Evidence on Integrating Pharmacokinetics to Find Truly Therapeutic Agent for Alzheimer’s Disease: Comparative Pharmacokinetics and Disposition Kinetics Profiles of Stereoisomers Isorhynchophylline and Rhynchophylline in Rats

Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla, a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheimer’s disease (AD). However, IRN and RN can interconvert into each other in vivo after oral administration. The present study aimed to elucidate the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of equal dose of IRN or RN to rats. Our study demonstrated that after oral administration, RN showed significantly higher systemic exposure (6.5 folds of IRN, p < 0.001) and disposition in the brain (2.5 folds of IRN, p < 0.01) and CSF (3 folds of IRN, p < 0.001) than IRN. The results indicated that interconversion between IRN and RN occurred. Notably, regardless of the orally administered IRN or RN, RN would always be one of the major or predominant forms present in the body. Our results provided sound evidence supporting further development of RN as a potential therapeutic agent for the treatment of AD. Moreover, the present study sets a solid example that integrating pharmacokinetics is crucial to identify the truly therapeutic agent.

Download Full-text

Alzheimer’s disease and its related Dementia types: A review on their management via nanotechnology based therapeutic strategies

Current Alzheimer Research ◽

10.2174/1567205018666210218160812 ◽

2021 ◽

Vol 18 ◽

Author(s):

Panoraia I. Siafaka ◽

Gökce Mutlu ◽

Neslihan Üstündağ Okur

Keyword(s):

Alzheimer’S Disease ◽

Drug Delivery ◽

Alzheimer's Disease ◽

Vascular Dementia ◽

Drug Delivery Systems ◽

Delivery Systems ◽

The Body ◽

Daily Routine ◽

Mixed Dementia ◽

The Brain

Background: Dementia and its related types such as Alzheimer’s disease, vascular dementia and mixed dementia belong to brain associated diseases, resulting in long-term progressive memory loss. These diseases are so severe that can affect a person's daily routine. Up to date, treatment of de- mentias is still an unmet challenge due to their complex pathophysiology and unavailable efficient pharmacological approaches. The use of nanotechnology based pharmaceutical products could possibly improve the management of dementia given that nanocarriers could more efficiently deliver drugs to the brain. Objective: The objective of this study is to provide the current nanotechnology based drug delivery systems for the treatment of various dementia types. In addition, the current diagnosis biomarkers for the mentioned dementia types along with their available pharmacological treatment are being dis- cussed. Method: An extensive review of the current nanosystems such as brain drug delivery systems against Alzheimer’s disease, vascular dementia and mixed dementia was performed. Moreover, nan- otheranostics as possible imaging markers for such dementias were also reported. Results: The field of nanotechnology is quite advantageous for targeting dementia given that nanoscale drug delivery systems easily penetrate the blood brain barrier and circulate in the body for prolonged time. These nanoformulations consist of polymeric nanoparticles, solid lipid nanoparticles, nanostruc- tured lipid carriers, microemulsions, nanoemulsions, and liquid crystals. The delivery of the nan- otherapeutics can be achieved via various administration routes such as transdermal, injectable, oral, and more importantly, through the intranasal route. Nonetheless, the nanocarriers are mostly limited to Alzheimer’s disease targeting; thus, nanocarriers for other types of dementia should be developed. Conclusion: To conclude, understanding the mechanism of neurodegeneration and reviewing the cur- rent drug delivery systems for Alzheimer’s disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on mul- tifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.

Download Full-text

Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽

10.1155/2018/2010675 ◽

2018 ◽

Vol 2018 ◽

pp. 1-20 ◽

Cited By ~ 18

Author(s):

Manoj Govindarajulu ◽

Priyanka D. Pinky ◽

Jenna Bloemer ◽

Nila Ghanei ◽

Vishnu Suppiramaniam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Effects ◽

Therapeutic Potential ◽

Protein Accumulation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Continuous Increase ◽

Therapeutic Benefits ◽

The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

Download Full-text

Therapeutic potential of astaxanthin and superoxide dismutase in Alzheimer's disease

Open Biology ◽

10.1098/rsob.210013 ◽

2021 ◽

Vol 11 (6) ◽

pp. 210013

Author(s):

Vyshnavy Balendra ◽

Sandeep Kumar Singh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Superoxide Dismutase ◽

Antioxidant System ◽

Tau Protein ◽

Therapeutic Potential ◽

Plaque Burden ◽

Memory Decline ◽

Endogenous Antioxidants ◽

The Brain

Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is composed of exogenous and endogenous antioxidants to maintain homeostasis. Superoxide dismutase (SOD) is an endogenous enzymatic antioxidant that converts superoxide ions to hydrogen peroxide in cells. SOD supplementation in mice prevented cognitive decline in stress-induced cells by reducing lipid peroxidation and maintaining neurogenesis in the hippocampus. Furthermore, SOD decreased expression of BACE1 while reducing plaque burden in the brain. Additionally, Astaxanthin (AST), a potent exogenous carotenoid, scavenges superoxide anion radicals. Mice treated with AST showed slower memory decline and decreased depositions of amyloid-beta (A β ) and tau protein. Currently, the neuroprotective potential of these supplements has only been examined separately in studies. However, a single antioxidant cannot sufficiently resist oxidative damage to the brain, therefore, a combinatory approach is proposed as a relevant therapy for ameliorating pathological changes in AD.

