What have we learnt from past failures in Alzheimer’s disease drug discovery?

Cacabelos, Ramón

doi:10.1080/17460441.2022.2033724

Cited by 13 publications

(4 citation statements)

References 28 publications

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“…In such patients, neurodegeneration may have progressed to the point where the disease cannot be treated. The earliest loss of neurons in AD occurs a decade or more before the onset of symptoms [62], and is the major reason we had chosen 10-14-month-old mice (equivalent to 38-47-year-old human adults) as this reflects the ages during which the earliest stages of AD begin. Detection and therapeutic intervention early in the AD continuum may therefore be the most effective strategy to reduce the burden of AD and improve the quality of life for patients with the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Neuroinflammation is critical to AD pathogenesis and its progression. IL-1β and IL-6 are upregulated in the blood and cerebrospinal fluid of AD patients [62][63][64] and in the cerebral cortex of APP/PS1 mice [65]. High IL-1β levels in the AD brain are directly linked to plaque formation and progression and the overexpression of neuronal Aβ precursorand other plaque-associated proteins [64].…”

Section: Discussionmentioning

confidence: 99%

“…High IL-1β levels in the AD brain are directly linked to plaque formation and progression and the overexpression of neuronal Aβ precursorand other plaque-associated proteins [64]. Elevated IL-6 levels are associated with the development of diffuse plaques, which represents the early prodromal stage of plaque formation [62]. TNFα, an important mediator of inflammation, is released by microglia and astrocytes [64] and is a key contributor to AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD), the most common cause of dementia, causes irreversible memory loss and cognitive deficits. Current AD drugs do not significantly improve cognitive function or cure the disease. Novel bioproducts are promising options for treating a variety of diseases, including neurodegenerative disorders. Targeting the epigenetic apparatus with bioactive compounds (epidrugs) may aid AD prevention treatment. The aims of this study were to determine the composition of a porcine brain-derived extract Nosustrophine, and whether treating young and older trigenic AD mice produced targeted epigenetic and neuroprotective effects against neurodegeneration. Nosustrophine regulated AD-related APOE and PSEN2 gene expression in young and older APP/BIN1/COPS5 mice, inflammation-related (NOS3 and COX-2) gene expression in 3–4-month-old mice only, global (5mC)- and de novo DNA methylation (DNMT3a), HDAC3 expression and HDAC activity in 3–4-month-old mice; and SIRT1 expression and acetylated histone H3 protein levels in 8–9-month-old mice. Mass spectrometric analysis of Nosustrophine extracts revealed the presence of adenosylhomocysteinase, an enzyme implicated in DNA methylation, and nicotinamide phosphoribosyltransferase, which produces the NAD+ precursor, enhancing SIRT1 activity. Our findings show that Nosustrophine exerts substantial epigenetic effects against AD-related neurodegeneration and establishes Nosustrophine as a novel nutraceutical bioproduct with epigenetic properties (epinutraceutical) that may be therapeutically effective for prevention and early treatment for AD-related neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease

et al. 2022

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“…When pharmacogenetics become a mature discipline, the most effective manner to optimize the available therapeutic resources and reduce ADRs and DDIs is the implementation of pharmacogenetic procedures as a daily routine in the clinic. The routine use of pharmacogenetics is limited by a series of educational factors (information deficit among health professionals), technical factors (poor characterization of the pharmacogenetic properties of more than 50% of commonly used drugs), biomedical factors (shortage of biomarkers of drug efficacy and toxicity), economic factors (high cost of pharmacogenetic screening), administrative factors (lack of organization in hospitals and health centers for personalized medicine), and regulatory factors (poor definition of pharmacogenetics parameters by regulatory agencies for the use of drugs and for the development of new pharmaceutical products) [ 185 , 186 ].…”

Section: Future Trendsmentioning

confidence: 99%

Personalized Management and Treatment of Alzheimer’s Disease

Cacabelos

Naidoo

Martínez-Iglesias

et al. 2022

Life

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Alzheimer’s disease (AD) is a priority health problem with a high cost to society and a large consumption of medical and social resources. The management of AD patients is complex and multidisciplinary. Over 90% of patients suffer from concomitant diseases and require personalized therapeutic regimens to reduce adverse drug reactions (ADRs), drug–drug interactions (DDIs), and unnecessary costs. Men and women show substantial differences in their AD-related phenotypes. Genomic, epigenetic, neuroimaging, and biochemical biomarkers are useful for predictive and differential diagnosis. The most frequent concomitant diseases include hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60–90%), neuropsychiatric disorders (60–90%), and cancer (10%). Over 90% of AD patients require multifactorial treatments with risk of ADRs and DDIs. The implementation of pharmacogenetics in clinical practice can help optimize the limited therapeutic resources available to treat AD and personalize the use of anti-dementia drugs, in combination with other medications, for the treatment of concomitant disorders.

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Sulfonyl thioureas with a benzo[d]thiazole ring as dual acetylcholinesterase/butyrylcholinesterase and human monoamine oxidase A and B inhibitors: An in vitro and in silico study

Dinh Thanh,

Son Hai,

Ngoc Toan

et al. 2024

Archiv der Pharmazie

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A series of sulfonyl thioureas 6a–q containing a benzo[d]thiazole ring with an ester functional group was synthesized from corresponding substituted 2‐aminobenzo[d]thiazoles 3a–q and p‐toluenesulfonyl isothiocyanate. They had remarkable inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO)‐A, and MAO‐B. Among thioureas, several compounds had notable activity in the order of 6k > 6 h > 6c (AChE), 6j > 6g > 6k (BChE), 6k > 6g > 6f (MAO‐A), and 6i > 6k > 6h (MAO‐B). Compound 6k was an inhibitor of interest due to its potent or good activity against all studied enzymes, with IC50 values of 0.027 ± 0.008 μM (AChE), 0.043 ± 0.004 μM (BChE), 0.353 ± 0.01 μM (MAO‐A), and 0.716 ± 0.02 μM (MAO‐B). This inhibitory capacity was comparable to that of the reference drugs for each enzyme. Kinetic studies of two compounds with potential activity, 6k (against AChE) and 6j (against BChE), had shown that both 6k and 6j followed competitive‐type enzyme inhibition, with Ki constants of 24.49 and 12.16 nM, respectively. Induced fit docking studies for enzymes 4EY7, 7BO4, 2BXR, and 2BYB showed active interactions between sulfonyl thioureas of benzo[d]thiazoles and the residues in the active pocket with ligands 6k, 6i, and 6j, respectively. The stability of the ligand–protein complexes while each ligand entered the active site of each enzyme (4EY7, 7BO4, 2BXR, or 2BYB) was confirmed by molecular dynamics simulations.

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What have we learnt from past failures in Alzheimer’s disease drug discovery?

Cited by 13 publications

References 28 publications

Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease

Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease

Personalized Management and Treatment of Alzheimer’s Disease

Sulfonyl thioureas with a benzo[d]thiazole ring as dual acetylcholinesterase/butyrylcholinesterase and human monoamine oxidase A and B inhibitors: An in vitro and in silico study

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