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 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.

MR Brain Screening using Optimization Techniques – A survey

2021 ◽  
Vol 17 ◽  
Author(s):  
Chitradevi D ◽  
Prabha S.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cell Loss ◽  
Optimization Techniques ◽  
Amyloid Β Protein ◽  
The Brain ◽  
Brain Tissues

Background: Alzheimer’s disease (AD) is associated with Dementia, and it is also a memory syndrome in the brain. It affects the brain tissues and causes major changes in day-to-day activities. Aging is a major cause of Alzheimer's disease. AD is characterized by two pathological hallmarks as, Amyloid β protein and neurofibrillary tangles of hyperphosphorylated tau protein. The imaging hallmarks for Alzheimer’s disease are namely, swelling, shrinkage of brain tissues due to cell loss, and atrophy in the brain due to protein dissemination. Based on the survey, 60% to 80% of dementia patients belong to Alzheimer’s disease. Introduction: AD is now becoming an increasing and important brain disease. The goal of AD pathology is to cause changes/damage in brain tissues. Alzheimer's disease is thought to begin 20 years or more before symptoms appear, with tiny changes in the brain that are undetectable to the person affected. The changes in a person's brain after a few years are noticeable through symptoms such as language difficulties and memory loss. Neurons in different parts of the brain have detected symptoms such as cognitive impairments and learning disabilities. In this case, neuroimaging tools are necessary to identify the development of pathology which relates to the clinical symptoms. Methods: Several approaches have been tried during the last two decades for brain screening to analyse AD with the process of pre-processing, segmentation and classification. Different individual such as Grey Wolf optimization, Lion Optimization, Ant Lion Optimization and so on. Similarly, hybrid optimization techniques are also attempted to segment the brain sub-regions which helps in identifying the bio-markers to analyse AD. Conclusion: This study discusses a review of neuroimaging technologies for diagnosing Alzheimer's disease, as well as the discovery of hallmarks for the disease and the methodologies for finding hallmarks from brain images to evaluate AD. According to the literature review, most of the techniques predicted higher accuracy (more than 90%), which is beneficial for assessing and screening neurodegenerative illness, particularly Alzheimer's disease.

scholarly journals Low-Dose Ionizing Radiation Modulates Microglia Phenotypes in the Models of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 4532 ◽  
Author(s):  
Sujin Kim ◽  
Hyunju Chung ◽  
Han Ngoc Mai ◽  
Yunkwon Nam ◽  
Soo Jung Shin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ionizing Radiation ◽  
Cognitive Deficits ◽  
Low Dose ◽  
Memory Loss ◽  
M2 Polarization ◽  
Phenotype Switching ◽  
5Xfad Mice ◽  
The Brain

Alzheimer’s disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aβ deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aβ pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aβ deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aβ accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aβ-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aβ deposition and memory loss.

scholarly journals IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

2016 ◽  
Vol 113 (19) ◽  
pp. E2705-E2713 ◽  
Author(s):  
Amy K. Y. Fu ◽  
Kwok-Wang Hung ◽  
Michael Y. F. Yuen ◽  
Xiaopu Zhou ◽  
Deejay S. Y. Mak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Innate Immune Response ◽  
Memory Loss ◽  
Neuronal Loss ◽  
Innate Immune ◽  
Therapeutic Role ◽  
Potential Therapeutic Role ◽  
The Brain

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.

scholarly journals Alzheimer’s disease under the purview of Graph Theory Centric Genetic Networks

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yegnanarayanan Venkatraman ◽  
◽  
Narayanaa Y Krithicaa ◽  
Valentina E. Balas ◽  
Marius M. Balas ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Graph Theory ◽  
Network Theory ◽  
Memory Loss ◽  
Amyloid Plaque ◽  
Brain Regions ◽  
Protein Protein Interaction ◽  
Communication Demands ◽  
The Brain

Notice that the synapsis of brain is a form of communication. As communication demands connectivity, it is not a surprise that "graph theory" is a fastest growing area of research in the life sciences. It attempts to explain the connections and communication between networks of neurons. Alzheimer’s disease (AD) progression in brain is due to a deposition and development of amyloid plaque and the loss of communication between nerve cells. Graph/network theory can provide incredible insights into the incorrect wiring leading to memory loss in a progressive manner. Network in AD is slanted towards investigating the intricate patterns of interconnections found in the pathogenesis of brain. Here, we see how the notions of graph/network theory can be prudently exploited to comprehend the Alzheimer’s disease. We begin with introducing concepts of graph/network theory as a model for specific genetic hubs of the brain regions and cellular signalling. We begin with a brief introduction of prevalence and causes of AD followed by outlining its genetic and signalling pathogenesis. We then present some of the network-applied outcome in assessing the disease-signalling interactions, signal transduction of protein-protein interaction, disturbed genetics and signalling pathways as compelling targets of pathogenesis of the disease.

scholarly journals Image processing for early detection of Alzheimer’s disease using Iridology

2020 ◽  
Vol 11 (4) ◽  
pp. 5555-5559
Author(s):  
Asuntha A ◽  
Sai Kalyan Reddy R ◽  
Vamshikrishna K ◽  
Premsagar N
Keyword(s):  
Alzheimer’S Disease ◽  
Image Processing ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
Region Of Interest ◽  
Colour Pattern ◽  
Training Methods ◽  
Iris Image ◽  
Alternative Research ◽  
The Brain