Download Full-text

Influencia del estrés en la Enfermedad de Alzheimer. // Stress influence in Alzheimer’s disease

Ciencia Unemi ◽

10.29076/issn.2528-7737vol10iss25.2017pp123-133p ◽

2018 ◽

Vol 10 (25) ◽

pp. 123

Author(s):

Maria Alejandra Vallejo-Johnson ◽

Patricia Marcial-Velastegui

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Damage ◽

The Body ◽

Daily Routine ◽

Stressful Situation ◽

The Individual ◽

Stress Influences ◽

The Brain

Existen diversos estudios que proponen las causas de la Enfermedad de Alzheimer (EA), las cuales pueden ser: biológicas, genéticas, cronológicas y ambientales, dentro de ésta última se encuentra el estrés como una influencia para el inicio de dicha patología. Según las distintas teorías del estrés, el sujeto, al encontrarse frente a una situación estresante, sufre diversos cambios en su cuerpo para sobrellevar dicho acontecimiento. El cerebro es el encargado de poner al cuerpo en alerta y en marcha para actuar frente a dicho cambio. El estrés prolongado conlleva a alteraciones en las vías cerebrales, específicamente un daño neuronal del hipocampo, el cual es el encargado de los recuerdos y memoria. Éste al verse afectado, repercute en la memoria del sujeto y por lo tanto empieza a fallar; el sujeto se ve en la incapacidad para recordar y realizar distintas actividades rutinarias. Mediante la investigación documental y encuestas a profesionales de la salud, se obtuvo información tanto del estrés como de la Enfermedad de Alzheimer para luego concluir en la influencia del mismo en el origen de la enfermedad. Se concluye que el estrés perenne repercute en la muerte de neuronas del hipocampo lo que conlleva a la EA. AbstractThere are different studies that propose that the causes of Alzheimer might be biological, genetic, chronological and environmental. Within the environmental aspects, the stress influences the beginning of this pathology. There are several studies that propose the causes of Alzheimer's disease (AD), which can be: biological, genetic, chronological and environmental, within the latter is the stress that influences the beginning of this pathology. According to different theories of stress, the individual, while facing a stressful situation, experiences many changes in the body in order to deal with this situation. The brain is in charge of alerting the body to protect itself against that change. The long-term stress alters the brain pathways, producing specifically a neuronal damage in the hippocampus that is responsible for memories and memory. This affects memory and therefore individual begins to fail, and then, the person cannot remember how to do the daily routine. Through bibliographical research and surveys applied to healthcare professionals, information was obtained on both stress and Alzheimer's disease to establish the influence of that condition on the disease. The study concludes that long-term stress affects the death of neurons in the hippocampus, which leads to AD.

Download Full-text

How Your Blood Knows Your Brain Is Sick

Frontiers for Young Minds ◽

10.3389/frym.2020.561561 ◽

2020 ◽

Vol 8 ◽

Author(s):

Sabrina Loudjani ◽

Sridar Narayanan ◽

Arsalan S. Haqqani ◽

AmanPreet Badhwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Complex Disease ◽

The Body ◽

The Brain

Alzheimer’s disease (AD) is a complex disease that attacks the brain that mostly affects people 65 years and older. AD affects more and more people each year. A major problem with AD is that it is diagnosed too late. A big goal is to find ways to help doctors identify the disease early, so they can better help AD patients. Biomarkers are something that can tell you if a part of the body is feeling healthy or is being attacked by a disease. This article will describe one exciting new category of biomarkers that carry information from the brain into the blood. These biomarkers can be used to see how healthy the brain is feeling or if it is getting hurt by a disease like AD.

Download Full-text

Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer’s Disease

BioMed Research International ◽

10.1155/2019/7420189 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 10

Author(s):

Henriette R. Frederiksen ◽

Henriette Haukedal ◽

Kristine Freude

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cellular Response ◽

The Body ◽

Cellular Damage ◽

Whole Body ◽

Toll Like Receptors ◽

Cell Type ◽

Cell Type Specific ◽

The Brain

Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer’s disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer’s disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer’s disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer’s disease.

