconclusive, molecular imaging markers for neuroinflammation can be used in combination with conventional markers to select appropriate patients for early intervention for neuroinflammation rather than as a single marker.
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Affiliation(s)
- Junhyung Kim
- Department of Psychiatry, Korea University College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Ku Kim
- Department of Psychiatry, Korea University Ansan Hospital, Ansan, Republic of Korea.
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17
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Stopschinski BE, Weideman RA, McMahan D, Jacob DA, Little BB, Chiang HS, Saez Calveras N, Stuve O. Microglia as a cellular target of diclofenac therapy in Alzheimer's disease. Ther Adv Neurol Disord 2023; 16:17562864231156674. [PMID: 36875711 PMCID: PMC9974624 DOI: 10.1177/17562864231156674] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 01/26/2023] [Indexed: 03/07/2023] Open
Abstract
Alzheimer's disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.
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Affiliation(s)
- Barbara E Stopschinski
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Danni McMahan
- Pharmacy Service, Dallas VA Medical Center, Dallas, TX, USA
| | - David A Jacob
- Veterans Integrated Service Network 17, Arlington, TX, USA
| | - Bertis B Little
- School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA
| | - Hsueh-Sheng Chiang
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nil Saez Calveras
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Olaf Stuve
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Neurology Section, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA
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18
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Luo JJ, Wallace W, Kusiak JW. A tough trek in the development of an anti-amyloid therapy for Alzheimer's disease: Do we see hope in the distance? J Neurol Sci 2022; 438:120294. [DOI: 10.1016/j.jns.2022.120294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/27/2022] [Accepted: 05/18/2022] [Indexed: 12/17/2022]
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19
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Harding A, Kanagasingam S, Welbury R, Singhrao SK. Periodontitis as a Risk Factor for Alzheimer's Disease: The Experimental Journey So Far, with Hope of Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1373:241-260. [PMID: 35612802 DOI: 10.1007/978-3-030-96881-6_13] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Periodontitis and Alzheimer's disease (AD) exist globally within the adult population. Given that the risk of AD incidence doubles within 10 years from the time of periodontal disease diagnosis, there is a window of opportunity for slowing down or preventing AD by risk-reduction-based intervention. Literature appraisal on the shared risk factors of these diseases suggests a shift to a healthy lifestyle would be beneficial. Generalised (chronic) periodontitis with an established dysbiotic polymicrobial aetiology affects the tooth supporting tissues with eventual tooth loss. The cause of AD remains unknown, however two neurohistopathological lesions - amyloid-beta plaques and neurofibrillary tangles, together with the clinical history, provide AD diagnosis at autopsy. Historically, prominence was given to the two hallmark lesions but now emphasis is placed on cerebral inflammation and what triggers it. Low socioeconomic status promotes poor lifestyles that compromise oral and personal hygiene along with reliance on poor dietary intake. Taken together with advancing age and a declining immune protection, these risk factors may negatively impact on periodontitis and AD. These factors also provide a tangible solution to controlling pathogenic bacteria indigenous to the oral and gastrointestinal tract microbioes in vulnerable subjects. The focus here is on Porphyromonas gingivalis, one of several important bacterial pathogens associated with both periodontitis and AD. Recent research has enabled advances in our knowledge of the armoury of P. gingivalis via reproduction of all clinical and neuropathological hallmark lesions of AD and chronic periodontal disease in vitro and in vivo experimental models, thus paving the way for better future management.
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Affiliation(s)
- Alice Harding
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | - Shalini Kanagasingam
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | - Richard Welbury
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | - Sim K Singhrao
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK.
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20
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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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21
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Onaolapo OJ, Olofinnade AT, Ojo FO, Onaolapo AY. Neuroinflammation and Oxidative Stress in Alzheimer's Disease; Can Nutraceuticals and Functional Foods Come to the Rescue? Antiinflamm Antiallergy Agents Med Chem 2022; 21:75-89. [PMID: 36043770 DOI: 10.2174/1871523021666220815151559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/17/2022] [Accepted: 06/29/2022] [Indexed: 06/15/2023]
Abstract
Alzheimer's disease (AD), the most prevalent form of age-related dementia, is typified by progressive memory loss and spatial awareness with personality changes. The increasing socioeconomic burden associated with AD has made it a focus of extensive research. Ample scientific evidence supports the role of neuroinflammation and oxidative stress in AD pathophysiology, and there is increasing research into the possible role of anti-inflammatory and antioxidative agents as disease modifying therapies. While, the result of numerous preclinical studies has demonstrated the benefits of anti-inflammatory agents, these benefits however have not been replicated in clinical trials, necessitating a further search for more promising anti-inflammatory agents. Current understanding highlights the role of diet in the development of neuroinflammation and oxidative stress, as well as the importance of dietary interventions and lifestyle modifications in mitigating them. The current narrative review examines scientific literature for evidence of the roles (if any) of dietary components, nutraceuticals and functional foods in the prevention or management of AD. It also examines how diet/ dietary components could modulate oxidative stress/inflammatory mediators and pathways that are crucial to the pathogenesis and/or progression of AD.
