Molecules

Editorial

Jump to: Research, Review, Other

169 KiB

Open AccessEditorial

Special Issue: “Molecules against Alzheimer”

by Michael Decker and Diego Muñoz-Torrero

Molecules 2016, 21(12), 1736; https://doi.org/10.3390/molecules21121736 - 16 Dec 2016

Cited by 3 | Viewed by 6400

Abstract

This Special Issue, entitled “Molecules against Alzheimer”, gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder [...] Read more.

This Special Issue, entitled “Molecules against Alzheimer”, gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

Research

Jump to: Editorial, Review, Other

2589 KiB

Open AccessArticle

Optimization and Biodistribution of [¹¹C]-TKF, An Analog of Tau Protein Imaging Agent [¹⁸F]-THK523

by Yanyan Kong, Yihui Guan, Fengchun Hua, Zhengwei Zhang, Xiuhong Lu, Tengfang Zhu, Bizeng Zhao, Jianhua Zhu, Cong Li and Jian Chen

Molecules 2016, 21(8), 1019; https://doi.org/10.3390/molecules21081019 - 5 Aug 2016

Cited by 3 | Viewed by 5016

Abstract

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer’s disease (AD) and allow monitoring of disease progression and treatment efficacy. [¹⁸F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention [...] Read more.

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer’s disease (AD) and allow monitoring of disease progression and treatment efficacy. [¹⁸F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [¹¹C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [¹¹C]-TKF can be made by reaction precursor with [¹¹C]MeOTf or ¹¹CH₃I, but [¹¹C]MeOTf will give us higher labeling yields and specific activity. [¹¹C]-TKF presented better brain uptake in normal mouse than [¹⁸F]-THK523 (3.23% ± 1.25% ID·g⁻¹ vs. 2.62% ± 0.39% ID·g⁻¹ at 2 min post-injection). The acute toxicity studies of [¹¹C]-TKF were unremarkable. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Figure 1

2084 KiB

Open AccessArticle

Naturally Inspired Molecules as Multifunctional Agents for Alzheimer’s Disease Treatment

by Angela Rampa, Andrea Tarozzi, Francesca Mancini, Letizia Pruccoli, Rita Maria Concetta Di Martino, Silvia Gobbi, Alessandra Bisi, Angela De Simone, Francesco Palomba, Nelsi Zaccheroni and Federica Belluti

Molecules 2016, 21(5), 643; https://doi.org/10.3390/molecules21050643 - 16 May 2016

Cited by 16 | Viewed by 6604

Abstract

Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic [...] Read more.

Alzheimer’s disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the “pharmacophores combination” strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu²⁺-induced ROS formation without any direct neurotoxic effect. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

1417 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

by Youssef Dgachi, Oscar M. Bautista-Aguilera, Mohamed Benchekroun, Hélène Martin, Alexandre Bonet, Damijan Knez, Justyna Godyń, Barbara Malawska, Stanislav Gobec, Mourad Chioua, Jana Janockova, Ondrej Soukup, Fakher Chabchoub, José Marco-Contelles and Lhassane Ismaili

Molecules 2016, 21(5), 634; https://doi.org/10.3390/molecules21050634 - 14 May 2016

Cited by 30 | Viewed by 6738

Abstract

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC₅₀ = 1.28 ± 0.03 μM), good antioxidant activity, and [...] Read more.

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC₅₀ = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Figure 1

735 KiB

Open AccessCommunication

Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer’s Disease

by Mike Jones, Jun Wang, Shona Harmon, Beata Kling, Jörg Heilmann and John F. Gilmer

Molecules 2016, 21(4), 440; https://doi.org/10.3390/molecules21040440 - 1 Apr 2016

Cited by 18 | Viewed by 5462

Abstract

Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid [...] Read more.

Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase (BuChE). The hybrid compounds were non-toxic to the murine hippocampal cell line HT-22 and lipoate esters were neuroprotective at 10 and 25 µM when the cells were challenged with glutamate (5 mM) in a similar manner to the positive control quercetin. The benzyl carbamate 7a was a potent inhibitor of BuChE (IC₅₀ 150 nM) and it was effective in reducing glutamate toxicity to neuronal cells at >5 µM. Representative compounds exhibited an antioxidant effect in the oxygen radical absorbance capacity assay as the lipoate 7d was not active, whereas the ferulate 8a showed a weak, but significant, activity with 0.635 ± 0.020 Trolox Equivalent. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

3807 KiB

Open AccessArticle

Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

by Michalina Hebda, Marek Bajda, Anna Więckowska, Natalia Szałaj, Anna Pasieka, Dawid Panek, Justyna Godyń, Tomasz Wichur, Damijan Knez, Stanislav Gobec and Barbara Malawska

Molecules 2016, 21(4), 410; https://doi.org/10.3390/molecules21040410 - 26 Mar 2016

Cited by 32 | Viewed by 8299

Abstract

Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized [...] Read more.

Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC₅₀ = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC₅₀ = 0.76 μM, EqBuChE IC₅₀ = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

2426 KiB

Open AccessArticle

Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer’s Disease

by John M. Saathoff, Kai Liu, Jeremy E. Chojnacki, Liu He, Qun Chen, Edward J. Lesnefsky and Shijun Zhang

Molecules 2016, 21(4), 412; https://doi.org/10.3390/molecules21040412 - 25 Mar 2016

Cited by 9 | Viewed by 5262

Abstract

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound [...] Read more.

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca²⁺ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca²⁺ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca²⁺ in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

1053 KiB

Open AccessArticle

Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer's Disease Therapy

by Houssem Boulebd, Lhassane Ismaili, Manuela Bartolini, Abdelmalek Bouraiou, Vincenza Andrisano, Helene Martin, Alexandre Bonet, Ignacio Moraleda, Isabel Iriepa, Mourad Chioua, Ali Belfaitah and José Marco-Contelles

Molecules 2016, 21(4), 400; https://doi.org/10.3390/molecules21040400 - 24 Mar 2016

Cited by 23 | Viewed by 8313

Abstract

Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a [...] Read more.

Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC₅₀ = 38.7 ± 1.7 μM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound). Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

1519 KiB

Open AccessArticle

Searching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif

by Leonardo Pisani, Roberta Farina, Ramon Soto-Otero, Nunzio Denora, Giuseppe Felice Mangiatordi, Orazio Nicolotti, Estefania Mendez-Alvarez, Cosimo Damiano Altomare, Marco Catto and Angelo Carotti

Molecules 2016, 21(3), 362; https://doi.org/10.3390/molecules21030362 - 17 Mar 2016

Cited by 49 | Viewed by 7479

Abstract

The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer’s disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel [...] Read more.

The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer’s disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC₅₀ = 8.99 µM) and a potent and selective MAO-B inhibitor (IC₅₀ = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

547 KiB

Open AccessCommunication

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

by Martin Krátký, Šárka Štěpánková, Katarína Vorčáková, Markéta Švarcová and Jarmila Vinšová

Molecules 2016, 21(2), 191; https://doi.org/10.3390/molecules21020191 - 11 Feb 2016

Cited by 40 | Viewed by 8082

Abstract

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC₅₀ [...] Read more.

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC₅₀ values within the range of 1.60 to 311.0 µM. IC₅₀ values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC₅₀ = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC₅₀ value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

1090 KiB

Open AccessArticle

Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

by Susimaire P. Mantoani, Talita P. C. Chierrito, Adriana F. L. Vilela, Carmen L. Cardoso, Ana Martínez and Ivone Carvalho

Molecules 2016, 21(2), 193; https://doi.org/10.3390/molecules21020193 - 5 Feb 2016

Cited by 55 | Viewed by 10632

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with [...] Read more.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC₅₀ values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

2471 KiB

Open AccessArticle

Graveoline Analogs Exhibiting Selective Acetylcholinesterase Inhibitory Activity as Potential Lead Compounds for the Treatment of Alzheimer’s Disease

by Zeng Li, Chaoyu Mu, Bin Wang and Juan Jin

Molecules 2016, 21(2), 132; https://doi.org/10.3390/molecules21020132 - 22 Jan 2016

Cited by 19 | Viewed by 5736

Abstract

This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against [...] Read more.

This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (Selectivity Index from 45 to 486). When the two sites in the graveoline parent ring substituting phenyl and amino terminal had six chemical bonds (n = 3) and the terminal amino was piperidine, compound 5c showed the best activity. Furthermore, the mechanism of action and binding mode were explored by enzyme kinetic simulation, molecular docking, and thioflavin T-based fluorometric assay. Cytotoxicity assay showed that the low concentration of the analogs did not affect the viability of the neurocyte SH-SY5Y. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Figure 1

539 KiB

Open AccessArticle

Long-Term Lithium Treatment Increases cPLA₂ and iPLA₂ Activity in Cultured Cortical and Hippocampal Neurons

by Vanessa De Jesus De-Paula, Daniel Shikanai Kerr, Marília Palma Fabiano De Carvalho, Evelin Lisete Schaeffer, Leda Leme Talib, Wagner Farid Gattaz and Orestes Vicente Forlenza

Molecules 2015, 20(11), 19878-19885; https://doi.org/10.3390/molecules201119663 - 4 Nov 2015

Cited by 10 | Viewed by 7130

Abstract

Background: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium [...] Read more.

