withaferin-a and Alzheimer-Disease

Background-Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disease that is characterized by memory loss, personality changes, and a decline in cognitive function. While the exact cause of AD is still unclear, recent studies point to lifestyle, diet, environmental, and genetic factors as contributors to disease progression. The pharmaceutical approaches developed to date do not alter disease progression. More than two hundred promising drug candidates have failed clinical trials in the past decade, suggesting that the disease and its causes may be highly complex. Medicinal plants and herbal remedies are now gaining more interest as complementary and alternative interventions and are a valuable source for developing drug candidates for AD. Indeed, several scientific studies have described the use of various medicinal plants and their principal phytochemicals for the treatment of AD. This article reviews a subset of herbs for their anti-inflammatory, antioxidant, and cognitive-enhancing effects. Methods-This article systematically reviews recent studies that have investigated the role of neuroprotective herbs and their bioactive compounds for dementia associated with Alzheimer's disease and pre-Alzheimer's disease. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter. Conclusions-Medicinal plants have great potential as part of an overall program in the prevention and treatment of cognitive decline associated with AD. It is hoped that these medicinal plants can be used in drug discovery programs for identifying safe and efficacious small molecules for AD.

Topics: Acorus; Alzheimer Disease; Centella; Central Nervous System; Ginkgo biloba; Humans; Phytochemicals; Plant Extracts; Plants, Medicinal

Globally, Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aβ) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Humans; Neuroprotective Agents; Peptide Fragments; Plaque, Amyloid; Solanaceae; tau Proteins; Withania; Withanolides

Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents.

Topics: Alzheimer Disease; Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Cardiotonic Agents; Humans; India; Inflammation; Medicine, Ayurvedic; Neuroprotective Agents; Parkinson Disease; Plants, Medicinal; Withania; Withanolides

Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera Dunal) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.

Topics: Alzheimer Disease; Humans; Medicine, Ayurvedic; Molecular Structure; Neurodegenerative Diseases; Neuroprotective Agents; Plant Extracts; Plant Roots; Spinal Cord Injuries; Withania

Ashwagandha (root of Withania somnifera) has been used for many purposes, it is mainly considered a tonic in traditional Ayurvedic medicine. This review focuses on the effects of compounds isolated from Ashwagandha on dementia models and on the spinal cord injury model. Our study demonstrated that the active constituents, withanolide A, withanoside IV, and withanoside VI, restored presynapses and postsynapses, in addition to both axons and dendrites in cortical neurons after Abeta(25-35)-induced injury. In vivo, oral withanolide A, withanoside IV, and withanoside VI (10 micromol/kg/day for 12 days) improved Abeta(25-35)-induced memory impairment, neurite atrophy, and synaptic loss in the cerebral cortex and hippocampus in mice. Since spinal cord injury (SCI) is also difficult to treat, and therefore practical and curable strategies for SCI are desired. Oral treatment with withanoside IV improved locomotor functions in mice with SCI. In mice treated with withanoside IV (10 micromol/kg/day for 21 days), the axonal density and peripheral nervous system myelin level increased. The loss of CNS myelin and increase in reactive gliosis were not affected by withanoside IV. Additionally, sominone, an aglycone of withanoside IV, was identified as the main metabolite after oral administration of withanoside IV in mice. Withanolide A, withanoside IV, and withanoside VI are therefore important candidates for the therapeutic treatment of neurodegenerative diseases. In particular, withanoside IV was shown to control neurons as well as glial cells for reconstruction neuronal networks. To clarify key events in overcoming neurodegeneration, we are now studying the molecular targets and signal cascades of sominone.

