scholarly journals Pharmacokinetic and Pharmacodynamic Evaluation of Nasal Liposome and Nanoparticle Based Rivastigmine Formulations in Acute and Chronic Models of Alzheimer’s Disease

2021 ◽  
Author(s):  
Sampath Kumar L Rompicherla ◽  
Karthik Arumugam ◽  
Sree Lalitha Bojja ◽  
Nitesh Kumar ◽  
Mallikarjuna Rao Chamallamudi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
Rapid Onset ◽  
Liposomal Formulation ◽  
Direct Access ◽  
Acetylcholinesterase Inhibition ◽  
Pharmacokinetic Parameters ◽  
Ageing Population ◽  
Onset Of Action

Abstract With the increasing ageing population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor is more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing first pass metabolism, exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver efficiently to brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in scopolamine induced amnesia model and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modelling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax=5 minutes), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F=118.65 ± 23.54; AUC= 35921.75 ± 9559.46), increased half-life (30.92 ± 8.38 minutes), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax= 15 minutes; Cmax= 56.29 ± 27.05; F=4.39 ± 1.82; AUC=1663.79 ± 813.54; t1/2= 13.48 ± 5.79; Kel (1/min) =0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modelling demonstrated strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

scholarly journals Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease

2021 ◽  
Author(s):  
Sampath Kumar L. Rompicherla ◽  
Karthik Arumugam ◽  
Sree Lalitha Bojja ◽  
Nitesh Kumar ◽  
C. Mallikarjuna Rao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
Rapid Onset ◽  
Liposomal Formulation ◽  
Direct Access ◽  
Acetylcholinesterase Inhibition ◽  
Pharmacokinetic Parameters ◽  
Onset Of Action ◽  
The Brain

AbstractWith the increasing aging population and progressive nature of the disease, Alzheimer’s disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

scholarly journals IN SILICO STUDY OF ACETYLCHOLINESTERASE INHIBITION IN ALZHEIMER'S DISEASE USING CHEMICAL CONSTITUENTS OF CANNABIS

2020 ◽  
Author(s):  
Roxanne Vasquez ◽  
Teobaldo Cuya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Chemical Constituents ◽  
Acetylcholinesterase Inhibitor ◽  
Memory Loss ◽  
Acetylcholinesterase Inhibition ◽  
Chemical Derivatives ◽  
In Silico Study ◽  
Derivatives Of

In recent years, studies have shown that some chemical derivatives of the cannabis plant help in the prevention and treatment of neurological diseases. Alzheimer's disease (AD) is a progressive form of dementia, which there is no cure. Therefore, its pharmacological treatment is crucial as it can help reduce the symptoms such as memory loss. Due to the limited choices of drug treatments for AD, this research will be using 9 chemical derivatives of the Cannabis plant as potential drug alternative. There is reduced levels of acetylcholine (ACh) neurotransmitter with AD patients, due to its hydrolysis carried out by the enzyme acetylcholinesterase (AChE). Thus, the focus of this in silico study will be if these 9 substances have the capacity to act as a human enzyme acetylcholinesterase inhibitor (HssAChE). Results shows that at least one Cannabis compound “Cannabicyclol” have a comparable binding energy to the commercial drug Donepezil. Moreover, the results gives insights about the what are the relevant residues in the binding process and the potential therapeutic properties of the cannabis compounds relating to the AD treatment.

The Therapeutic Potential of Purinergic Receptors in Alzheimer’s Disease and Promising Therapeutic Modulators

2020 ◽  
Vol 20 ◽  
Author(s):  
Lili Pan ◽  
Yu Ma ◽  
Yunchun Li ◽  
Haoxing Wu ◽  
Rui Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Purinergic Signaling ◽  
Memory Loss ◽  
Related Research ◽  
Central Nervous System Disorders ◽  
G Protein Coupled

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

The Involvement of Post-Translational Modifications in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 313-335 ◽  
Author(s):  
Serena Marcelli ◽  
Massimo Corbo ◽  
Filomena Iannuzzi ◽  
Lucia Negri ◽  
Fabio Blandini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Modification ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Normal Function ◽  
Ageing Population ◽  
Covalent Bonds ◽  
Post Translational Modifications ◽  
Related Proteins

Background: Alzheimer's disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Methods: Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Results: Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. Conclusion: We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs.