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Affiliation(s)
- Olakunle J Onaolapo
- Department of Pharmacology, Behavioural Neuroscience Unit, Neuropharmacology Subdivision, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Anthony T Olofinnade
- Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Clinical Sciences, College of Medicine, Lagos State University, Ikeja, Lagos State, Nigeria
| | - Folusho O Ojo
- Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - Adejoke Y Onaolapo
- Department of Anatomy, Behavioural Neuroscience Unit, Neurobiology Subdivision, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
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22
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Mavroudis I, Chowdhury R, Petridis F, Karantali E, Chatzikonstantinou S, Balmus IM, Luca IS, Ciobica A, Kazis D. YKL-40 as a Potential Biomarker for the Differential Diagnosis of Alzheimer's Disease. MEDICINA (KAUNAS, LITHUANIA) 2021; 58:medicina58010060. [PMID: 35056368 PMCID: PMC8777884 DOI: 10.3390/medicina58010060] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 11/16/2022]
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, associated with extensive neuronal loss, dendritic and synaptic changes resulting in significant cognitive impairment. An increased number of studies have given rise to the neuroinflammatory hypothesis in AD. It is widely accepted that AD brains show chronic inflammation, probably triggered by the presence of insoluble amyloid beta deposits and neurofibrillary tangles (NFT) and is also related to the activation of neuronal death cascade. In the present study we aimed to investigate the role of YKL-40 levels in the cerebrospinal fluid (CSF) in the diagnosis of AD, and to discuss whether there are further potential roles of this protein in the management and treatment of AD. We conducted an online search on PubMed, Web of Science, and the Cochrane library databases from 1990 to 2021. The quantitative analysis showed that the levels of YKL-40 were significantly higher in Alzheimer’s disease compared to controls, to mild cognitive impairment (MCI) AD (MCI-AD) and to stable MCI. They were also increased in MCI-AD compared to stable MCI. The present study shows that the CSF levels of YKL-40 could be potentially used as a biomarker for the prognosis of mild cognitive impairment and the likelihood of progression to AD, as well as for the differential diagnosis between AD and MCI.
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Affiliation(s)
- Ioannis Mavroudis
- Department of Neurology, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK; (I.M.); (R.C.)
| | - Rumana Chowdhury
- Department of Neurology, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK; (I.M.); (R.C.)
| | - Foivos Petridis
- Third Department of Neurology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (F.P.); (E.K.); (S.C.); (D.K.)
| | - Eleni Karantali
- Third Department of Neurology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (F.P.); (E.K.); (S.C.); (D.K.)
| | - Symela Chatzikonstantinou
- Third Department of Neurology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (F.P.); (E.K.); (S.C.); (D.K.)
| | - Ioana Miruna Balmus
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, ”Alexandru Ioan Cuza” University of Iasi, Alexandru Lapsuneanu Street, No. 26, 700057 Iasi, Romania;
| | - Iuliana Simona Luca
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, No. 20A, 700505 Iasi, Romania
- Correspondence: (I.S.L.); (A.C.)
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, No. 20A, 700505 Iasi, Romania
- Correspondence: (I.S.L.); (A.C.)
| | - Dimitrios Kazis
- Third Department of Neurology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (F.P.); (E.K.); (S.C.); (D.K.)
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23
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Brod SA. Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer's Disease. J Alzheimers Dis 2021; 85:457-472. [PMID: 34842189 DOI: 10.3233/jad-215125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Systemic inflammation is an organism's response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer's disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the "principal culprit" in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.
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Affiliation(s)
- Staley A Brod
- Department of Neurology, Medical College of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
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24
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Indomethacin Disrupts the Formation of β-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism. Int J Mol Sci 2021; 22:ijms22158185. [PMID: 34360951 PMCID: PMC8348656 DOI: 10.3390/ijms22158185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 12/26/2022] Open
Abstract
Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer’s disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of β-amyloid protein (Aβ) but also induced Aβ efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aβ. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aβ production and clearing Aβ from the brains of AD mice.
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25
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Kaduševičius E. Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular, Neurodegenerative, Diabetes and Cancer Disease Therapy. Int J Mol Sci 2021; 22:6637. [PMID: 34205719 PMCID: PMC8235426 DOI: 10.3390/ijms22126637] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 01/22/2023] Open
Abstract
Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. This review discusses the novel mechanism of action of NSAIDs and its potential use in the pharmacotherapy of neurodegenerative, cardiovascular, diabetes and cancer diseases. Many different molecular and cellular factors which are not yet fully understood play an important role in the pathogenesis of inflammation, axonal damage, demyelination, atherosclerosis, carcinogenesis thus further NSAID studies for a new potential indications based on precise pharmacotherapy model are warranted since NSAIDs are a heterogeneous group of medicines with relative different pharmacokinetics and pharmacodynamics profiles. Hopefully the new data from studies will fill in the gap between experimental and clinical results and translate our knowledge into successful disease therapy.
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Affiliation(s)
- Edmundas Kaduševičius
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, 9 A. Mickeviciaus Street, LT-44307 Kaunas, Lithuania
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26
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Barmpa A, Geromichalos GD, Hatzidimitriou AG, Psomas G. Nickel(II)-meclofenamate complexes: Structure, in vitro and in silico DNA- and albumin-binding studies, antioxidant and anticholinergic activity. J Inorg Biochem 2021; 222:111507. [PMID: 34139455 DOI: 10.1016/j.jinorgbio.2021.111507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/28/2021] [Accepted: 05/30/2021] [Indexed: 10/21/2022]
Abstract
Five novel nickel(II) complexes with the non-steroidal anti-inflammatory drug sodium meclofenamate (Na-mclf) have been synthesized and characterized in the absence or co-existence of the nitrogen-donors imidazole (Himi), 2,2'-bipyridylamine (bipyam), 2,2'-bipyridylketoxime (Hpko) and 2,9-dimethyl-1,10-phenanthroline (neoc); namely [Ni(mclf-O)2(Himi)2(MeOH)2], [Ni(mclf-O)2(MeOH)4], [Ni(mclf-O)(mclf-O,O')(bipyam)(MeOH)]·0.25MeOH, [Ni(mclf-O,O')2(neoc)] and [Ni(mclf-O)2(Hpko-N,N')2]·MeOH·0.5H2O. The affinity of the complexes for calf-thymus (CT) DNA was investigated by various techniques and intercalation is suggested as the most possible interaction mode. The interaction of the complexes for bovine and human serum albumins was also investigated in order to determine the binding constants, concluding that the complexes bind reversibly to albumins for the transportation towards their target cells or tissues and their release upon arrival at biotargets. The antioxidant activity of the compounds was evaluated via their ability to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) free radicals and to reduce H2O2. For the determination of the anticholinergic ability of the complexes the in vitro inhibitory activity against the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated and presented promising results. The in silico molecular modeling calculations employed provide useful insights for the understanding of the mechanism of action of the studied complexes at a molecular level. This applies on both the impairment of DNA by its binding with the studied complexes and transportation through serum albumins, as well as the ability of these compounds to act as anticholinergic agents.