Download Full-text

β-hydroxybutyrate Impedes the Progression of Alzheimer’s Disease and Atherosclerosis in ApoE-Deficient Mice

Nutrients ◽

10.3390/nu12020471 ◽

2020 ◽

Vol 12 (2) ◽

pp. 471 ◽

Cited By ~ 3

Author(s):

Manigandan Krishnan ◽

Jong Su Hwang ◽

Mikyung Kim ◽

Yun Jin Kim ◽

Ji Hae Seo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Density Lipoprotein ◽

In Vitro Study ◽

Substantia Nigra Pars Compacta ◽

Apo E ◽

The Brain ◽

Deficient Mice

β-hydroxybutyrate (β-OHB) has been shown to exert an anti-inflammatory activity. Apolipoprotein-E (ApoE) is strongly associated with atherosclerosis and Alzheimer’s disease (AD). This study aimed to explore the therapeutic effect of β-OHB in the brain and the aorta of high-fat diet (HFD)-fed ApoE-deficient mice. We found in Apo-E deficient mice that β-OHB attenuated lipid deposition in the choroid plexus (ChP) and decreased amyloid plaque in the substantia nigra pars compacta. We also found decreased CD68-positive macroglia infiltration of the ChP in β-OHB-treated ApoE-deficient mice. β-OHB treatment ameliorated IgG extravasation into the hippocampal region of the brain. In vitro study using ChP mice cell line revealed that β-OHB attenuated oxidized low-density lipoprotein-induced ApoE-specific differentially expressed inflammatory ChP genes. Treatment with β-OHB reduced aortic plaque formation without affecting blood lipid profiles and decreased serum production of resistin, a well-established risk factor for both AD and atherosclerosis. Thus, the current study suggests and describes the therapeutic potential of β-OHB for the treatment of AD and atherosclerosis.

Download Full-text

Ultrasound Delivery of an Anti-Aβ Therapeutic Agent to the Brain in a Mouse Model of Alzheimer’s Disease

10.1063/1.3131464 ◽

2009 ◽

Cited By ~ 1

Author(s):

Jessica F. Jordão ◽

Carlos A. Ayala-Grosso ◽

Rajiv Chopra ◽

JoAnne McLaurin ◽

Isabelle Aubert ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Therapeutic Agent ◽

Model Of Alzheimer’S Disease ◽

The Brain

Download Full-text

Therapeutic Potential of Direct Clearance of the Amyloid-β in Alzheimer’s Disease

Brain Sciences ◽

10.3390/brainsci10020093 ◽

2020 ◽

Vol 10 (2) ◽

pp. 93 ◽

Cited By ~ 1

Author(s):

Dong Eun Kim ◽

Ronny Priefer

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Advanced Glycation Endproducts ◽

Amyloid Β ◽

Solute Concentration ◽

Advanced Glycation ◽

Glycation Endproducts ◽

The Brain ◽

Lipoprotein Receptor Related Protein

Alzheimer’s disease (AD) is characterized by deposition and accumulation of amyloid-β (Aβ) and its corresponding plaques within the brain. Although much debate exists whether these plaques are the cause or the effect of AD, the accumulation of Aβ is linked with the imbalance between the production and clearance of Aβ. The receptor for advanced glycation endproducts (RAGE) facilitates entry of free Aβ from the peripheral stream. Conversely, lipoprotein receptor-related protein 1 (LRP1), located in the abluminal side at the blood–brain barrier mediates the efflux of Aβ. Research on altering the rates of clearance of Aβ by targeting these two pathways has been extensively study. Additionally, a cerebrospinal fluid (CSF) circulation assistant device has also been evaluated as an approach to increase solute concentration in the CSF via mechanical drainage, to allow for removal of Aβ from the brain. Herein, we provide a brief review of these approaches that are designed to re-establish a homeostatic Aβ balance in the brain.

Download Full-text

Mitochondrial Dysfunction in Alzheimer’s Disease: A Biomarker of the Future?

Biomedicines ◽

10.3390/biomedicines9010063 ◽

2021 ◽

Vol 9 (1) ◽

pp. 63

Author(s):

Simon M. Bell ◽

Katy Barnes ◽

Matteo De Marco ◽

Pamela J. Shaw ◽

Laura Ferraiuolo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Function ◽

Imaging Techniques ◽

The Body ◽

Atp Production ◽

Disease Modifying Therapies ◽

Mitochondrial Functions ◽

Species Production ◽

The Brain

Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain of people with AD. As well as abnormalities in protein aggregation, other pathological changes are seen in this condition. The function of mitochondria in both the nervous system and rest of the body is altered early in this disease, and both amyloid and tau have detrimental effects on mitochondrial function. In this review article, we describe how the function and structure of mitochondria change in AD. This review summarises current imaging techniques that use surrogate markers of mitochondrial function in both research and clinical practice, but also how mitochondrial functions such as ATP production, calcium homeostasis, mitophagy and reactive oxygen species production are affected in AD mitochondria. The evidence reviewed suggests that the measurement of mitochondrial function may be developed into a future biomarker for early AD. Further work with larger cohorts of patients is needed before mitochondrial functional biomarkers are ready for clinical use.

Download Full-text