Many caregivers of persons with memory loss or Alzheimer's disease are unaware of the abilities of their persons with AD to recall their drugs and medical histories

Dementia ◽  
2018 ◽  
pp. 147130121882096
Author(s):  
Thomas A Ala ◽  
GaToya Simpson ◽  
Marshall T Holland ◽  
Vajeeha Tabassum ◽  
Maithili Deshpande ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
Medical Histories ◽  
With Memory

scholarly journals High-throughput screening of natural compounds and inhibition of a major therapeutic target HsGSK-3β for Alzheimer’s disease using computational approaches

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rohit Shukla ◽  
Tiratha Raj Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Throughput Screening ◽  
Complex Disease ◽  
Glycogen Synthase ◽  
Binding Free Energy ◽  
Drug Candidate ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Computational Approaches

Abstract Background Alzheimer’s disease is a leading neurodegenerative disease worldwide and is the 6th leading cause of death in the USA. AD is a very complex disease and the drugs available in the market cannot fully cure it. The glycogen synthase kinase 3 beta plays a major role in the hyperphosphorylation of tau protein which forms the neurofibrillary tangles which is a major hallmark of AD. In this study, we have used a series of computational approaches to find novel inhibitors against GSK-3β to reduce the TAU hyperphosphorylation. Results We have retrieved a set of compounds (n=167,741) and screened against GSK-3β in four sequential steps. The resulting analysis of virtual screening suggested that 404 compounds show good binding affinity and can be employed for pharmacokinetic analysis. From here, we have selected 20 compounds those were good in terms of pharmacokinetic parameters. All these compounds were re-docked by using Autodock Vina followed by Autodock. Four best compounds were employed for MDS and here predicted RMSD, RMSF, Rg, hydrogen bonds, SASA, PCA, and binding-free energy. From all these analyses, we have concluded that out of 167,741 compounds, the ZINC15968620, ZINC15968622, and ZINC70707119 can act as lead compounds against HsGSK-3β to reduce the hyperphosphorylation. Conclusion The study suggested three compounds (ZINC15968620, ZINC15968622, and ZINC70707119) have great potential to be a drug candidate and can be tested using in vitro and in vivo experiments for further characterization and applications.

scholarly journals Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1802
Author(s):  
Enrique Armijo ◽  
George Edwards ◽  
Andrea Flores ◽  
Jorge Vera ◽  
Mohammad Shahnawaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cerebral Atrophy ◽  
Brain Inflammation ◽  
Neural Precursors ◽  
Model Of Alzheimer’S Disease ◽  
Induced Pluripotent

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

scholarly journals Promoting Conversations About Cognitive Decline Between Older Adults and Primary Care Providers

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 157-158
Author(s):  
Benjamin Olivari ◽  
Christopher Taylor ◽  
Nia Reed ◽  
Lisa McGuire
Keyword(s):  
Alzheimer’S Disease ◽  
Primary Care ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Chronic Conditions ◽  
Memory Loss ◽  
Primary Care Providers ◽  
Subjective Cognitive Decline ◽  
Care Providers

Abstract Alzheimer’s disease and related dementias often begin with symptoms of mild memory loss, eventually leading to more severe cognitive impairment, functional impairment, and ultimately, death. Data from the Behavioral Risk Factor Surveillance System core questions related to chronic diseases and from the cognitive decline optional module on subjective cognitive decline (SCD) from the years 2015-2018 were aggregated across the participating 50 states, D.C., and Puerto Rico for this analysis. Among U.S. adults aged 65 years and older, only 39.8% (95%CI=37.6-42.1) of those experiencing SCD reported discussing their SCD symptoms with a healthcare provider. The prevalence of discussing SCD symptoms with a provider was higher among those with at least one chronic condition than among those with no chronic conditions. 30.7% (28.6-32.8) of those aged 65 years and older reported that their SCD led to functional limitations and 28.8% (26.5-31.2) needed assistance with day-to-day activities. For patients aged 65 years and older, Welcome to Medicare visits and Medicare Annual Wellness Visits are critically underutilized primary care access points. Primary care providers can manage chronic conditions, cognitive health, and initiate referrals for testing. Efforts to promote the use of toolkits and diagnostic codes that are available to primary care providers to initiate conversations about memory loss with patients may be utilized to improve detection, diagnosis, and planning for memory problems. Discussions may lead to earlier detection and diagnosis of cognitive impairment, such as Alzheimer’s disease, or other treatable conditions such as delirium or pressure in the brain and avoid costly hospitalizations.