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Affiliation(s)
- Amalia Barmpa
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - George D Geromichalos
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Antonios G Hatzidimitriou
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - George Psomas
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
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27
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Vinuesa A, Pomilio C, Gregosa A, Bentivegna M, Presa J, Bellotto M, Saravia F, Beauquis J. Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer's Disease. Front Neurosci 2021; 15:653651. [PMID: 33967682 PMCID: PMC8102834 DOI: 10.3389/fnins.2021.653651] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/31/2021] [Indexed: 12/21/2022] Open
Abstract
Overnutrition and modern diets containing high proportions of saturated fat are among the major factors contributing to a low-grade state of inflammation, hyperglycemia and dyslipidemia. In the last decades, the global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to an increased risk for premature brain aging and the development of neurodegenerative disorders such as Alzheimer's disease (AD). Cognitive impairment and decreased neurogenic capacity could be a consequence of metabolic disturbances. In these scenarios, the interplay between inflammation and insulin resistance could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive impairment. The present review aims to provide an update on the impact of metabolic stress pathways on AD with a focus on inflammation and insulin resistance as risk factors and therapeutic targets.
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Affiliation(s)
- Angeles Vinuesa
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Pomilio
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Amal Gregosa
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Melisa Bentivegna
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jessica Presa
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Melina Bellotto
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Flavia Saravia
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Beauquis
- Laboratorio de Neurobiología del Envejecimiento, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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Celecoxib in a Preclinical Model of Repetitive Mild Traumatic Brain Injury: Hippocampal Learning Deficits Persist with Inflammatory and Excitotoxic Neuroprotection. TRAUMA CARE 2021. [DOI: 10.3390/traumacare1010003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Repetitive mild traumatic brain injuries (mTBIs) contribute to inflammation-induced neurodegeneration. Cycloxygenase (COX) enzymes produce inflammatory cytokines that influence the microglia response to neurotrauma. Celecoxib is a selective COX-2 inhibitor that is prescribed in some conditions of mTBI to alleviate symptoms of concussion, and has shown benefits in neurodegenerative conditions. We investigated molecular pathways of neuroinflammation in response to celecoxib treatment in a mouse model of repetetive mTBI. Fifteen mTBIs were delivered over 23 days in adult male C57BL/6J mice in one of four groups (control, celecoxib without impact, celecoxib with impact, and vehicle with impact). Cognitive function was assessed at 48 h and three months following the final mTBI. Morris Water Maze testing revealed impaired hippocampal spatial learning performance in the celecoxib treatment with the impact group compared to the vehicle with impact control in the acute phase, with celecoxib treatment providing no improvement compared with the control at chronic testing; mRNA analysis of the cerebral cortex and hippocampus revealed expression change, indicating significant improvement in microglial activation, inflammation, excitotoxicity, and neurodegeneration at chronic measurement. These data suggest that, in the acute phase following injury, celecoxib protected against neuroinflammation, but exacerbated clinical cognitive disturbance. Moreover, while there was evidence of neuroprotective alleviation of mTBI pathophysiology at chronic measurement, there remained no change in clinical features.
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29
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Gliszczyńska A, Nowaczyk M. Lipid Formulations and Bioconjugation Strategies for Indomethacin Therapeutic Advances. Molecules 2021; 26:1576. [PMID: 33809343 PMCID: PMC7998224 DOI: 10.3390/molecules26061576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/04/2021] [Accepted: 03/09/2021] [Indexed: 11/17/2022] Open
Abstract
Indomethacin (IND) is a drug which after successful clinical trials became available for general prescription in 1965 and from that time is one of the most widely used anti-inflammatory drug with the highest potencies in the in vitro and in vivo models. However, despite its high therapeutic efficacy in relieving the symptoms of certain arthritis and in treating gout or collagen diseases, administration of IND causes a number of adverse effects, such as gastrointestinal ulceration, frequent central nervous system disorders and renal toxicity. These obstacles significantly limit the practical applications of IND and make that 10-20% of patients discontinue its use. Therefore, during the last three decades many attempts have been made to design novel formulations of IND aimed to increase its therapeutic benefits minimizing its adverse effects. In this review we summarize pharmacological information about IND and analyze its new lipid formulations and lipid bioconjugates as well as discuss their efficacy and potential application.
