Effects of New Galantamine Derivatives in a Scopolamine Model of Dementia in Mice

2021 ◽  
pp. 1-20
Author(s):  
Maria Lazarova ◽  
Lyubka Tancheva ◽  
Albena Alexandrova ◽  
Elina Tzvetanova ◽  
Almira Georgieva ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Cholinergic Neurons ◽  
Inhibitory Avoidance ◽  
Acetylcholinesterase Activity ◽  
Long Term Memory ◽  
Therapeutic Benefits ◽  
Board Test ◽  
Hole Board Test

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive functions decline, is a leading cause for dementia and currently ranked as the sixth foremost cause of death. As of present, treatment of AD is symptomatic without convincing therapeutic benefits and new, effective, therapeutic agents are pursued. Due to massive loss of cholinergic neurons and decreased acetylcholine levels, cholinesterase inhibitors like galantamine, remain the backbone of pharmacological treatment of the disease. In the present study, using behavioral and biochemical methods, four newly synthesized galantamine derivatives, Gal 34, Gal 43, Gal 44, and Gal 46, were evaluated for a beneficial effect in a scopolamine model of dementia in mice. They were designed to have all the advantages of galantamine and additionally to inhibit β-secretase and exert favorable effects on plasma lipids. Behavioral tests included step-through inhibitory avoidance, T-maze, and the hole-board test, whereas biochemical evaluations involved assessment of acetylcholinesterase activity, brain monoamines levels, lipid peroxidation, catalase, glutathione peroxidase, and superoxide dismutase activities along with measurement of total glutathione. Results show that Gal 43, Gal 44, and, in particular, Gal 46 are especially effective in improving both short- and long-term memory and in the case of Gal 46 having a significant effect on exploratory activity as well. Although Gal 34 did not show behavioral effects as convincing as those of the other three galantamine derivatives, it demonstrated persuasive antioxidant and restorative capacities, making all four galantamine derivatives promising AD treatment agents and prompting further research, especially that in many of our studies they performed better than galantamine.

scholarly journals Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

2019 ◽  
Author(s):  
Viviana Soto-Mercado ◽  
Miguel Mendivil-Perez ◽  
Carlos Velez-Pardo ◽  
Francisco Lopera ◽  
Marlene Jimenez-Del-Rio
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Cholinergic Neurons ◽  
Tau Phosphorylation ◽  
Cellular Mechanisms ◽  
Limited Effectiveness ◽  
Aβ42 Peptide

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra- and extracellular Aβ42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey

2020 ◽  
Vol 18 (4) ◽  
pp. 354-359
Author(s):  
Shirin Tarbiat ◽  
Azize Simay Türütoğlu ◽  
Merve Ekingen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Acetylcholinesterase Activity ◽  
Rosa Damascena ◽  
Free Radical Damage

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impairment of language. Alzheimer's disease is strongly associated with oxidative stress and impairment in the cholinergic pathway, which results in decreased levels of acetylcholine in certain areas of the brain. Hence, inhibition of acetylcholinesterase activity has been recognized as an acceptable treatment against Alzheimer's disease. Nature provides an array of bioactive compounds, which may protect against free radical damage and inhibit acetylcholinesterase activity. This study compares the in vitro antioxidant and anticholinesterase activities of hydroalcoholic extracts of five cultivars of Rosa Damascena Mill. petals (R. damascena 'Bulgarica', R. damascena 'Faik', R. damascena 'Iranica', R. damascena 'Complex-635' and R. damascena 'Complex-637') from Isparta, Turkey. The antioxidant activities of the hydroalcoholic extracts were tested for ferric ion reduction and DPPH radical scavenging activities. The anti-acetylcholinesterase activity was also evaluated. All rose cultivars showed a high potency for scavenging free radical and inhibiting acetylcholinesterase activity. There was a significant correlation between antioxidant and acetylcholinesterase inhibitory activity. Among cultivars, Complex-635 showed the highest inhibitory effect with an IC50 value of 3.92 µg/mL. Our results suggest that all these extracts may have the potential to treat Alzheimer's disease with Complex-635 showing more promise.

