Privileged Quinolylnitrones for the Combined Therapy of Ischemic Stroke and Alzheimer’s Disease

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer’s disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and combined therapy. For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen–glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide Aβ25–35, modeling toxic insults found among the effects of AD.

Download Full-text

Amylin Pharmacology in Alzheimer's Disease Pathogenesis and Treatment

Current Neuropharmacology ◽

10.2174/1570159x19666211201093147 ◽

2021 ◽

Vol 19 ◽

Author(s):

Rachel R Corrigan ◽

Helen Piontkivska ◽

Gemma Casadesus

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Type Ii Diabetes ◽

Peptide Hormone ◽

Type Ii Diabetes Mellitus ◽

Amyloid Peptide ◽

Type Ii ◽

Disease Pathogenesis ◽

Neuroprotective Effects

: The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer’s disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer’s disease. The traditional “gain of toxic function” properties assigned to amyloid proteins are however contrasted by several reports highlighting neuroprotective effects amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address paradoxical nature of this hormone's signaling in the context of AD pathogenesis.

Download Full-text

Adaptation to intermittent hypoxia prevents the decrease in cerebral vascular density in rats with experimental Alzheimer’s disease

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2021-20-2-59-64 ◽

2021 ◽

Vol 20 (2) ◽

pp. 59-64

Author(s):

A. V. Goryacheva ◽

I. V. Barskov ◽

H. F. Downey ◽

Eu. B. Manukhina

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Neurons ◽

Hypoxia Inducible Factor ◽

Memory Loss ◽

Amyloid Peptide ◽

Cresyl Violet ◽

Vascular Density ◽

Endothelial Growth Factor ◽

Cerebral Vascular

Introduction. Patients with Alzheimer’s disease (AD) have reduced cerebral vascular density (VD), which impairs blood flow to neurons and may contribute to progression of AD. Earlier we showed that prior adaptation to intermittent hypobaric hypoxia (IHH) prevented memory loss and degeneration of cortical neurons in rats with experimental AD (EAD). The aim of this study was to test if IHH might prevent EAD-induced vascular rarefaction in rats. Materials and methods. EAD was induced with bilateral injection of neurotoxic beta-amyloid peptide fragment (A) (25–35) into n. basalis magnocellularis. IHH was simulated at a 4,000 m altitude, for 4 hours a day, for 14 days. Brain blood vessels were stained by transcardiac infusion of Indian ink; brain sections were stained with 0.3 % cresyl violet by Nissle method. Vascular density was assessed in the cortex and hippocampus using the Infinity Analysis Software. Results. In the EAD rats, VD was significantly decreased in the hippocampus (13.3±0.9 vs 17.8±1.0 in field of view, FOV, p<0.03) and in the cortex (17.3±1.5 vs 22.3±1.3 in FOV, p<0.03). AIH increased VD in the hippocampus to 27.0±3.5 in FOV (p=0.01) and in cortex to 26.0±1.1 in FOV (p<0.03). In EAD+AIH rats, VD did not differ significantly from the control rats neither in the hippocampus, nor in the cortex. AIH may stimulate angiogenesis through hypoxia inducible factor-1α-mediated expression of vascular endothelial growth factor and/or by increasing expression and activity of antioxidant enzymes. Conclusion. One of the mechanisms of AIH beneficial effect in AD-related neurodegeneration is preserving the capability for compensatory angiogenesis in brain.

Download Full-text

Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2018850118 ◽

2021 ◽

Vol 118 (32) ◽

pp. e2018850118

Author(s):

Hiroo Takahashi ◽

Ryo Asahina ◽

Masayuki Fujioka ◽

Takeshi K. Matsui ◽

Shigeki Kato ◽

...

Keyword(s):

Ischemic Stroke ◽

Cortical Neurons ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Small Gtpase ◽