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Affiliation(s)
- Anna Gliszczyńska
- Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland;
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30
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Sarkar S, Biswas SC. Astrocyte subtype-specific approach to Alzheimer's disease treatment. Neurochem Int 2021; 145:104956. [PMID: 33503465 DOI: 10.1016/j.neuint.2021.104956] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 01/08/2023]
Abstract
Astrocytes respond to any pathological condition in the central nervous system (CNS) including Alzheimer's disease (AD), and this response is called astrocyte reactivity. Astrocyte reaction to a CNS insult is a highly heterogeneous phenomenon in which the astrocytes undergo a set of morphological, molecular and functional changes with a characteristic secretome profile. Such astrocytes are termed as 'reactive astrocytes'. Controversies regarding the reactive astrocytes abound. Recently, a continuum of reactive astrocyte profiles with distinct transcriptional states has been identified. Among them, disease-associated astrocytes (DAA) were uniquely present in AD mice and expressed a signature set of genes implicated in complement cascade, endocytosis and aging. Earlier, two stimulus-specific reactive astrocyte subtypes with their unique transcriptomic signatures were identified using mouse models of neuroinflammation and ischemia and termed as A1 astrocytes (detrimental) and A2 astrocytes (beneficial) respectively. Interestingly, although most of the A1 signature genes were also detected in DAA, as opposed to A2 astrocyte signatures, some of the A1 specific genes were expressed in other astrocyte subtypes, indicating that these nomenclature-based signatures are not very specific. In this review, we elaborate the disparate functions and cytokine profiles of reactive astrocyte subtypes in AD and tried to distinguish them by designating neurotoxic astrocytes as A1-like and neuroprotective ones as A2-like without directly referring to the A1/A2 original nomenclature. We have also focused on the dual nature from a functional perspective of some cytokines depending on AD-stage, highlighting a number of them as major candidates in AD therapy. Therefore, we suggest that promoting subtype-specific beneficial roles, inhibiting subtype-specific detrimental roles or targeting subtype-specific cytokines constitute a novel therapeutic approach to AD treatment.
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Affiliation(s)
- Sukanya Sarkar
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700 032, India
| | - Subhas C Biswas
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700 032, India.
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31
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Barmpa A, Hatzidimitriou AG, Psomas G. Copper(II) complexes with meclofenamate ligands: Structure, interaction with DNA and albumins, antioxidant and anticholinergic activity. J Inorg Biochem 2021; 217:111357. [PMID: 33556771 DOI: 10.1016/j.jinorgbio.2021.111357] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 12/27/2022]
Abstract
The interaction of copper(II) with the non-steroidal anti-inflammatory drug sodium meclofenamate (Na-mclf) in the presence or absence of the nitrogen-donor co-ligands pyridine (py) or 2,2'-bipyridylamine (bipyam), yielded the novel Cu(II) complexes [Cu2(mclf-O,O')4(MeOH)2]·2MeOH (1·2MeOH), [Cu(mclf-O)2(py)3]·H2O·0.5MeOH (2·H2O·0.5MeOH) and [Cu(mclf-O,O')2(bipyam)] (3). The characterization of the complexes was achieved by various techniques, including single-crystal X-ray crystallography. In order to study the binding mode and strength of the complexes to calf-thymus (CT) DNA, various techniques were employed which suggested intercalation between the DNA-bases as the most possible interaction mode. Competitive studies with ethidium bromide (EB) revealed the ability of the complexes to displace the EB from the EB-DNA adduct, verifying the intercalative binding mode. The affinity of the complexes to bovine and human serum albumin proteins (SAs) was investigated by fluorescence emission spectroscopy and the corresponding binding constants bear relatively high values, showing that the complexes bind tightly and possibly reversibly to SAs. The antioxidant activity of the complexes against 1,1-diphenyl-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and the ability to reduce H2O2 proved to be of significant magnitude. The in vitro inhibitory activity against the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was evaluated, in order to assess the anticholinergic ability of the complexes, which appeared promising.
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Affiliation(s)
- Amalia Barmpa
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Antonios G Hatzidimitriou
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - George Psomas
- Department of General and Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
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Mohamed MY, Masocha W. Indomethacin augments lipopolysaccharide-induced expression of inflammatory molecules in the mouse brain. PeerJ 2020; 8:e10391. [PMID: 33240677 PMCID: PMC7680052 DOI: 10.7717/peerj.10391] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 10/27/2020] [Indexed: 12/22/2022] Open
Abstract
Indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and fever including during infections. However, some studies suggest that NSAIDs protect against neuroinflammation, while some find no effects or worsening of neuroinflammation. We evaluated the effect of indomethacin alone on in combination with minocycline, a drug that inhibits neuroinflammation, on the expression of transcripts of neuroinflammatory molecules-induced by lipopolysaccharide (LPS) in the brain of mice. Inoculation of male BALB/c mice with LPS induced the expression of the microglia marker ionized calcium binding adaptor molecule protein, mRNA expression of the genes for cytokines interleukin-1beta (Il1b) and tumor necrosis factor-alpha (Tnf) and inducible nitric oxide synthase gene (Nos2), but not Il10, in the brain. Treatment with indomethacin had no significant effect on the cytokines or Nos2 mRNA expression in naïve animals. However, pretreatment with indomethacin increased LPS-induced Nos2 mRNA and inducible nitric oxide (iNOS) protein expression, but had no significant effect on LPS-induced mRNA expression of the cytokines. Minocycline reduced LPS-induced Il1b and Tnf, but not Nos2, mRNA expression. Treatment with indomethacin plus minocycline had no effect on LPS-induced Il1b, Tnf and Nos2 mRNA expression. In conclusion these results show that indomethacin significantly augments LPS-induced Nos2 mRNA and iNOS protein expression in the brain. In the presence of indomethacin, minocycline could not inhibit LPS-induced pro-inflammatory cytokine expression. Thus, indomethacin could exacerbate neuroinflammation by increasing the expression of iNOS and also block the anti-inflammatory effects of minocycline.
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Affiliation(s)
- Mona Yasin Mohamed
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait
| | - Willias Masocha
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait
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33
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Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 2020; 9:42. [PMID: 33239064 PMCID: PMC7689983 DOI: 10.1186/s40035-020-00221-2] [Citation(s) in RCA: 1375] [Impact Index Per Article: 275.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 11/03/2020] [Indexed: 12/14/2022] Open
Abstract
Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.
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Affiliation(s)
- Hyuk Sung Kwon
- Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Seong-Ho Koh
- Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
- Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea.