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

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.

In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

2020 ◽  
Vol 20 ◽  
Author(s):  
Dnyaneshwar Baswar ◽  
Abha Sharma ◽  
Awanish Mishra
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
Biological Activities ◽  
Cholinergic Neurons ◽  
In Silico Screening ◽  
In Silico Studies ◽  
Bbb Permeability ◽  
Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

scholarly journals Can the Hole–Board Test Predict a Rat’s Exploratory Behavior in a Free-Exploration Test?

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1068
Author(s):  
Wojciech Pisula ◽  
Klaudia Modlinska ◽  
Katarzyna Goncikowska ◽  
Anna Chrzanowska
Keyword(s):  
Exploratory Behavior ◽  
Predictive Value ◽  
Previous Experience ◽  
General Hypothesis ◽  
Free Exploration ◽  
Laboratory Rodents ◽  
Board Test ◽  
Motivational Mechanism ◽  
Hole Board ◽  
Hole Board Test

This study focuses on the rat activity in a hole–board setting that we considered a type of exploratory behavior. The general hypothesis is based on the claim that a motivational mechanism is central to both the response to novelty in a highly familiarized environment and the activity in the hole–board apparatus. Our sample consisted of 80 experimentally naive Lister Hooded rats. All rats were tested in the hole–board apparatus. Twenty individuals with the highest hole-board scores and twenty subjects with the lowest hole–board scores subsequently underwent an established free-exploration test. In our study, the scores obtained in the hole–board test had little predictive value for the rats’ activity in the free-exploration test. Based on our previous experience in studying exploratory behavior in the free-exploration test and the data presented in this paper, we suggest that the hole–board test is not an appropriate tool for measuring exploratory behavior in laboratory rodents.

scholarly journals Amelioration of Scopolamine-Induced Learning and Memory Impairment byα-Pinene in C57BL/6 Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Gil-Yong Lee ◽  
Chan Lee ◽  
Gyu Hwan Park ◽  
Jung-Hee Jang
Keyword(s):  
Learning And Memory ◽  
Memory Impairment ◽  
Manganese Superoxide Dismutase ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Memory Loss ◽  
Cholinergic Neurons ◽  
Morris Water Maze Test ◽  
Heme Oxygenase 1 ◽  
Related Factor

Increasing evidence suggests that neurodegenerative disorders such as Alzheimer’s disease (AD) are mediated via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, attention has been focused on searching for antioxidant phytochemicals for the prevention and/or treatment of AD through their ability to fortify cholinergic function and antioxidant defense capacity. In this study, we have investigated the neuroprotective effect ofα-pinene (APN) against learning and memory impairment induced by scopolamine (SCO, 1 mg/kg, i.p.), a muscarinic receptor antagonist in C57BL/6 mice. Administration of APN (10 mg/kg, i.p.) significantly improved SCO-induced cognitive dysfunction as assessed by Y-maze and passive avoidance tests. In Morris water-maze test, APN effectively shortened the mean escape latency to find the hidden platform during training days. To further elucidate the molecular mechanisms underlying the neuroprotective effect of APN, the expression of proteins involved in the acetylcholine metabolism and antioxidant system was examined. Particularly, APN treatment increased mRNA expression of choline acetyltransferase in the cortex and protein levels of antioxidant enzymes such as heme oxygenase-1 and manganese superoxide dismutase in the hippocampus via activation of NF-E2-related factor 2. These findings suggest the possible neuroprotective potentials of APN for the management of dementia with learning and memory loss.