scholarly journals ADeditome provides the genomic landscape of A-to-I RNA editing in Alzheimer’s disease

2021 ◽  
Author(s):  
Sijia Wu ◽  
Mengyuan Yang ◽  
Pora Kim ◽  
Xiaobo Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Editing ◽  
Memory Loss ◽  
Brain Regions ◽  
Disease Stage ◽  
Mirna Regulation ◽  
Annotation Database ◽  
Functional Annotations ◽  
Genomic Landscape

Abstract A-to-I RNA editing, contributing to nearly 90% of all editing events in human, has been reported to involve in the pathogenesis of Alzheimer’s disease (AD) due to its roles in brain development and immune regulation, such as the deficient editing of GluA2 Q/R related to cell death and memory loss. Currently, there are urgent needs for the systematic annotations of A-to-I RNA editing events in AD. Here, we built ADeditome, the annotation database of A-to-I RNA editing in AD available at https://ccsm.uth.edu/ADeditome, aiming to provide a resource and reference for functional annotation of A-to-I RNA editing in AD to identify therapeutically targetable genes in an individual. We detected 1676 363 editing sites in 1524 samples across nine brain regions from ROSMAP, MayoRNAseq and MSBB. For these editing events, we performed multiple functional annotations including identification of specific and disease stage associated editing events and the influence of editing events on gene expression, protein recoding, alternative splicing and miRNA regulation for all the genes, especially for AD-related genes in order to explore the pathology of AD. Combing all the analysis results, we found 108 010 and 26 168 editing events which may promote or inhibit AD progression, respectively. We also found 5582 brain region-specific editing events with potentially dual roles in AD across different brain regions. ADeditome will be a unique resource for AD and drug research communities to identify therapeutically targetable editing events. Significance: ADeditome is the first comprehensive resource of the functional genomics of individual A-to-I RNA editing events in AD, which will be useful for many researchers in the fields of AD pathology, precision medicine, and therapeutic researches.

Main Plant Extracts’ Active Properties Effective on Scopolamine-Induced Memory Loss

2017 ◽  
Vol 32 (7) ◽  
pp. 418-428 ◽  
Author(s):  
Ioana-Miruna Balmus ◽  
Alin Ciobica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plant Extracts ◽  
Current Knowledge ◽  
Symptomatic Relief ◽  
Memory Loss ◽  
Current Treatment ◽  
General Effect ◽  
Function Loss ◽  
Theory Research

Alzheimer’s disease leads to progressive cognitive function loss, which may impair both intellectual capacities and psychosocial aspects. Although the current knowledge points to a multifactorial character of Alzheimer’s disease, the most issued pathological hypothesis remains the cholinergic theory. The main animal model used in cholinergic theory research is the scopolamine-induced memory loss model. Although, in some cases, a temporary symptomatic relief can be obtained through targeting the cholinergic or glutamatergic neurotransmitter systems, no current treatment is able to stop or slow cognitive impairment. Many potentially successful therapies are often blocked by the blood–brain barrier since it exhibits permeability only for several classes of active molecules. However, the plant extracts’ active molecules are extremely diverse and heterogeneous regarding the biochemical structure. In this way, many active compounds constituting the recently tested plant extracts may exhibit the same general effect on acetylcholine pathway, but on different molecular ground, which can be successfully used in Alzheimer’s disease adjuvant therapy.

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