Phytotherapeutics Against Alzheimer’s Disease: Mechanism, Molecular Targets and Challenges for Drug Development

2021 ◽  
Vol 20 ◽  
Author(s):  
Gayathri S ◽  
Raghu Chandrashekar H ◽  
Fayaz S M
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Medicinal Plants ◽  
Herbal Medicines ◽  
Molecular Targets ◽  
Holistic Approach ◽  
Tinospora Cordifolia ◽  
Acorus Calamus ◽  
Approved Drugs

: Alzheimer's disease is inflating worldwide and is combatted by only a few approved drugs. At best, these drugs treat symptomatic conditions by targeting cholinesterase and N-methyl-D-aspartate receptors. Most of the clinical trials in progress are focused to develop disease-modifying agents that aim single targets. The ‘one drug-one target’ approach is failing in the case of Alzheimer’s disease due to its labyrinth etiopathogenesis. Traditional medicinal systems like ayurveda uses a holistic approach encompassing legion of medicinal plants exhibiting multimodal activity. Recent advances in high-throughput technologies have catapulted the research in the arena of ayurveda, specifically in identifying plants with potent anti-Alzheimer’s disease properties and their phytochemical characterization. Nonetheless, clinical trials of very few herbal medicines are in progress. This review is a compendium of Indian plants and ayurvedic medicines against Alzheimer’s disease and their paraphernalia. A record of 230 plants that are found in India with anti-Alzheimer’s disease potential and about 500 phytochemicals from medicinal plants has been solicited with the hope of exploring the unexplored. Further, the molecular targets of phytochemicals isolated from commonly used medicinal plants such as Acorus calamus, Bacopa monnieri, Convolvulus pluricaulis, Tinospora cordifolia and Withania somnifera have been reviewed with respect to their multidimensional property such as antioxidant, anti-inflammation, anti-aggregation, synaptic plasticity modulation, cognition and memory enhancing activity. In addition, the strengths, and challenges in ayurvedic medicine that limit its use as mainstream therapy is discussed and a framework for the development of herbal medicine has been proposed.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

Botanical Sources for Alzheimer’s: A Review on Reports From Traditional Persian Medicine

2017 ◽  
Vol 32 (7) ◽  
pp. 429-437 ◽  
Author(s):  
Ayda Hosseinkhani ◽  
Ali Sahragard ◽  
Aida Namdari ◽  
Mohammad M. Zarshenas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medicinal Plants ◽  
Herbal Medicines ◽  
Mechanisms Of Action ◽  
Cholinesterase Inhibition ◽  
Clinical Validation ◽  
Persian Medicine ◽  
Traditional Persian Medicine ◽  
Butyryl Cholinesterase

Herbal medicines for the treatment of Alzheimer’s disease (AD) have attracted considerable attention nowadays. Alzheimer’s disease is described in traditional Persian medicine (TPM) by the term Nesyān. In this study, 5 main medicinal medieval Persian manuscripts were reviewed to filter plants reported for the treatment of Nesyān. Databases were searched for related possible mechanisms of action of these medicinal plants. Each herb was searched for along with these keywords: “acetyl and butyryl cholinesterase inhibition,” “antioxidant,” “anti-inflammatory,” and “anti-amyloidogenic.” In Total, 44 herbs were used for the treatment of Nesyān; 40 of those were authenticated. Also, 30 plants had at least one of the mechanisms of action that were searched for or related pharmacological functions known for the treatment of AD. In this work, we introduce promising candidates in TPM that could undergo further investigation for identification of their active compounds and clinical validation in the treatment of AD.

scholarly journals Alzheimer’s disease: natural products as inhibitors of neuroinflammation

2020 ◽  
Vol 28 (6) ◽  
pp. 1439-1455
Author(s):  
Olumayokun A. Olajide ◽  
Satyajit D. Sarker
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Natural Products ◽  
Molecular Targets ◽  
Limited Success ◽  
Clinical Investigations ◽  
Anti Inflammatory

Abstract Alzheimer’s disease (AD) is the most common form of dementia and affects 44 million people worldwide. New emerging evidence from pre-clinical and clinical investigations shows that neuroinflammation is a major pathological component of AD suggesting that anti-inflammatory strategies are important in delaying the onset or slowing the progression of the disease. However, efforts to employ current anti-inflammatory agents in AD clinical trials have produced limited success. Consequently, there is a need to explore anti-inflammatory natural products, which target neuroinflammatory pathways relevant to AD pathogenesis. This review summarises important druggable molecular targets of neuroinflammation and presents classes of anti-neuroinflammatory natural products with potentials for preventing and reducing symptoms of AD.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

