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Alzheimer disease

Juliana C C Dallagnol, Elham Khajehali, Emma T van der Westhuizen, Manuela Jörg, Celine Valant, Alan G Goncalves, Ben Capuano, Arthur Christopoulos, Peter J Scammells
Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators may not only potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh), but may also possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles...
March 15, 2018: Journal of Medicinal Chemistry
Kyeongjun Lee, Chowee Park, Yeonsoo Oh, Heesoon Lee, Jungsook Cho
Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer's disease (AD). In the present study, we investigated the effect of N -((3,4-dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to that of memantine, a non-competitive N -methyl-d-aspartate (NMDA) receptor antagonist clinically used to treat AD. We found that BL-M inhibited glutamate- or N -methyl-d-aspartate (NMDA)-induced excitotoxic cell damage...
March 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Fabio Sonvico, Adryana Clementino, Francesca Buttini, Gaia Colombo, Silvia Pescina, Silvia Stanisçuaski Guterres, Adriana Raffin Pohlmann, Sara Nicoli
In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer's disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality...
March 15, 2018: Pharmaceutics
Lisa K Gouwens, Mudar S Ismail, Victoria A Rogers, Nathan T Zeller, Evan C Garrad, Fatima S Amtashar, Nyasha J Makoni, David C Osborn, Michael R Nichols
Microvesicles (MVs) and exosomes comprise a class of cell-secreted particles termed extracellular vesicles (EVs). These cargo-holding vesicles mediate cell-to-cell communication and have recently been implicated in neurodegenerative diseases such as Alzheimer's disease (AD). The two types of EVs are distinguished by the mechanism of cell release and their size, with the smaller exosomes and the larger MVs ranging from 30 to 100 nm and 100 nm to 1 μm in diameter, respectively. MV numbers are increased in AD and appear to interact with amyloid-β peptide (Aβ), the primary protein component of the neuritic plaques in the AD brain...
March 15, 2018: ACS Chemical Neuroscience
Weijun Huang, Yujun Wang, Jiaming Li, Yanchun Zhang, Xiaodong Ma, Panhu Zhu, Yang Zhang
Twenty two novel genipin derivatives have been designed, synthesized and evaluated for their inhibitory activity against acetylcholinesterase (AChE). As a result, compound 13a bearing ligustrazine moiety displayed the most potent AChE inhibitory activity in this serieswith IC50 value of 218 nM. Besides, MTT assay was performed to investigate the neuroprotection of these compounds against PC12 cells injured by Amyloid β-protein 1-42 (Aβ1-42 ). Among them, 8a showed higher inhibition rate (%Inhibition = 22...
March 15, 2018: Chemical Biology & Drug Design
Jing Chen, Yan Qi, Cui-Fang Liu, Jing-Min Lu, Yan Shi
INTRODUCTION: MicroRNAs have been increasing prevalent due to the association of their deregulation with neurodegenerative disorders, especially Alzheimer's disease (AD). However, the association between miRNAs and AD hasn't been made clear. PURPOSE: In this study, Nine representative miRNA datasets were selected for the identification of the critical miRNAs by analyzing the overlap relations among them. TargetScan software was further used to predict the target genes of these miRNAs...
March 15, 2018: Journal of Gene Medicine
Jun Zhang, Alexander Sandberg, Audun Konsmo, Xiongyu Wu, Sofie Nyström, K Peter Nilsson, Peter Konradsson, Harry LeVine, Mikael Lindgren, Per Hammarström
We revisited the Congo red analogue 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimer's disease (AD) pathology comprising Aβ and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed determining absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes...
March 15, 2018: Chemistry: a European Journal
Akhil Kumar, Ashish Tiwari, Ashok Sharma
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target...
March 15, 2018: Current Neuropharmacology
Sheikh Arslan Sehgal, Mirza A Hammad, Rana Adnan Tahir, Hafiza Nisha Akram, Faheem Ahmad
BACKGROUND: As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. OBJECTIVE: To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases...
March 15, 2018: Current Neuropharmacology
Amit Shivajirao Waghmare, Shivaji Sandu Pandit, Dayanand M Suryawanshi
AIM AND OBJECTIVE: 4H-pyran is one of the most well-known groups of synthetic heterocyclic compounds and it has attracted considerable attention of chemists in recent years because of their extensive range of biological and pharmaceutical activities. These compounds are used as antibacterial, anticancer agents, anti-coagulants, spasmolytics and anti-anaphylactic. 4H-pyran derivatives are utilized in cosmetics, pigments, biodegradable agrochemicals as well as photoactive materials. In addition, 4H-pyrans are also helpful as cognitive enhancers for the treatment of neuro degenerative diseases, including Alzheimer's disease, as well as for the treatment of schizophrenia and myoclonus...
March 14, 2018: Combinatorial Chemistry & High Throughput Screening
Renata Valle Pedroso, José Maria Cancela, Carlos Ayán, Angelica Miki Stein, Gilson Fuzaro, José Luiz Riani Costa, Francisco J Fraga, Ruth Ferreira Santos-Galduróz
BACKGROUND: Evidence regarding the benefits of physical activity on the mental processing information of patients with Alzheimer's disease assessed objectively is scarce and can be observed through event-related potentials, such as the P300. The aim of the study was to identify the effects of physical exercises on mental processing information in the elderly with Alzheimer's disease through neurophysiological measures (P300 amplitude and latency) and reaction time. METHODS: A total of 31 patients with Alzheimer's disease participated in this study: 14 in functional exercise (FE) group and 17 in social gathering (SG) group who carried out three 1-hour sessions per week of FE and SG activities, respectively, for a 12-week period...