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Manji Z, Rojas A, Wang W, Dingledine R, Varvel NH, Ganesh T. 5xFAD Mice Display Sex-Dependent Inflammatory Gene Induction During the Prodromal Stage of Alzheimer's Disease. J Alzheimers Dis 2020; 70:1259-1274. [PMID: 31322556 DOI: 10.3233/jad-180678] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Alzheimer's disease (AD) pathology consists of extracellular deposits of amyloid-β peptides (Aβ) and intracellular neurofibrillary tangles. These pathological alterations are accompanied by a neuroinflammatory response consisting of increased expression of inflammatory mediators. An anti-inflammatory strategy designed to prevent or delay the development of AD would benefit from knowing when neuroinflammation appears in the transgenic models during prodromal disease stages relative to Aβ pathology. We investigated the expression patterns of inflammatory mediators in the brain of 5xFAD mice in comparison to development of Aβ deposition. Expression changes in inflammatory mediators and glial markers are more robust in female mice starting at three months of age, in contrast to males in which there is no clear trend through five months. Female and male 5xFAD mice also displayed an age-dependent increase in cortical Aβ deposition congruent with neuroinflammation. Thus, in the 5xFAD mouse model of AD, administration of an anti-inflammatory agent would be most efficacious when administered before three months of age.
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Affiliation(s)
- Zahra Manji
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Asheebo Rojas
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Wenyi Wang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Raymond Dingledine
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Nicholas H Varvel
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Thota Ganesh
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
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35
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Dexamethasone does not ameliorate gliosis in a mouse model of neurodegenerative disease. Biochem Biophys Rep 2020; 24:100817. [PMID: 33015377 DOI: 10.1016/j.bbrep.2020.100817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 11/21/2022] Open
Abstract
Prolonged neuroinflammation is a driving force for neurodegenerative disease, and agents against inflammatory responses are regarded as potential treatment strategies. Here we aimed to evaluate the prevention effects on gliosis by dexamethasone (DEX), an anti-inflammation drug. We used DEX to treat the nicastrin conditional knockout (cKO) mouse, a neurodegenerative mouse model. DEX (10 mg/kg) was given to 2.5-month-old nicastrin cKO mice, which have not started to display neurodegeneration and gliosis, for 2 months. Immunohistochemistry (IHC) and Western blotting techniques were used to detect changes in neuroinflammatory responses. We found that activation of glial fibrillary acidic protein (GFAP) positive or ionized calcium binding adapter molecule1 (Iba1) positive cells was not inhibited in nicastrin cKO mice treated with DEX as compared to those treated with saline. These data suggest that DEX does not prevent or ameliorate gliosis in a neurodegenerative mouse model when given prior to neuronal or synaptic loss.
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36
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Stuve O, Weideman RA, McMahan DM, Jacob DA, Little BB. Diclofenac reduces the risk of Alzheimer's disease: a pilot analysis of NSAIDs in two US veteran populations. Ther Adv Neurol Disord 2020; 13:1756286420935676. [PMID: 32647537 PMCID: PMC7325551 DOI: 10.1177/1756286420935676] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 05/04/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer’s disease (AD). Materials and methods: Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates. Results: Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84–1.20, p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09–0.68, p <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07–1.09, p <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60–5.81) indicating that as comorbidities increase, the risk for AD increases very significantly. Conclusion: Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.
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Affiliation(s)
- Olaf Stuve
- Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical School, Neurology Section (111H), Dallas VA Medical Center, 4500 Lancaster Road, Dallas, TX 75216, USA
| | | | | | - David A Jacob
- Pharmacy Service, Veterans Integrated Service Network 17, Arlington, TX, USA
| | - Bertis B Little
- School of Public Health and Information Sciences, University of Louisville, KY, USA
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37
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Wilson B, Geetha KM. Neurotherapeutic applications of nanomedicine for treating Alzheimer's disease. J Control Release 2020; 325:25-37. [PMID: 32473177 DOI: 10.1016/j.jconrel.2020.05.044] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/25/2020] [Accepted: 05/26/2020] [Indexed: 01/30/2023]
Abstract
Alzheimer's disease (AD) is a progressive, irreversible, fatal brain disease which disturbs cognitive functions. It affects 35 million people worldwide and the number of people suffering may increase to 100 million by 2050 if no effective treatments are available. The present treatment improves cognitive functions and provide temporary symptomatic relief, but do not stop or delay the disease progression. Moreover, they are mainly available as conventional oral dosage forms and these conventional oral medications lack brain specificity and also produce side effects which leads to poor patient compliance. Brain drug targeting by nanomedicines is a promising approach to improve brain targeting specificity, brain bioavailability and patient compliance. The present review discuses about the currently available pharmacotherapy for AD and the neurotherapeutic applications as well as the advancements of nanomedicine for treating AD. It also highlights the recent advancements of various nanomedicines containing phytopharmaceuticals for treating AD. It is believed that nanomedicines containing approved drugs can be transformed into the clinics hence improve the life style of AD patients.
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Affiliation(s)
- Barnabas Wilson
- Department of Pharmaceutics, College of Pharmaceutical Sciences, Dayananda Sagar University, Kumaraswamy Layout, Bangalore, Karnataka 560078, India.
| | - Kannoth Mukundan Geetha
- Department of Pharmacology, College of Pharmaceutical Sciences, Dayananda Sagar University, Kumaraswamy Layout, Bangalore, Karnataka 560078, India
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38
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Uddin MS, Kabir MT, Mamun AA, Barreto GE, Rashid M, Perveen A, Ashraf GM. Pharmacological approaches to mitigate neuroinflammation in Alzheimer's disease. Int Immunopharmacol 2020; 84:106479. [PMID: 32353686 DOI: 10.1016/j.intimp.2020.106479] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/13/2020] [Accepted: 04/02/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases characterized by the formation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Growing evidence suggested that there is an association between neuronal dysfunction and neuroinflammation (NI) in AD, coordinated by the chronic activation of astrocytes and microglial cells along with the subsequent excessive generation of the proinflammatory molecule. Therefore, a better understanding of the relationship between the nervous and immune systems is important in order to delay or avert the neurodegenerative events of AD. The inflammatory/immune pathways and the mechanisms to control these pathways may provide a novel arena to develop new drugs in order to target NI in AD. In this review, we represent the influence of cellular mediators which are involved in the NI process, with regards to the progression of AD. We also discuss the processes and the current status of multiple anti-inflammatory agents which are used in AD and have gone through or going through clinical trials. Moreover, new prospects for targeting NI in the development of AD drugs have also been highlighted.