Evaluating Thrombin Inhibition in Alzheimer’s Disease (The BEACON Trial): Protocol for a Pilot Study (Preprint)

2019 ◽  
Author(s):  
Cláudia Yang Santos ◽  
Christine Getter ◽  
John Stoukides ◽  
Brian Ott ◽  
Stephen Salloway ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pilot Study ◽  
Cognitive Performance ◽  
Thrombin Inhibitor ◽  
Placebo Control ◽  
Open Label ◽  
Double Blind ◽  
Thrombin Inhibition ◽  
Approved Drugs

BACKGROUND The precise mechanisms whereby cardiovascular risk factors increase the risk of Alzheimer’s disease (AD) have not been delineated. We reported that microvessels isolated from AD brains overexpress a diverse array of neurotoxic and inflammatory proteins, which is consistent with the process of vascular activation. In pre-clinical studies using AD animal models we showed that a vascular activation inhibitor reduced vascular-derived neuroinflammation and improved cognitive performance. Thrombin is a key mediator of cerebrovascular activation in AD. OBJECTIVE This study aims to investigate the safety and potential efficacy of the direct thrombin inhibitor dabigatran, in patients with mild cognitive impairment (MCI) or mild AD to decrease vascular-derived neuroinflammation and improve cognitive performance. METHODS Participants will be enrolled then evaluated quarterly throughout the 24-month study. This is a 24-month randomized-control, double-blind, placebo-controlled, multicenter, delayed-start, pilot study evaluating thrombin inhibition in people with biomarker-confirmed MCI probably due to AD or mild AD. 40 - 60 participants will be recruited between 50 - 85 years old. In the initial 9-months of study, either dabigatran or placebo will be orally administered to patients at a dose of 150 mg per day. After 9 months of the placebo-control (Phase I), the placebo arm will cross-over to an active, open-label (Phase II) where all patients will be treated with a 150 mg daily dose of dabigatran orally for an additional 12 months. A 3-month non-treatment follow-up period will assess duration of effects. RESULTS Beginning in July 2019, and concluding in August 2022, this study is expected to publish final results in January 2023. CONCLUSIONS BEACON is a first-in-kind randomized clinical trial targeting thrombin activation in AD therapeutics. This trial will stimulate translational investigations of an FDA-approved drugs in a newly defined therapeutic areas. CLINICALTRIAL Clinicaltrials.gov NCT03752294

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

scholarly journals Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

2021 ◽  
Vol 14 (5) ◽  
pp. 458
Author(s):  
Barbara Miziak ◽  
Barbara Błaszczyk ◽  
Stanisław J. Czuczwar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Ischemia ◽  
Neurodegenerative Disorder ◽  
Neuropsychiatric Symptoms ◽  
Antidepressant Drugs ◽  
Cancer Drug ◽  
Novel Treatments ◽  
Close Relationship ◽  
Approved Drugs

Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

scholarly journals Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zahra Ayati ◽  
Guoyan Yang ◽  
Mohammad Hossein Ayati ◽  
Seyed Ahmad Emami ◽  
Dennis Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Function ◽  
Daily Living ◽  
Randomised Clinical Trials ◽  
Disease Assessment ◽  
Significant Difference

Abstract Background Saffron (stigma of Crocus sativus L.) from Iridaceae family is a well-known traditional herbal medicine that has been used for hundreds of years to treat several diseases such as depressive mood, cancer and cardiovascular disorders. Recently, anti-dementia property of saffron has been indicated. However, the effects of saffron for the management of dementia remain controversial. The aim of the present study is to explore the effectiveness and safety of saffron in treating mild cognitive impairment and dementia. Methods An electronic database search of some major English and Chinese databases was conducted until 31st May 2019 to identify relevant randomised clinical trials (RCT). The primary outcome was cognitive function and the secondary outcomes included daily living function, global clinical assessment, quality of life (QoL), psychiatric assessment and safety. Rev-Man 5.3 software was applied to perform the meta-analyses. Results A total of four RCTs were included in this review. The analysis revealed that saffron significantly improves cognitive function measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB), compared to placebo groups. In addition, there was no significant difference between saffron and conventional medicine, as measured by cognitive scales such as ADAS-cog and CDR-SB. Saffron improved daily living function, but the changes were not statistically significant. No serious adverse events were reported in the included studies. Conclusions Saffron may have the potential to improve cognitive function and activities of daily living in patients with Alzheimer’s disease and mild cognitive impairment (MCI). However, due to limited high-quality studies there is insufficient evidence to make any recommendations for clinical use. Further clinical trials on larger sample sizes are warranted to shed more light on its efficacy and safety.

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