Alzheimer's disease is caused by genetics, personal lifestyle and other environmental factors. It is an irreversible disease that slowly destroys the brain memory cells. There are no specific methods for the detection of Alzheimer's disease. The primary symptoms of Alzheimer's disease are memory loss, difficulty in thinking, a problem in writing and speaking and others. Iridology is alternative research that has gained more popularity in recent years, which studies the alterations of the iris in correspondence with the organs of the human body. The combination of digital image processing with Iridology gives an excellent opportunity to explore and learn about different neuronal diseases, specifically Alzheimer's disease. In this work, MATLAB software is applied to determine the colour, pattern and other factors that show the existence of Alzheimer's disease. The noise in the iris image is removed by the Gaussian filter, followed by histogram analyses and cropping. The Hough circle transform is used to identify the region of interest and to convert the circular iris image into rectangle form. In the training methods, the SVM and CNN classifiers are used to classify whether the person has Alzheimer's disease. Finally, the results are compared with the real-time images.

scholarly journals 326 Whey proteins for prevention and intervention in Alzheimer’s Disease

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 68-69
Author(s):  
Louise E Bennett
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Whey Proteins ◽  
Memory Loss ◽  
Aβ Peptides ◽  
Over Expression ◽  
Potential Benefits ◽  
Individual Potential ◽  
The Individual ◽  
The Brain

Abstract Alzheimer’s disease, resulting from the over-expression of amyloid precursor protein (APP) and accumulation of plaques comprising the APP-derived amyloid beta (Aβ), is a diagnostic and pathological brain feature of Alzheimer’s disease (AD). For older, predisposed people, accumulation of Aβ plaque in the brain precedes symptoms of memory loss by decades. There is a growing consensus that over-expression of APP may also reflect a defense response against infection, via the antibiotic effects of Aβ, which becomes toxic when Aβ peptides cannot be cleared from the brain. These scenarios permit two possible pathways of potential intervention from whey proteins mediated by lactoferrin and hydrolyzed whey proteins. In particular, the interference of fibril assembly whey-derived peptides can promote opportunity for clearance of aggregating forms of Aβ, while the anti-microbial activity of whey proteins such as lactoferrin have potential to suppress the activity of microbes (and viruses) and collectively manage the progress of AD. This presentation will explain the individual potential benefits of whey peptides and lactoferrin, based on available evidence. More research is required to determine if a synergistic effect might be possible from this therapeutic combination.

scholarly journals Effects of Reactive Oxygen and Nitrogen Species on TrkA Expression and Signalling: Implications for proNGF in Aging and Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1983
Author(s):  
Erika Kropf ◽  
Margaret Fahnestock
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Basal Forebrain ◽  
Memory Loss ◽  
Reactive Oxygen ◽  
Neurotrophin Receptor ◽  
Nitrogen Species ◽  
Age Related ◽  
The Brain

Nerve growth factor (NGF) and its precursor form, proNGF, are critical for neuronal survival and cognitive function. In the brain, proNGF is the only detectable form of NGF. Dysregulation of proNGF in the brain is implicated in age-related memory loss and Alzheimer’s disease (AD). AD is characterized by early and progressive degeneration of the basal forebrain, an area critical for learning, memory, and attention. Learning and memory deficits in AD are associated with loss of proNGF survival signalling and impaired retrograde transport of proNGF to the basal forebrain. ProNGF transport and signalling may be impaired by the increased reactive oxygen and nitrogen species (ROS/RNS) observed in the aged and AD brain. The current literature suggests that ROS/RNS nitrate proNGF and reduce the expression of the proNGF receptor tropomyosin-related kinase A (TrkA), disrupting its downstream survival signalling. ROS/RNS-induced reductions in TrkA expression reduce cell viability, as proNGF loses its neurotrophic function in the absence of TrkA and instead generates apoptotic signalling via the pan-neurotrophin receptor p75NTR. ROS/RNS also interfere with kinesin and dynein motor functions, causing transport deficits. ROS/RNS-induced deficits in microtubule motor function and TrkA expression and signalling may contribute to the vulnerability of the basal forebrain in AD. Antioxidant treatments may be beneficial in restoring proNGF signalling and axonal transport and reducing basal forebrain neurodegeneration and related deficits in cognitive function.

scholarly journals Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

2021 ◽  
Author(s):  
Niall Murphy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Life Expectancy ◽  
Amyloid Beta ◽  
Memory Loss ◽  
Phosphorylated Tau ◽  
Disease Research ◽  
Neurodegenerative Process ◽  
The Relationship ◽  
The Brain

Alzheimer’s Disease is defined as progressive memory loss coincident with accumulation of aggregated amyloid beta and phosphorylated tau. Identifying the relationship between these features has guided Alzheimer’s Disease research for decades, principally with the view that aggregated proteins drive a neurodegenerative process. Here I propose that amyloid beta and phospho-tau write-protect and tag neuroplastic changes as they form, protecting and insuring established neuroplasticity from corruption. In way of illustration, binding of oligomeric amyloid beta to the prion receptor is presented as an example possible mechanism. The write-protecting process is conjected to occur at least partially under the governance of isodendritic neuromodulators such as norepinephrine and acetylcholine. Coincident with aging, animals are exposed to accumulating amounts of memorable information. Compounded with recent increases in life expectancy and exposure to information-rich environments this causes aggregating proteins to reach unforeseen toxic levels as mnemonic circuits overload. As the brain cannot purposefully delete memories nor protect against overaccumulation of aggregating proteins, the result is catastrophic breakdown on cellular and network levels causing memory loss.

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