March 15, 2018: Journal of Physical Activity & Health
Yingying Liu, Yudiao Huang, Yueyue Xu, Peng Qu, Minghua Wang
Increased transendothelial permeability and subsequent blood-brain barrier damage play a key role in the pathological progression of human brain ischemia and secondary reperfusion. Memantine is a licensed drug providing clinically relevant efficacy in patients with Alzheimer's disease. However, little information is known regarding its effects on brain endothelial permeability. In this study, we investigated the effects of memantine on endothelial permeability and the underlying mechanisms in an ischemia-reperfusion (I/R) injury model in primary human brain microvascular endothelial cells...
March 15, 2018: IUBMB Life
Yuanyuan Wang, Qinwen Wang, Xiaoming Bao, Yanfei Ding, Jieyi Shentu, Wei Cui, Xiaowei Chen, Xiaofei Wei, Shujun Xu
Taxifolin is a potent flavonoid with anti-inflammatory activity. Taxifolin has been reported to decrease the accumulation of β-amyloid (Aβ), and reduce Aβ-induced neurotoxicity. However, the detail molecular mechanism of taxifolin against Aβ-induced neurotoxicity is largely unknown. In this study, we revealed the protective effects and the underlying mechanisms of taxifolin on the impairments of cognitive function and synapse formation induced by soluble Aβ oligomers. Our results showed that taxifolin prevented neuronal cell death in a concentration-dependent manner...
March 14, 2018: Metabolic Brain Disease
Min Wen, Lin Ding, Lingyu Zhang, Peixu Cong, Tiantian Zhang, Jie Xu, Yaoguang Chang, Yuming Wang, Changhu Xue
Abundant studies have highlighted the protective effects of docosahexaenoic acid (DHA), in the form of glycerolipids (glycerophosphatides and triglycerides) and DHA-ethyl esters (DHA-EE) in Alzheimer's disease (AD); however, eicosapentaenoic acid (EPA) has rarely been implicated. In the present study, we compared the effects of dietary EPA in the form of phosphatidylcholine (EPA-PC) and EE with DHA-EE (DHA/EPA = 60 mg kg-1 d-1 , i.g., 20 days) on cognitive deficits in AD rats. EPA-PC, rather than EPA-EE, significantly improved Aβ-induced cognitive impairment and has a comparable effect with DHA-EE...
March 15, 2018: Food & Function
Shinji Ouma, Midori Suenaga, Funda F Bölükbaşı Hatip, Izzettin Hatip-Al-Khatib, Yoshio Tsuboi, Yoichi Matsunaga
Objectives: To determine the relevance of Mini-Mental State Examination (MMSE), serum 25-hydroxyvitamin D (25(OH)D3), and 1,25(OH)2D3 concentrations to mild cognitive impairment (MCI) and various stages of Alzheimer's disease (AD). Materials and Methods: The study included 230 participants (>74 years) allocated to three main groups: 1-healthy subjects (HS, n  = 61), 2-patients with MCI ( n  = 61), and 3- patients with Alzheimer's disease (AD) subdivided into three stages: mild ( n  = 41), moderate ( n  = 35), and severe AD ( n  = 32)...
March 2018: Brain and Behavior
Po-Chi Chan, Cheng-Yu Wei, Guang-Uei Hung, Pai-Yi Chiu
Objectives: The association of vascular risk factors (VRFs) with incidence of Alzheimer's disease (AD) and vascular dementia (VaD) has been well studied. However, the association between VRFs and non-AD dementia is seldom investigated. In this study, we aim to compare the concurrence of VRFs of Lewy body dementia (LBD) to AD. Materials & Methods: We consecutively enrolled patients with dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and AD, and the prevalence of arterial hypertension, diabetes mellitus, hypercholesterolemia, hyperlipidemia, smoking, and obesity was assessed and compared...
March 2018: Brain and Behavior
Maria Garranzo-Asensio, Pablo San Segundo-Acosta, Javier Martínez-Useros, Ana Montero-Calle, María Jesús Fernández-Aceñero, Anna Häggmark-Månberg, Alberto Pelaez-Garcia, Mayte Villalba, Alberto Rabano, Peter Nilsson, Rodrigo Barderas
Alzheimer's disease (AD) is the most common form of dementia in developed countries. A better understanding of the events taking place at the molecular level would help to identify novel protein alterations, which might be used in diagnosis or for treatment development. In this study, we have performed the high-throughput analysis of 706 molecules mostly implicated in cell-cell communication and cell signaling processes by using two antibody microarray platforms. We screened three AD pathological groups -each one containing four pooled samples- from Braak stages IV, V and VI, and three control groups from two healthy subjects, five frontotemporal and two vascular dementia patients onto Panorama and L-Series antibody microarrays to identify AD-specific alterations not common to other dementias...
February 16, 2018: Oncotarget
Andreas Kling, Katja Jantos, Helmut Mack, Wilfried Hornberger, Gisela Backfisch, Yanbin Lao, Marjoleen Nijsen, Beatrice Rendenbach-Mueller, Achim Moeller
Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1 H )-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays...
March 8, 2018: ACS Medicinal Chemistry Letters
Xue-Yang Jiang, Ting-Kai Chen, Jun-Ting Zhou, Si-Yu He, Hong-Yu Yang, Yao Chen, Wei Qu, Feng Feng, Hao-Peng Sun
Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) and human acetylcholinesterase ( h AChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both h AChE (IC50 = 6...
March 8, 2018: ACS Medicinal Chemistry Letters
Benjamin E Blass
No abstract text is available yet for this article.
March 8, 2018: ACS Medicinal Chemistry Letters
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