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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
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Mamunur Rashid
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Asma Perveen
- School of Life Sciences, The Glocal University, Saharanpur, Uttar Pradesh 247121, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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Dhingra AK, Chopra B. Inflammation as a Therapeutic Target for Various Deadly Disorders: A Review. Curr Drug Targets 2020; 21:582-588. [DOI: 10.2174/1389450120666191204154115] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 11/22/2022]
Abstract
Inflammation is the multifaceted biological response of vascular tissues against injurious
stimuli such as pathogens, irritants or infection. However, when inflammation goes away, it leads to
produce quite serious life-threatening diseases like Alzheimer's, rheumatoid arthritis, heart attacks, colon
cancer, etc. Therefore, inflammation suddenly has become one of the hottest areas of medical research.
The present review article is aimed to provide a detailed outline of the fundamental causes and
the surprising relationship of inflammation in the onset of sundry diseases or illnesses. Furthermore,
the role of various anti-inflammatory drugs alone and in combination with other therapeutic drugs, in
alleviating the life-threatening diseases has also been discussed.
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Affiliation(s)
- Ashwani K. Dhingra
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar-135001, Haryana, India
| | - Bhawna Chopra
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar-135001, Haryana, India
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40
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Hampel H, Caraci F, Cuello AC, Caruso G, Nisticò R, Corbo M, Baldacci F, Toschi N, Garaci F, Chiesa PA, Verdooner SR, Akman-Anderson L, Hernández F, Ávila J, Emanuele E, Valenzuela PL, Lucía A, Watling M, Imbimbo BP, Vergallo A, Lista S. A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease. Front Immunol 2020; 11:456. [PMID: 32296418 PMCID: PMC7137904 DOI: 10.3389/fimmu.2020.00456] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 02/27/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
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Affiliation(s)
- Harald Hampel
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | - Filippo Caraci
- Department of Drug Sciences, University of Catania, Catania, Italy.,Oasi Research Institute-IRCCS, Troina, Italy
| | - A Claudio Cuello
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.,Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.,Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | | | - Robert Nisticò
- Laboratory of Neuropharmacology, EBRI Rita Levi-Montalcini Foundation, Rome, Italy.,School of Pharmacy, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Massimo Corbo
- Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, Italy
| | - Filippo Baldacci
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.,Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France.,Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.,Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nicola Toschi
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.,Department of Radiology, "Athinoula A. Martinos" Center for Biomedical Imaging, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Francesco Garaci
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.,Casa di Cura "San Raffaele Cassino", Cassino, Italy
| | - Patrizia A Chiesa
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.,Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France.,Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | | | | | - Félix Hernández
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.,Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jesús Ávila
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.,Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | | | | | - Alejandro Lucía
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain.,Research Institute of the Hospital 12 de Octubre ("imas"), Madrid, Spain.,Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
| | | | - Bruno P Imbimbo
- Research & Development Department, Chiesi Farmaceutici, Parma, Italy
| | - Andrea Vergallo
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | - Simone Lista
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.,Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France.,Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
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Candasamy M, Mohamed Elhassan SA, Kumar Bhattamisra S, Hua WY, Sern LM, Binti Busthamin NA, Mohamad Ilni NB, Shun NS, Baohong L, Ya NS, Ying NW. Type 3 diabetes (Alzheimer's disease): new insight for promising therapeutic avenues. Panminerva Med 2020; 62:155-163. [PMID: 32208408 DOI: 10.23736/s0031-0808.20.03879-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) are two of the most commonly occurring diseases worldwide, especially among the elderly population. In particular, the increased prevalence of AD has imposed tremendous psychological and financial burdens on society. Growing evidence suggests both AD and T2D share many similar pathological traits. AD is characterized as a metabolic disorder whereby the glucose metabolism in the brain is impaired. This closely resembles the state of insulin resistance in T2D. Insulin resistance of the brain has been heavily implicated two prominent pathological features of AD, Aβ plaques and neurofibrillary tangles. Brain insulin resistance is known to elicit a positive feed-forward loop towards the formation of AD pathology in which they affect each other in a synergistic manner. Other physiological traits shared between the two diseases include inflammation, oxidative stress and autophagic dysfunction, which are also closely associated with brain insulin resistance. In this review and depending on these underlying pathways that link these two diseases, we have discussed the potential therapeutic implications of AD. By expanding our knowledge of the overlapping pathophysiology involved, we hope to provide scientific basis to the discovery of novel therapeutic strategies to improve the clinical outcomes of AD in terms of diagnosis and treatment.
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Affiliation(s)
- Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia -
| | | | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Wong Y Hua
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Lim M Sern
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | | | | | - Ng S Shun
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Lim Baohong
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Ng S Ya
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Ng W Ying
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
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Abstract
Neuroinflammation is implicated in contributing to a variety of neurologic and somatic illnesses including Alzheimer's disease (AD), Parkinson's disease (PD), and depression. In this chapter, we focus on the role of neuroinflammation in mediating these three illnesses and portray interactions between the immune response and the central nervous system in the context of sex differences in disease progression. The majority of this chapter is supported by clinical findings; however, we occasionally utilize preclinical models where human studies are currently lacking. We begin by detailing the pathology of neuroinflammation, distinguishing between acute and chronic inflammation, and examining contributions from the innate and adaptive immune systems. Next, we summarize potential mechanisms of immune cell mediators including interleukin-1 beta (IL-1β), tumor necrosis factor α, and IL-6 in AD, PD, and depression development. Given the strong sex bias seen in these illnesses, we additionally examine the role of sex hormones, e.g., estrogen and testosterone in mediating neuroinflammation at the cellular level. Systematically, we detail how sex hormones may contribute to distinct behavioral and clinical symptoms and prognosis between males and females with AD, PD, or depression. Finally, we highlight the possible role of exercise in alleviating neuroinflammation, as well as evidence that antiinflammatory drug therapies improve cognitive symptoms observed in brain-related diseases.
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Affiliation(s)
- Deepika Mukhara
- Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Unsong Oh
- Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
| | - Gretchen N Neigh
- Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.
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43
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Webers A, Heneka MT, Gleeson PA. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer's disease. Immunol Cell Biol 2019; 98:28-41. [PMID: 31654430 DOI: 10.1111/imcb.12301] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 09/20/2019] [Accepted: 10/24/2019] [Indexed: 12/18/2022]
Abstract
Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation, tau pathology and neuroinflammation. Recently, there has been considerable interest in the role of neuroinflammation in directly contributing to the progression of AD. Studies in mice and humans have identified a role for microglial cells, the resident innate immune cells of the central nervous system, in AD. Activated microglia are a key hallmark of the disease and the secretion of proinflammatory cytokines by microglia may result in a positive feedback loop between neurons and microglia, resulting in ongoing low-grade inflammation. Traditionally, the pathways of Aβ production and neuroinflammation have been considered independently; however, recent studies suggest that these processes may converge to promote the pathology associated with AD. Here we review the importance of inflammation and microglia in AD development and effects of inflammatory responses on cellular pathways of neurons, including Aβ generation.
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Affiliation(s)
- Alessandra Webers
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.,Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, Bonn, Germany
| | - Michael T Heneka
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, Bonn, Germany.,German Center for Neurodegenerative Diseases, Bonn, Germany
| | - Paul A Gleeson
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
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44
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Baran TM, Lin FV. Amyloid and FDG PET of Successful Cognitive Aging: Global and Cingulate-Specific Differences. J Alzheimers Dis 2019; 66:307-318. [PMID: 30282358 DOI: 10.3233/jad-180360] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied. OBJECTIVE The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, 172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference. RESULTS SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions. CONCLUSION Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories.
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Affiliation(s)
- Timothy M Baran
- Departments of Imaging Sciences and Biomedical Engineering, University of Rochester, Rochester, NY, USA
| | - Feng Vankee Lin
- Departments of Imaging Sciences and Biomedical Engineering, University of Rochester, Rochester, NY, USA
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45
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O'Bryant SE, Zhang F, Johnson LA, Hall J, Edwards M, Grammas P, Oh E, Lyketsos CG, Rissman RA. A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. J Alzheimers Dis 2019; 66:97-104. [PMID: 30198872 DOI: 10.3233/jad-180619] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. OBJECTIVE To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. METHODS Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. RESULTS 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. CONCLUSION Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.
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Affiliation(s)
- Sid E O'Bryant
- Department of Pharmacology & Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Fan Zhang
- Vermont Genetics Network, University of Vermont, VT, USA
| | - Leigh A Johnson
- Department of Pharmacology & Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - James Hall
- Department of Pharmacology & Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA
| | | | - Paula Grammas
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, RI, USA
| | - Esther Oh
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.,Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA
| | | | - Robert A Rissman
- Department of Neurosciences, UCSD School of Medicine, La Jolla, CA, USA.,VA San Diego Healthcare System, San Diego, CA, USA
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46
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Biringer RG. The Role of Eicosanoids in Alzheimer's Disease. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16142560. [PMID: 31323750 PMCID: PMC6678666 DOI: 10.3390/ijerph16142560] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/09/2019] [Accepted: 07/13/2019] [Indexed: 12/21/2022]
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders known. Estimates from the Alzheimer's Association suggest that there are currently 5.8 million Americans living with the disease and that this will rise to 14 million by 2050. Research over the decades has revealed that AD pathology is complex and involves a number of cellular processes. In addition to the well-studied amyloid-β and tau pathology, oxidative damage to lipids and inflammation are also intimately involved. One aspect all these processes share is eicosanoid signaling. Eicosanoids are derived from polyunsaturated fatty acids by enzymatic or non-enzymatic means and serve as short-lived autocrine or paracrine agents. Some of these eicosanoids serve to exacerbate AD pathology while others serve to remediate AD pathology. A thorough understanding of eicosanoid signaling is paramount for understanding the underlying mechanisms and developing potential treatments for AD. In this review, eicosanoid metabolism is examined in terms of in vivo production, sites of production, receptor signaling, non-AD biological functions, and known participation in AD pathology.
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Affiliation(s)
- Roger G Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Blvd., Bradenton, FL 34211, USA.
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47
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Karadurmus L, Sahin IF, Kurbanoglu S, Ozkan SA. Electrochemical Determination of Non-Steroidal Anti-Inflammatory Drugs. CURR ANAL CHEM 2019. [DOI: 10.2174/1573411014666180917113920] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Electrochemical methods have been used for the determination of nonsteroidal antiinflammatory
drugs (NSAID) just as used in the determination of various drugs. Among voltammetric
methods; differential pulse voltammetric method, square wave voltammetric method and linear
sweep voltammetric method are the most commonly used ones. NSAIDs are widely used in the
treatment of inflammatory conditions such as musculoskeletal disorders (rheumatoid arthritis, osteoarthritis,
acute gouty arthritis) and dental pain, menstrual pain, postoperative pain and migraine. In
this review, some selected recent electrochemical studies were selected related to the nonsteroidal antiinflammatory
drug analyzes. The aim of this review is to evaluate and discuss the advantages, details
and usages of electroanalytical methods in the determination of nonsteroidal anti-inflammatory drug.
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Affiliation(s)
- Leyla Karadurmus
- Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - I. Firat Sahin
- Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Sevinc Kurbanoglu
- Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Sibel A. Ozkan
- Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
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48
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Eden BD, Rice AJ, Lovett TD, Toner OM, Geissler EP, Bowman WE, Young SC. Microwave-assisted synthesis and in vitro stability of N-benzylamide non-steroidal anti-inflammatory drug conjugates for CNS delivery. Bioorg Med Chem Lett 2019; 29:1487-1491. [PMID: 30987893 DOI: 10.1016/j.bmcl.2019.04.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 03/27/2019] [Accepted: 04/08/2019] [Indexed: 02/05/2023]
Abstract
More effective delivery of non-steroidal anti-inflammatory drugs (NSAIDs) to the brain could treat the underlying inflammatory pathology of a range of CNS diseases and conditions. Use of a blood-brain barrier shuttle such as the N-benzylamide moiety, which has been largely unexplored for this purpose, could improve the brain bioavailabilities of NSAIDs. A series of novel N-benzylamide NSAID conjugates was synthesized via a three-step process with a microwave-assisted bimolecular nucleophilic substitution as the final step. We explored conditions to promote substitution over a competing elimination reaction, which was successfully suppressed with isopropyl alcohol solvent. All molecules exhibit physicochemical properties consistent with those of brain-penetrant molecules. Furthermore, they exhibit long (>48 h) half-lives in phosphate-buffered saline (PBS; pH 7.4) and short to moderate half-lives in human plasma. N-Benzylamide NSAID conjugates represent promising CNS drug discovery leads.
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Affiliation(s)
- Brandon D Eden
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States
| | - Andrew J Rice
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States
| | - Troy D Lovett
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States
| | - Olivia M Toner
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States
| | - Evan P Geissler
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States
| | - William E Bowman
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States
| | - Sherri C Young
- Department of Chemistry, Muhlenberg College, 2400 Chew Street, Allentown, PA 18104, United States.
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49
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Erdal A, Ballard C, Vahia IV, Husebo BS. Analgesic treatments in people with dementia - how safe are they? A systematic review. Expert Opin Drug Saf 2019; 18:511-522. [PMID: 31038371 DOI: 10.1080/14740338.2019.1614166] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 04/29/2019] [Indexed: 01/01/2023]
Abstract
INTRODUCTION People with dementia may be unable to verbally express pain and suffer from untreated pain. Use of analgesics in people with dementia has increased during the last decade, in particular opioid analgesics with high potential for adverse effects. AREAS COVERED This article presents a systematic review of the current evidence for safety and tolerability of analgesic drugs from randomized controlled trials in people with dementia. Relevant trials were identified by a literature search in the EMBASE, MEDLINE, and Cochrane databases from inception to November 2018. The search included the main terms 'dementia' and 'analgesic' or their subterms, and was filtered to limit results to clinical trials. EXPERT OPINION Although pain treatment is increasingly recognized as an important clinical issue in people with advanced dementia, there is currently a lack of evidence to support safety evaluations of commonly used analgesics in this group. To inform treatment decisions and enable care providers to appropriately monitor patients at risk of adverse effects, it is necessary to conduct well-designed clinical trials to investigate the relative efficacy and safety of analgesics in people with dementia, with particular emphasis on harmful effects of long-term opioid use as well as short-term use of nonsteroidal anti-inflammatory drugs.
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Affiliation(s)
- Ane Erdal
- a Department of Global Public Health and Primary Care , Centre for Elderly and Nursing Home Medicine, University of Bergen , Bergen , Norway
| | | | - Ipsit Vihang Vahia
- c McLean Institute for Technology in Psychiatry and Geriatric Psychiatry Outpatient Services , McLean Hospital , Belmont , MA , USA
- d Department of Psychiatry , Harvard Medical School , Boston , MA , USA
| | - Bettina Sandgathe Husebo
- a Department of Global Public Health and Primary Care , Centre for Elderly and Nursing Home Medicine, University of Bergen , Bergen , Norway
- e Department of Health and Care , Municipality of Bergen , Bergen , Norway
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50
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Ali MM, Ghouri RG, Ans AH, Akbar A, Toheed A. Recommendations for Anti-inflammatory Treatments in Alzheimer's Disease: A Comprehensive Review of the Literature. Cureus 2019; 11:e4620. [PMID: 31312547 PMCID: PMC6615583 DOI: 10.7759/cureus.4620] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in elderly patients, affecting individuals older than 60 years. It is a complex degenerative brain disease characterized by progressive cognitive impairment. AD constitutes a major global health concern. A central role for inflammation has been implicated in the pathogenesis of AD. Despite the understanding of multiple molecular pathways in the pathophysiology of AD, novel treatment agents with a possible role in modifying the disease activity are still lacking. Our article provides a comprehensive review of various observational studies and randomized trials encompassing the use of anti-inflammatory agents in the management of AD patients and utilizes the conclusions derived therefrom to give recommendations in this regard.
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Affiliation(s)
- Muhammad Mohsin Ali
- Internal Medicine, Mayo Hospital, King Edward Medical University, Lahore, PAK
| | - Raza G Ghouri
- Internal Medicine, Mayo Hospital, King Edward Medical University, Lahore, PAK
| | - Armghan H Ans
- Cardiology, University of Pennsylvania, Philadelphia, USA
| | - Arshia Akbar
- Internal Medicine, Rawalpindi Medical College, Rawalpindi, PAK
| | - Ahmed Toheed
- Internal Medicine, Mayo Hospital, King Edward Medical University, Lahore, PAK
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