Topics: Alzheimer Disease; Animals; Axons; Dendrites; Disease Models, Animal; Ergosterol; Humans; Medicine, Ayurvedic; Memory Disorders; Mice; Motor Activity; Neurodegenerative Diseases; Phytotherapy; Plant Extracts; Spinal Cord Injuries; Stimulation, Chemical; Synapses; Withania; Withanolides

Fluorescence spectroscopy for in vitro amyloid-β (Aβ) fibrillation diagnosis and spectral fluorescence signature for the identification of bioactive compounds were applied to study traditional Ayurvedic nutraceuticals - Brahmi, Ashwagandha, Shanka pushpi, and Gotu kola - as well as their plant extracts for possible treatment of Alzheimer's disease. All samples manifest as inhibitors on three different variants of the Aβ peptide: methionine Aβ1-40, Aβ1-40, and Aβ1-42. The main compounds within the nutraceuticals were identified. Since related medicals are known to have reduced negative post- and side-effects and even may introduce further positive health impacts by preventing pathogen plaque formation and reducing free Aβ to a natural level, such treatment approaches could be of further interest.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Centella; Dietary Supplements; Humans; Peptide Fragments; Plant Extracts; Spectrometry, Fluorescence; Triterpenes

Withania somnifera (WS), also referred to as Medhya Rasayana (nootropic or rejuvenating), has traditionally been prescribed for various neurological ailments, including dementia. Despite substantial evidence, pharmacological roles of WS, neither as nootropic nor as an antidementia agent, are well-understood at the cellular and molecular levels.. We aimed at elucidating the pharmacological action mechanisms of WS root constituents against Alzheimer's Disease (AD) pathology.. Various bioinformatics tools and resources, including DAVID, Cytoscape, NetworkAnalyst and KEGG pathway database were employed to analyze the interaction of WS root bioactive molecules with the protein targets of AD-associated cellular processes. We also used a molecular simulation approach to validate the interaction of compounds with selected protein targets.. Network analysis revealed that β-sitosterol, withaferin A, stigmasterol, withanolide A, and withanolide D are the major constituents of WS root that primarily target the cellular pathways such as PI3K/Akt signaling, neurotrophin signaling and toll-like receptor signaling and proteins such as Tropomyosin receptor Kinase B (TrkB), Glycogen Synthase Kinase-3β (GSK-3β), Toll-Like Receptor 2/4 (TLR2/4), and β-secretase (BACE-1). Also, the in silico analysis further validated the interaction patterns and binding affinity of the major WS compounds, particularly stigmasterol, withanolide A, withanolide D and β-sitosterol with TrkB, GSK-3β, TLR2/4, and BACE-1.. The present findings demonstrate that stigmasterol, withanolide A, withanolide D and β-sitosterol are the major metabolites that are responsible for the neuropharmacological action of WS root against AD-associated pathobiology, and TrkB, GSK-3β, TLR2/4, and BACE-1 could be the potential druggable targets.

Topics: Alzheimer Disease; Computer Simulation; Glycogen Synthase Kinase 3 beta; Humans; Phosphatidylinositol 3-Kinases; Plant Extracts; Sitosterols; Withania; Withanolides

Keeping in view the fact that the most pathognomonic feature of Alzheimer's disease is the abnormal processing of neuronal cell membrane amyloid precursor protein accompanied by significantly elevated human serum and CSF levels of 24-hydroxycholesterol recognised widely as the specific endogenous ligand of Liver X receptor (LXR-α), the present study was addressed to explore the epigenomic-pathway (if any) that connects LXR-α activation with the genes recognised to be involved in the regulation of aberrant Abeta production leading to the generation of toxic and inflammatory mediators responsible for neuronal death. The results of such a study revealed that LXR-α activation by its specific endogenous or exogenous ligands within neuroblastoma cells resulted in the over-expression of PAR-4 gene accompanied by suppression of AATF gene through its inherent capacity to regulate genes coding for SREBP and NF-κB. Over-expression of PAR-4 gene was accompanied by aberrant Abeta production followed by ROS generation and subsequent death of neuroblastoma cells used in the present study as a cellular model for neurons. Further based upon these results, it was proposed that Abeta-induced heme oxygenase-1 can ensure cholesterol-oxidation to provide endogenous ligands for the sustained activation of neuronal LXR-α dependent epigenomic-pathway leading to neuronal death observed in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Apoptosis Regulatory Proteins; Cloning, Molecular; Epigenomics; Gene Expression Regulation; Humans; Hydroxycholesterols; Liver X Receptors; Neuroblastoma; Neurons; Orphan Nuclear Receptors; Reactive Oxygen Species; Recombinant Proteins; Repressor Proteins; Tumor Cells, Cultured; Withanolides