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Potential of glycowithanolides from Withania somnifera (Ashwagandha) as therapeutic agents for the treatment of Alzheimer's disease,
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia. As
of 2014, there were an estimated nearly 36 million people have
Alzheimer’s disease or a related dementia worldwide. This number
will increase to an estimated 75.6 million in 2030, and 135.5 million in
2050. Today, someone develops AD every 67 seconds. By 2050, one
new case of AD is expected to develop every 33 seconds in United
States. Already 62% of people with dementia live in developing
countries, but by 2050 this will rise to 71%. Currently FDA approved
drugs such as acetylcholinesterase inhibitors (AChEI): Donepezil,
Rivastigmine and Galantamine and N-methyl-daspartate (NMDA)
antagonist: Memantine are prescribed for the treatment of AD.
Meanwhile less than 20% of AD patients are responding moderately to
these drugs with an average benefit for six to twelve months, often
with serious side effects. Therefore there is an urgent need to develop and evaluate more
effective pharmacological interventions with fewer side effects. Plant Withania somnifera
which is used as herb in Ayurvedic medicine contain steroidal lactones glycowithanolides
(Withaferin A, Withasomniferin-A) which has potential as therapeutic agent for AD. In this
review, we compare that immunomodulatory, antioxidative, anticholinesterase and antiinflammatory properties of glycowithanolides with the market available drugs.
... AD is a major global health problem that results in significant burden on the patients due to the high cost of managing AD [1]. Neuropathologically, AD is characterized by brain atropy, loss of neurons, synaptic dysfunction, extracellular accumulation of amyloid- (A), and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau [2,3]. Despite indistinguishable clinical dementia symptoms, less than 1% familial early-onset AD is caused by missense mutations in three genes of presenilin-1, presenilin-2, and amyloid precursor protein [4]. ...
To date, dysregulation of the insulin signaling pathway in the brain has not been demonstrated unequivocally in Alzheimer’s disease (AD). The purpose of the study was to examine the possible dysregulation of insulin signaling pathway in an AD rat model. Furthermore, the present study investigated the effect of Donepezil and Curcumin on insulin signaling, insulin, and glucose levels in AD rat brain. The rats were induced to develop AD by intraperitoneal administration of Scopolamine. We found that glucose levels in plasma and brain were decreased in AD rats, whereas the insulin levels was increased in plasma but decreased in brain in AD rats. In addition, insulin signaling proteins IR-β, IGF-1, IRS-1, IRS-2 p-Akt (Ser473), and Akt were markedly reduced in the AD rats. Furthermore, GLUT3 and GLUT4 levels in the brain were markedly reduced in AD rats. All these data were compared to Saline-treated control rats. Curcumin significantly increased glucose levels in plasma and in brain. However, insulin levels was decreased in plasma and was increased in AD rats’ brain. Moreover, GLUT3 and GLUT4 levels were significantly increased in Curcumin-treated AD rats. All these data were compared to Scopolamine– induced AD rats. Thus amelioration of impaired insulin signaling and improved glucose regulation in AD rats by Curcumin may be beneficial in the management of AD.
Bacopa monnieri has been used for centuries in Ayurvedic medicine, alone or in combination with other herbs, as a memory and learning enhancer, sedative, and anti-epileptic. This review aimed to highlight the health benefits of B. monnieri extracts (BME), focusing on anti-cancer and neurodegenerative diseases. We examined the clinical studies on phytochemistry and pharmacological application of BME. We further highlighted the mechanism of action of these extracts in varying types of cancer and their therapeutic implications. In addition, we investigated the underlying molecular mechanism in therapeutic interventions, toxicities, safety concerns and synergistic potential in cognition and neuroprotection. Overall, this review provides deeper insights into the therapeutic implications of Brahmi as a lead formulation for treating neurological disorders and exerting cognitive-enhancing effects.
Alzheimer’s disease (AD) is the most common form of dementia. Extracellular amyloid-β (Aβ) aggregation and tau hyperphosphorylation are the key drivers of AD. Glycogen synthase kinase 3 (GSK3) and cyclin dependent kinase 5 (Cdk5) have been known as leading applicants arbitrating abnormal tau hyperphosphorylation. Thus, we evaluated the efficacy and underlying mechanism of action of curcumin in scopolamine-induced AD rats in our study. We found that curcumin-treated AD rats markedly reduced the levels of Aβ40 and Aβ42 in the brain and in the plasma in comparison to untreated AD rats. Moreover, the levels of phosphorylated tau at Ser396 (PHF13), Ser202/Thr205 (AT8), and Aβ40/42 (MOAB2) were decreased significantly in AD rats treated with curcumin. Phospho-GSK3β (Tyr216), the active form of GSK3β, and total GSK3β were significantly decreased in AD rats treated with curcumin. Furthermore, Cdk5 and its activators p35 and p25 were significantly decreased in curcumin-treated AD rats. The reduced levels of Cdk5, p35, p25, and GSK3β in curcumin-treated AD rats may result decreased Aβ aggregation and tau hyperphosphorylation, thus ameliorating AD. Impaired spatial memory and locomotor activity in AD rats were partially reversed by curcumin. Therefore, curcumin, as a natural compound present in turmeric, may be a more effective therapeutic agent in the treatment of AD in humans.
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