NF-κB transcription factor is required for inhibitory avoidance long-term memory in mice

2005 ◽  
Vol 21 (10) ◽  
pp. 2845-2852 ◽  
Author(s):  
Ramiro Freudenthal ◽  
Mariano M. Boccia ◽  
Gabriela B. Acosta ◽  
Mariano G. Blake ◽  
Emiliano Merlo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Inhibitory Avoidance ◽  
Long Term Memory ◽  
Term Memory

New Galantamine Derivatives with Inhibitory Effect on Acetylcholinesterase Activity

2021 ◽  
Vol 83 (3) ◽  
pp. 1211-1220 ◽  
Author(s):  
Maria I. Lazarova ◽  
Daniela S. Tsekova ◽  
Lyubka P. Tancheva ◽  
Kiril T. Kirilov ◽  
Diamara N. Uzunova ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Memory Performance ◽  
Acetylcholinesterase Activity ◽  
Inhibitory Effect ◽  
Long Term Memory ◽  
Molegro Virtual Docker ◽  
Ache Inhibitors ◽  
Hybrid Molecules ◽  
Ache Inhibitory Activity ◽  
Biological Assessments

Background: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer’s disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). Objective: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. Methods: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. Results: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. Conclusion: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention.

Neuropharmacological Activity of Various Fractions Obtained from Solanum aethiopicum (Linn.) Fruit in Mice.

2020 ◽  
Vol 1 (5) ◽  
pp. 12-23
Author(s):  
A.R. Abubakar ◽  
◽  
I.H. Sani ◽  
S. Malami ◽  
A.H. Yaro ◽  
...  
Keyword(s):  
Open Field ◽  
Elevated Plus Maze ◽  
Toxicity Testing ◽  
Aqueous Fraction ◽  
Solanum Aethiopicum ◽  
Elevated Plus Maze Test ◽  
Board Test ◽  
Plus Maze ◽  
Hole Board ◽  
Hole Board Test

Background: Solanum aethiopicum (L.), family Solanaceae, is known as garden eggs. The fruit is used in the treatment of insomnia, diabetes and constipation. Objective: The aim of this study was to evaluate anxiolytic-like activity of fractions obtained from crude methanol extract of Solanum aethiopicum fruit. Method: Acute toxicity testing was conducted according to the OECD guidelines 420 via oral and intraperitoneal routes (ip). n-Hexane (HF), chloroform (CHF), ethyl-acetate (EAF), n-butanol (BF) and residual aqueous fraction (RAF) at doses of 25, 50 and 100 mg/kg ip were experimented using the open field, elevated plus maze, staircase, light dark box and hole-board tests. Results: Results: In open field test, there was statistically significant increase in frequency of central square entry by EAF 25mg/kg, 50mg/kg and 100mg/kg and RAF 25mg/kg, 50mg/kg and 100mg/kg all at p<0.05 compared to distilled water (D/W) group. Elevated plus maze test showed statistically significant increases in open arm entry and duration by CHF 25mg/kg, RAF 25mg/kg and 50mg/kg again at p<0.05. Also, in the staircase test, statistically significant decrease in frequency of rearing with no effect on step climbing was observed by RAF 25mg/kg (p< 0.05) compared to D/W. Light and dark box test produced increased light box entry and duration by EAF 25mg/kg, RAF 25mg/kg and 50mg/ kg at p<0.05. Furthermore, the hole -board test showed statistically significant increases in number of head dips by EAF 50mg/kg and 100mg/kg as well as RAF 25mg/kg, 50mg/kg and 100 mg/kg at p<0.05. Conclusion: The fractions obtained from Solanum aethiopicum fruits possesses anxiolytic-like activity.

scholarly journals Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-αAgonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Dedeepya Uppalapati ◽  
Nihar R. Das ◽  
Rahul P. Gangwal ◽  
Mangesh V. Damre ◽  
Abhay T. Sangamwar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Pbpk Modeling ◽  
Pharmacokinetic Parameters ◽  
Peroxisome Proliferator ◽  
Fenofibric Acid ◽  
Peroxisome Proliferator Activated Receptor

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR-αagonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 µg/1 µL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100 mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF-α, and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR-αagonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment.

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