Cholinesterase Inhibiting Withanolides from Withania somnifera

Choudhary, M. Iqbal; Yousuf, Sammer; Nawaz, Syed Junaid; Ahmed, Shakil; Atta-ur-Rahman, _

doi:10.1248/cpb.52.1358

Cited by 101 publications

(36 citation statements)

References 23 publications

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“…One of the active constituents of Ashwagandha extract, withanolide, has a steroidal structure [11]. Ashwagandha might stimulate signal cascades similar to steroids, particularly estradiol that has also been shown to improve spatial and working memory via cholinergic mechanisms [40], [41]. Like estradiol, i-Extract might activate three kinase pathways (CaMKII, Akt and ERK/MAPK) that contribute to CREB phosphorylation to different degrees.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Ashwagandha Leaf Extract and Its Component Withanone on Scopolamine-Induced Changes in the Brain and Brain-Derived Cells

et al. 2011

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BackgroundScopolamine is a well-known cholinergic antagonist that causes amnesia in human and animal models. Scopolamine-induced amnesia in rodent models has been widely used to understand the molecular, biochemical, behavioral changes, and to delineate therapeutic targets of memory impairment. Although this has been linked to the decrease in central cholinergic neuronal activity following the blockade of muscarinic receptors, the underlying molecular and cellular mechanism(s) particularly the effect on neuroplasticity remains elusive. In the present study, we have investigated (i) the effects of scopolamine on the molecules involved in neuronal and glial plasticity both in vivo and in vitro and (ii) their recovery by alcoholic extract of Ashwagandha leaves (i-Extract).Methodology/Principal FindingsAs a drug model, scopolamine hydrobromide was administered intraperitoneally to mice and its effect on the brain function was determined by molecular analyses. The results showed that the scopolamine caused downregulation of the expression of BDNF and GFAP in dose and time dependent manner, and these effects were markedly attenuated in response to i-Extract treatment. Similar to our observations in animal model system, we found that the scopolamine induced cytotoxicity in IMR32 neuronal and C6 glioma cells. It was associated with downregulation of neuronal cell markers NF-H, MAP2, PSD-95, GAP-43 and glial cell marker GFAP and with upregulation of DNA damage- γH2AX and oxidative stress- ROS markers. Furthermore, these molecules showed recovery when cells were treated with i-Extract or its purified component, withanone.ConclusionOur study suggested that besides cholinergic blockade, scopolamine-induced memory loss may be associated with oxidative stress and Ashwagandha i-Extract, and withanone may serve as potential preventive and therapeutic agents for neurodegenerative disorders and hence warrant further molecular analyses.

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Section: Discussionmentioning

confidence: 99%

Protective Role of Ashwagandha Leaf Extract and Its Component Withanone on Scopolamine-Induced Changes in the Brain and Brain-Derived Cells

et al. 2011

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“…Standards 1 , 3 and 8 were purchased from Chromadex, while other compounds were obtained from the compound bank of the Dr. Panjwani Center for Molecular Medicine and Drug Research (International Centre for Chemical and Biological Sciences), University of Karachi. The isolation procedures and characterization of these withanolides have already been reported 8–14…”

Section: Methodsmentioning

confidence: 99%

“…The isolation procedures and characterization of these withanolides have already been reported. [8][9][10][11][12][13][14]…”

Section: Experimental Chemicals and Reagentsmentioning

confidence: 99%

Analysis and development of structure‐fragmentation relationships in withanolides using an electrospray ionization quadropole time‐of‐flight tandem mass spectrometry hybrid instrument

Musharraf

Ali

et al. 2010

Rapid Comm Mass Spectrometry

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Structural elucidation and gas-phase fragmentation of ten withanolides (steroidal lactones) were studied using a positive ion electrospray ionization quadropole time-of-flight mass spectrometry (ESI-QqTOF-MS/MS) hybrid instrument. Withanolides form an important class of plant secondary metabolites, known to possess a variety of biological activities. Withanolides which possess hydroxyl groups at C-4, C-5, C-17, C-20, and C-27, and an epoxy group at C-5/C-6, were evaluated to determine the characteristic fragments and their possible pathways. ESI-QqTOF-MS (positive ion mode) showed the presence of the protonated molecules [M + H](+) . Low-energy collision-induced dissociation tandem mass spectrometric (CID-MS/MS) analysis of the protonated molecule [M + H](+) indicated multiple losses of water and the removal of the C-17-substituted lactone moiety affording the [M + H-Lac](+) product ion as the predominant pathways. However, withanolides containing a hydroxyl group at C-24 of the lactone moiety showed a different fragmentation pathway, which include the loss of steroidal part as a neutral molecule, with highly diagnostic ions at m/z 95 and 67 being generated from the cleavage of lactone moiety. Our results also determined the influence of the presence and positions of hydroxyl and epoxy groups on product ion formation and stability. Moreover, the knowledge of the fragmentation pattern was utilized in rapid identification of withanolides by the LC/MS/MS analysis of a Withania somnifera extract.

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“…Several studies have underlined marked AChE inhibitory activity of the withanolide derivatives. For instance; two new 6a,7a-epoxy-3b,5a,20b-trihydroxy-1-oxowitha-24-enolide (1) and 5b,6b-epoxy-4b,17a,27-trihydroxy-1-oxowitha-2,24-dienolide (2) and four known withanolides withaferin A (3) , 2,3-dihydrowithaferin-A (4) , 6a,7a-epoxy-5a,20b-dihydroxy-1-oxowitha-2,24-dienolide (5) , and 5b,6b-epoxy-4b-hydroxy-1-oxowitha-2,14,24-trienolide (6) isolated from the methanol extract of W. somnifera collected in Karachi (Pakistan) were tested for their possible AChE inhibitory effect and only four of the compounds, whose IC 50 values varied between 50±2.0 and 161.5±1.1 µM, were found to display moderate level of inhibition towards AChE as compared to galanthamine (IC 50 = 0.50±0.001 µM) employed as the reference [30]. Among them, withaferin A (3) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Nature: A Substantial Source of Auspicious Substances with Acetylcholinesterase Inhibitory Action

Orhan

2013

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Acetylcholinesterase (AChE) (EC 3.1.1.7) is an important enzyme that breaks down of acetylcholine in synaptic cleft in neuronal junctions. Inhibition of AChE is associated with treatment of several diseases such as Alzheimer’s disease (AD), myasthenia gravis, and glaucoma as well as the mechanisms of insecticide and anthelmintic drugs. Several AChE inhibitors are available in clinical use currently for the treatment of AD; however, none of them has ability, yet, to seize progress of the disease. Consequently, an extensive research has been going on finding new AChE inhibitors. In this sense, natural inhibitors have gained great attention due to their encouraging effects toward AChE. In this review, promising candidate molecules with marked AChE inhibition from both plant and animal sources will be underlined.

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Cholinesterase Inhibiting Withanolides from Withania somnifera

Cited by 101 publications

References 23 publications

Protective Role of Ashwagandha Leaf Extract and Its Component Withanone on Scopolamine-Induced Changes in the Brain and Brain-Derived Cells

Protective Role of Ashwagandha Leaf Extract and Its Component Withanone on Scopolamine-Induced Changes in the Brain and Brain-Derived Cells

Analysis and development of structure‐fragmentation relationships in withanolides using an electrospray ionization quadropole time‐of‐flight tandem mass spectrometry hybrid instrument

Nature: A Substantial Source of Auspicious Substances with Acetylcholinesterase Inhibitory Action

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