Neuroprotective Effects ◽

Necessary And Sufficient ◽

Activity Dependent

Ischemic stroke, which results in loss of neurological function, initiates a complex cascade of pathological events in the brain, largely driven by excitotoxic Ca2+ influx in neurons. This leads to cortical spreading depolarization, which induces expression of genes involved in both neuronal death and survival; yet, the functions of these genes remain poorly understood. Here, we profiled gene expression changes that are common to ischemia (modeled by middle cerebral artery occlusion [MCAO]) and to experience-dependent activation (modeled by exposure to an enriched environment [EE]), which also induces Ca2+ transients that trigger transcriptional programs. We found that the activity-dependent transcription factor Npas4 was up-regulated under MCAO and EE conditions and that transient activation of cortical neurons in the healthy brain by the EE decreased cell death after stroke. Furthermore, both MCAO in vivo and oxygen-glucose deprivation in vitro revealed that Npas4 is necessary and sufficient for neuroprotection. We also found that this protection involves the inhibition of L-type voltage-gated Ca2+ channels (VGCCs). Next, our systematic search for Npas4-downstream genes identified Gem, which encodes a Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of L-type VGCCs to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death after in vitro and in vivo ischemia. Collectively, our findings indicate that Gem expression via Npas4 is necessary and sufficient to promote neuroprotection in the injured brain. Importantly, Gem is also induced in human cerebral organoids cultured under an ischemic condition, revealing Gem as a new target for drug discovery.

Download Full-text

Amyloid-Beta Peptide, Oxidative Stress and Inflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Omega-3 Polyunsaturated Fatty Acids

International Journal of Alzheimer s Disease ◽

10.4061/2010/274128 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

S. C. Dyall

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Amyloid Peptide ◽

Omega 3 ◽

Neuroprotective Effects ◽

Beta Peptide ◽

The Brain

Alzheimer's disease is the most common form of dementia in the elderly and is a progressive neurodegenerative disorder characterised by a decline in cognitive function and also profound alterations in mood and behaviour. The pathology of the disease is characterised by the presence of extracellular amyloid peptide deposits and intracellular neurofibrillary tangles in the brain. Although many hypotheses have been put forward for the aetiology of the disease, increased inflammation and oxidative stress appear key to be features contributing to the pathology. The omega-3 polyunsaturated fats, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have well-characterised effects on inflammation and may have neuroprotective effects in a number of neurodegenerative conditions including Alzheimer's disease. The aims of this paper are to review the neuroprotective effects of EPA and DHA in Alzheimer's disease, with special emphasis on their role in modulating oxidative stress and inflammation and also examine their potential as therapeutic agents.

Download Full-text

Biochemical investigations in patients with dementia

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/0004563021902143 ◽

2002 ◽

Vol 39 (3) ◽

pp. 211-220 ◽

Cited By ~ 1

Author(s):

Alison Green

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Acetylcholinesterase Inhibitors ◽

Amyloid Peptide ◽

Number Of Patients ◽

Diagnosis Of Dementia ◽

Jakob Disease ◽

Β Amyloid ◽

Detection And Diagnosis ◽

Β Amyloid Peptide

The recent development of acetylcholinesterase inhibitors to treat patients with Alzheimer's disease has increased interest in the use of biochemical markers for the early detection and diagnosis of dementia, but only the measurement of the protein 14-3-3 in cerebrospinal fluid (CSF) to help diagnose sporadic Creutzfeldt-Jakob disease has become accepted clinical practice. CSF concentrations of t protein and β-amyloid peptide 42 have been widely investigated as potential diagnostic tests for Alzheimer's disease, but neither has shown sufficient sensitivity and specificity for clinical use. Preliminary investigations suggest that β-amyloid peptide 42 may be useful in monitoring disease progression, but this needs to be verified. In addition, biochemical investigations may help to identify the small number of patients with treatable causes of dementia such as hypothyroidism and vitamin B12 deficiency, as well as any other compounding condition such as anaemia or diabetes mellitus that increase morbidity.

Download Full-text

Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities

Molecules ◽

10.3390/molecules26051303 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1303

Author(s):

Yingda Zang ◽

Ke Liu ◽

Weiping Wang ◽

Chuangjun Li ◽

Jie Ma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Free Radical ◽

Radical Scavenging Activity ◽

Radical Scavenging ◽

Glucose Deprivation ◽

Free Radical Scavenging ◽

Neuroprotective Effects ◽

Catalytic Active Site

The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63–4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood–brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation.

Download Full-text

Nutritional aspects and their influences on the pathophysiology of

Revista de Ciências Médicas ◽

10.24220/2318-0897v23n1a2413 ◽

2014 ◽

Vol 23 (1) ◽

pp. 33

Author(s):

Nathalia Liberato Nascimento ◽

Iwyson Henrique Fernandes da Costa ◽

Rivelilson Mendes de Freitas

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fatty Acids ◽

Folic Acid ◽

Saturated Fatty Acids ◽

Free Radical Scavengers ◽

Radical Scavengers ◽

High Intake ◽

Neuroprotective Effects ◽

Nutritional Factors

The objective of this study was to conduct a review about the nutritional aspects and their influences on the pathophysiology of Alzheimer’s disease. The review describes the pathophysiology of Alzheimer’s disease, the generally indicated diets, and the nutritional factors that may aggravate the disease based on a literature review using the following keywords in English and Portuguese: “Alzheimer’s disease”, “physiopathology”, “nutritional aspects”, and “antioxidants”. A total of 100 articles were found, 48 in Lilacs and 52 in MedLine, but only 54 articles were selected for the review. The use of antioxidants as free radical scavengers is generally indicated in diets for Alzheimer’s patients. Studies also suggest that caffeine, vitamin B12, and folic acid have neuroprotective effects. Cohort studies found that a high intake of saturated fatty acids and obesity increase the risk of Alzheimer’s disease. People with Alzheimer’s disease should avoid diets high in carbohydrates and saturated fats, and prefer foods high in antioxidants.Keywords: Alzheimer disease; Antioxidants; Neurophysiology; Review literture as topic.

Download Full-text

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

Current Pharmaceutical Design ◽

10.2174/1381612826666201112144006 ◽

2020 ◽

Vol 26 ◽

Author(s):

Nimra Javaid ◽

Muhammad Ajmal Shah ◽

Azhar Rasul ◽

Zunera Chauhdary ◽

Uzma Saleem ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ellagic Acid ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Acetylcholinesterase Activity ◽

Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

Download Full-text

Identify Compounds' Target Against Alzheimer's Disease Based on In-Silico Approach

Current Alzheimer Research ◽

10.2174/1567205016666190103154855 ◽

2019 ◽

Vol 16 (3) ◽

pp. 193-208 ◽

Cited By ~ 2

Author(s):

Yan Hu ◽

Guangya Zhou ◽

Chi Zhang ◽

Mengying Zhang ◽

Qin Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Small Molecule ◽

Characteristic Curve ◽

Machine Learning Algorithms ◽

Learner Model ◽

Mao B ◽

Number Of Patients ◽

Sar Model ◽

Set Up

Background: Alzheimer's disease swept every corner of the globe and the number of patients worldwide has been rising. At present, there are as many as 30 million people with Alzheimer's disease in the world, and it is expected to exceed 80 million people by 2050. Consequently, the study of Alzheimer’s drugs has become one of the most popular medical topics. Methods: In this study, in order to build a predicting model for Alzheimer’s drugs and targets, the attribute discriminators CfsSubsetEval, ConsistencySubsetEval and FilteredSubsetEval are combined with search methods such as BestFirst, GeneticSearch and Greedystepwise to filter the molecular descriptors. Then the machine learning algorithms such as BayesNet, SVM, KNN and C4.5 are used to construct the 2D-Structure Activity Relationship(2D-SAR) model. Its modeling results are utilized for Receiver Operating Characteristic curve(ROC) analysis. Results: The prediction rates of correctness using Randomforest for AChE, BChE, MAO-B, BACE1, Tau protein and Non-inhibitor are 77.0%, 79.1%, 100.0%, 94.2%, 93.2% and 94.9%, respectively, which are overwhelming as compared to those of BayesNet, BP, SVM, KNN, AdaBoost and C4.5. Conclusion: In this paper, we conclude that Random Forest is the best learner model for the prediction of Alzheimer’s drugs and targets. Besides, we set up an online server to predict whether a small molecule is the inhibitor of Alzheimer's target at http://47.106.158.30:8080/AD/. Furthermore, it can distinguish the target protein of a small molecule.

Download Full-text

Formononetin Ameliorates Cognitive Disorder via PGC-1α Pathway in Neuroinflammation Conditions in High-Fat Diet-Induced Mice

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190807160137 ◽

2019 ◽

Vol 18 (7) ◽

pp. 566-577 ◽

Cited By ~ 4

Author(s):

Xinxin Fu ◽

Tingting Qin ◽

Jiayu Yu ◽

Jie Jiao ◽

Zhanqiang Ma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Fat Diet ◽

Trifolium Pratense ◽

Amyloid Β ◽

Cognitive Disorder ◽

Mechanism Study ◽

High Fat ◽

Neuroprotective Effects ◽

Underlying Mechanisms

Background: Alzheimer’s disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer’s disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-β generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer’s disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer’s disease with Formononetin. Objective: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms. Methods: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg). Results: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1β and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-κB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice. Conclusion: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.

Download Full-text