Background: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium may also affect membrane homeostasis. Objective: To investigate the effect of lithium on cytosolic phospholipase A₂ (PLA₂) activity, a key player on membrane phospholipid turnover which has been found to be reduced in blood and brain tissue of patients with Alzheimer’s disease (AD). Methods: Primary cultures of cortical and hippocampal neurons were treated for 7 days with different concentrations of lithium chloride (0.02 mM, 0.2 mM and 2 mM). A radio-enzymatic assay was used to determine the total activity of PLA₂ and two PLA₂ subtypes: cytosolic calcium-dependent (cPLA₂); and calcium-independent (iPLA₂). Results: cPLA₂ activity increased by 82% (0.02 mM; p = 0.05) and 26% (0.2 mM; p = 0.04) in cortical neurons and by 61% (0.2 mM; p = 0.03) and 57% (2 mM; p = 0.04) in hippocampal neurons. iPLA₂ activity was increased by 7% (0.2 mM; p = 0.04) and 13% (2 mM; p = 0.05) in cortical neurons and by 141% (0.02 mM; p = 0.0198) in hippocampal neurons. Conclusion: long-term lithium treatment increases membrane phospholipid metabolism in neurons through the activation of total, c- and iPLA₂. This effect is more prominent at sub-therapeutic concentrations of lithium, and the activation of distinct cytosolic PLA₂ subtypes is tissue specific, i.e., iPLA₂ in hippocampal neurons, and cPLA₂ in cortical neurons. Because PLA₂ activities are reported to be reduced in Alzheimer’s disease (AD) and bipolar disorder (BD), the present findings provide a possible mechanism by which long-term lithium treatment may be useful in the prevention of the disease. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research, Other

1197 KiB

Open AccessReview

Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases

by Clara Herrera-Arozamena, Olaia Martí-Marí, Martín Estrada, Mario De la Fuente Revenga and María Isabel Rodríguez-Franco

Molecules 2016, 21(9), 1165; https://doi.org/10.3390/molecules21091165 - 1 Sep 2016

Cited by 32 | Viewed by 10753

Abstract

The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever [...] Read more.

The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis. Therefore, the controlled pharmacological stimulation of the endogenous neural stem cells (NSCs) niches might counteract the neuronal loss in Alzheimer’s disease (AD) and other pathologies, opening an exciting new therapeutic avenue. In the last years, druggable molecular targets and signalling pathways involved in neurogenic processes have been identified, and as a consequence, different drug types have been developed and tested in neuronal plasticity. This review focuses on recent advances in neurogenic agents acting at serotonin and/or melatonin systems, Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase (NAMPT) and nuclear erythroid 2-related factor (Nrf2). Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Figure 1

708 KiB

Open AccessReview

The Rationale for Insulin Therapy in Alzheimer’s Disease

by Samo Ribarič

Molecules 2016, 21(6), 689; https://doi.org/10.3390/molecules21060689 - 26 May 2016

Cited by 15 | Viewed by 8140

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Figure 1

1238 KiB

Open AccessReview

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

by Federica Prati, Andrea Cavalli and Maria Laura Bolognesi

Molecules 2016, 21(4), 466; https://doi.org/10.3390/molecules21040466 - 8 Apr 2016

Cited by 94 | Viewed by 10844

Abstract

Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, [...] Read more.

Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Graphical abstract

Other

Jump to: Editorial, Research, Review

2666 KiB

Open AccessConference Report

Treatment with Akebia Saponin D Ameliorates Aβ_1–42-Induced Memory Impairment and Neurotoxicity in Rats

by Yongde Chen, Xiaolin Yang, Tong Chen, Jing Ji, Li Lan, Rong Hu and Hui Ji

Molecules 2016, 21(3), 323; https://doi.org/10.3390/molecules21030323 - 8 Mar 2016

Cited by 7 | Viewed by 5403

Abstract

Amyloid-β peptide (Aβ) is known to be directly associated with the progressive neuronal death observed in Alzheimer’s disease (AD). However, effective neuroprotective approaches against Aβ neurotoxicity are still unavailable. In the present study, we investigated the protective effects of Akebia saponin D (ASD), [...] Read more.

Amyloid-β peptide (Aβ) is known to be directly associated with the progressive neuronal death observed in Alzheimer’s disease (AD). However, effective neuroprotective approaches against Aβ neurotoxicity are still unavailable. In the present study, we investigated the protective effects of Akebia saponin D (ASD), a typical compound isolated from the rhizome of Dipsacus asper Wall, on Aβ_1–42-induced impairment of learning and memory formation and explored the probable underlying molecular mechanisms. We found that treatment with ASD (30, 90 or 270 mg/kg) significantly ameliorated impaired spatial learning and memory in intracerebroventricularly (ICV) Aβ_1–42-injected rats, as evidenced by a decrease tendency in escape latency during acquisition trials and improvement in exploratory activities in the probe trial in Morris water maze (MWM). Further study showed that ASD reversed Aβ_1–42-induced accumulation of Aβ_1–42 and Aβ_1–40 in the hippocampus through down-regulating the expression of BACE and Presenilin 2 accompanied with increased the expression of TACE, IDE and LRP-1. Taken together, our findings suggested that ASD exerted therapeutic effects on Aβ-induced cognitive deficits via amyloidogenic pathway. Full article

(This article belongs to the Special Issue Molecules against Alzheimer)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Molecules against Alzheimer

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (17 papers)

Editorial

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI