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Alzheimers disease treatment

Chye Soi Moi, Chia Kin Yen, Khuen Yen Ng, Koh Rhun Yian
Protein misfolding and aggregation have been considered the common pathological hallmarks for a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). These abnormal proteins aggregation damage mitochondria and induce oxidative stress and resulting neuronal cell death. Prolong neuronal damage activates microglia and astrocytes, development of inflammation reaction and further promotes neurodegeneration. Thus, elimination of abnormal proteins aggregation without eliciting any adverse effects are the main treatment strategies...
March 15, 2018: CNS & Neurological Disorders Drug Targets
Anat Elmann, Alona Telerman, Rivka Ofir, Yoel Kashman, Orly Lazarov
Alzheimer's disease (AD) is the most prevalent cause of dementia in adults. Current available drugs for AD transiently alleviate some of the symptoms, but do not modify the disease mechanism or cure it. Therefore, new drugs are desperately needed. Key contributors to AD are amyloid beta (Aβ)- and reactive oxygen species (ROS)-induced cytotoxicities. Plant-derived substances have been shown to affect various potential targets in various diseases including AD. Therefore, phytochemicals which can protect neuronal cells against these insults might help in preventing and treating this disease...
March 15, 2018: Journal of Natural Medicines
Xueying Wang, Ksenia V Kastanenka, Michal Arbel-Ornath, Caitlin Commins, Akira Kuzuya, Amanda J Lariviere, Grant A Krafft, Franz Hefti, Jasna Jerecic, Brian J Bacskai
Soluble amyloid β oligomers (AβOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer's disease (AD). One of the profound downstream consequences of AβO-triggered events is dysregulation of cytosolic calcium concentration ([Ca2+ ]i ), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AβO-blocking candidates by measuring AβO-induced real-time changes in [Ca2+ ]i ...
March 15, 2018: Scientific Reports
Dicson Sheeja Malar, Venkatesan Suryanarayanan, Mani Iyer Prasanth, Sanjeev Kumar Singh, Krishnaswamy Balamurugan, Kasi Pandima Devi
Amyloid beta (Aβ) formation is one of the neuropathological hallmarks of Alzheimer's disease (AD), which induces the generation of reactive oxygen species (ROS), further leading to the alteration of several signalling pathways. In the present study, vitexin has been evaluated for its neuroprotective activity against Aβ25-35 induced toxicity in Neuro-2a cells. Results of cell free studies indicated that vitexin significantly inhibited the aggregation of Aβ25-35 . Studies in Neuro-2a cells revealed that Aβ25-35 significantly affected the cell viability by inducing ROS mediated toxicity and apoptosis...
March 12, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Yijun Pan, Jennifer L Short, Stephanie A Newman, Kwok H C Choy, Durgesh Tiwari, Christopher Yap, Danielle Senyschyn, William A Banks, Joseph A Nicolazzo
Epidemiological evidence suggests that people with bipolar disorder prescribed lithium exhibit a lower risk of Alzheimer's disease (AD) relative to those prescribed other mood-stabilizing medicines. Lithium chloride (LiCl) reduces brain β-amyloid (Aβ) levels, and the brain clearance of Aβ is reduced in AD. Therefore, the purpose of this study was to assess whether the cognitive benefits of LiCl are associated with enhanced brain clearance of exogenously-administered Aβ. The brain clearance of intracerebroventricularly (icv) administered125 I-Aβ42 was assessed in male Swiss outbred mice administered daily oral NaCl or LiCl (300 mg/kg for 21 days)...
March 12, 2018: Brain, Behavior, and Immunity
Charlotte E Teunissen, Markus Otto, Sebastiaan Engelborghs, Sanna-Kaisa Herukka, Sylvain Lehmann, Piotr Lewczuk, Alberto Lleó, Armand Perret-Liaudet, Hayrettin Tumani, Martin R Turner, Marcel M Verbeek, Jens Wiltfang, Henrik Zetterberg, Lucilla Parnetti, Kaj Blennow
Body fluid biomarkers have great potential for different clinical purposes, including diagnosis, prognosis, patient stratification and treatment effect monitoring. This is exemplified by current use of several excellent biomarkers, such as the Alzheimer's disease cerebrospinal fluid (CSF) biomarkers, anti-neuromyelitis optica antibodies and blood neurofilament light. We still, however, have a strong need for additional biomarkers and several gaps in their development and implementation should be filled. Examples of such gaps are i) limited knowledge of the causes of neurological diseases, and thus hypotheses about the best biomarkers to detect subclinical stages of these diseases; ii) the limited success translating discoveries obtained by e...
March 15, 2018: Alzheimer's Research & Therapy
O V Galzitskaya, E I Galushko, O M Selivanova
Studies of the process of amyloid formation by Aβ peptide have been topical due to the critical role of this peptide in the pathogenesis of Alzheimer's disease. Many articles devoted to this process are available in the literature; however, none of them gives a detailed description of the mechanism of the process of generation of amyloids. Moreover, there are no reliable data on the influence of modified forms of Aβ peptide on its amyloid formation. To appreciate the role of Aβ aggregation in the pathogenesis of Alzheimer's disease and to develop a strategy for its treatment, it is necessary to have a well-defined description of the molecular mechanism underlying the formation of amyloids as well as the contribution of each intermediate to this process...
January 2018: Biochemistry. Biokhimii︠a︡
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
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
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
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
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
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
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
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
Fan-Cheng Meng, Zheng-Feng Wu, Zhi-Qi Yin, Li-Gen Lin, Ruibing Wang, Qing-Wen Zhang
Background: Coptidis rhizoma (CR) is the dried rhizome of Coptis chinensis Franch., C. deltoidea C. Y. Cheng et Hsiao or C. teeta Wall. (Ranunculaceae) and is commonly used in Traditional Chinese Medicine for the treatment of various diseases including bacillary dysentery, typhoid, tuberculosis, epidemic cerebrospinal meningitis, empyrosis, pertussis, and other illnesses. Methods: A literature survey was conducted via SciFinder, ScieneDirect, PubMed, Springer, and Wiley databases...
2018: Chinese Medicine
Warren Winick-Ng, R Jane Rylett
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons...
2018: Frontiers in Molecular Neuroscience
Jodi R Paul, Hira A Munir, Thomas van Groen, Karen L Gamble
Disruption of circadian rhythms is commonly reported in individuals with Alzheimer's disease (AD). Neurons in the primary circadian pacemaker, the suprachiasmatic nucleus (SCN), exhibit daily rhythms in spontaneous neuronal activity which are important for maintaining circadian behavioral rhythms. Disruption of SCN neuronal activity has been reported in animal models of other neurodegenerative disorders; however, the effect of AD on SCN neurophysiology remains unknown. In this study we examined circadian behavioral and electrophysiological changes in a mouse model of AD, using male mice from the Tg-SwDI line which expresses human amyloid precursor protein with the familial Swedish (K670N/M671L), Dutch (E693Q), Iowa (D694N) mutations...
March 11, 2018: Neurobiology of Disease
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