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Cited by 111Cholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatmentsMedicinal Plants and Neuroprotection

Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy

Open access
Arya, Ashwani, Chahal, Rubal, Rao, Rekha, Rahman, Md. Habibur, Kaushik, Deepak, Akhtar, Muhammad Furqan, Saleem, Ammara, Khalifa, Shaden M. A. +5 more·2021·Biomolecules
DOI 10.3390/biom11030350PMC PMC7996600
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Abstract

Alzheimer’s disease (AD) is a gradually growing irreversible illness of the brain that almost affects every fifth person (aged > 80 years) in the world. World Health Organization (WHO) also revealed that the prevalence of this disease will enhance (upto double) significantly upto 2030. The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder. Natural inhibitors of acetylcholine (ACh) such as galanthamine and rivastigmine are used commercially in the treatmentof AD. The biomolecules such assesquiterpenes, possess a great structural diversity and are responsible for a plethora of pharmacological properties. The potential of various sesquiterpenes as anticholinesterase has been reviewed in this article. For this purpose, the various databases, mainly PubMed, Scopus, and Web of Science were investigatedwith different keywords such as “sesquiterpenes+acetylcholinesterase” and “sesquiterpenes+cholinesterase+inhibitors” in the surveyed time frame (2010–2020). A vast literature was evident in the last decade, which affirms the potential of various sesquiterpenes in the improvement of cholinergic transmission by inhibiting the AChE. After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9 μM and can be considered as potential candidates for the improvement of learning and memory. Sesquiterpene is an important category of terpenoids, found to possess a large spectrum of biological activities. The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol, etc.) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review surveys sesquiterpenes and sesquiterpene-containing extracts as acetylcholinesterase (AChE) inhibitors for Alzheimer’s disease, drawing on literature from 2010–2020. It reports that 12 of 58 sesquiterpenes had AChE IC50 <9 µM and highlights amberboin and lipidiol as promising leads, while noting assay and safety caveats.

Key findings

  • Across 58 sesquiterpenes reviewed, 12 had AChE IC50 <9 µM and were considered potential candidates for improving learning and memory.
  • Amberboin and lipidiol from *Volutaria abyssinica* inhibited AChE with IC50 = 0.8 ± 0.03 µM and 0.5 ± 0.01 µM, respectively; amberboin also inhibited BChE (IC50 = 0.6 ± 0.13 µM), compared with galanthamine (AChE IC50 = 3 ± 0.2 µM; BChE IC50 = 47 ± 1 µM).
  • Volvalerenic acid K had in vitro AChE IC50 = 0.16 µM and improved learning/memory in APPswe/PS1E9 mice; Huperzine-A showed reversible AChE inhibition (IC50 = 22 µM) and is described as the only sesquiterpene alkaloid clinically established and USFDA-approved for AD.
  • Sesquiterpenes were also linked to alternate AD targets: Stigmene A and B reduced Aβ aggregation by 82.9 ± 2.52% and 70.1 ± 3.01% vs 69.8 ± 1.55% for positive control; bilobalide antagonized GABA_A receptors (IC50 = 4.6 ± 0.5 µM); nootkatone and ambrosin reduced NF-κβp65 expression.

Methods

  • Narrative review; PubMed, Scopus, and Web of Science were searched with keywords “sesquiterpenes+acetylcholinesterase” and “sesquiterpenes+cholinesterase+inhibitors” for 2010–2020.
  • Synthesized studies on sesquiterpenoids, sesquiterpene lactones, coumarins, agarofuran, and alkaloids; AChE inhibition was commonly assessed by Ellman’s method, with some docking and in vivo mouse studies.
  • Qualitative synthesis; the paper reports counting 58 sesquiterpenes and identifying 12 with IC50 <9 µM.

Limitations

  • Stated: IC50 alone should not determine anti-Alzheimer potential; Ellman assays with carbonyl-containing compounds can produce false positives; most plant actives were not evaluated for unwanted side effects; animal-model and clinical confirmation are needed; galliardin has cytotoxic properties.
  • Evident: as a narrative review, it lacks a formal systematic protocol, explicit inclusion/exclusion criteria, risk-of-bias assessment, or meta-analysis; evidence is heterogeneous (in vitro IC50 values, essential-oil mixtures, docking, and mouse models) and IC50 units vary (µM, µg/mL, mg/mL).
  • Evident: many compounds are discussed without blood-brain barrier permeability, bioavailability, or toxicity data, though the paper notes lipophilicity may aid bioavailability and calls for toxicological profiling.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/biom11030350

Cites

164 of 164 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 141 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Monodora myristica and Piper nigrum seed oils showed significant AChE and BChE inhibitory activity (p < 0.05) in a dose-dependent manner at 416 μg/mL.

    “Both the oils showed significant AChE and BChE inhibitory activity (p < 0.05) in a dose-dependent manner at the concentration of 416 µg/mL.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Olawuni, 2018, In vitro anti-cholinesterase and cognitive enhancing properties of essential oils from Piper nigrum L. and Monodora myristica (Gaertn) dunal, Int.J. Pharmacol. Toxicol. source

      Not checked in the free run.

  • Findingcitation

    Salvia chionantha extract exhibited 63 ± 0.8% activity only against BChE at 500 μg/mL.

    “In contrast, the extract exhibited 63 ± 0.8% activity only against BChE at the concentration of 500 μg/mL.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Tel, 2010, Chemical composition of the essential oil and hexane extract of Salvia chionantha and their antioxidant and anticholinesterase activities, Food Chem. Toxicol. source

      Not checked in the free run.

  • Findingcitation

    Amberboin also inhibited BChE with IC50 = 0.6 ± 0.13 μM.

    “Further, amberboin also inhibited the BChE at IC50 of 0.6 ± 0.13 µM.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Elsebaia, 2018, Amberboin and lipidiol: X-ray crystalographic data, absolute configuration and inhibition of cholinesterase, Phytochem. Lett. source

      Not checked in the free run.

  • Findingcitation

    Petroleum ether fraction of Sphaeranthus indicus was loaded with sesquiterpene lactones (about 80%), accounting for its anti-AChE activity.

    “Petroleum ether fraction was found to be loaded with SLs (about 80%), accounting for its anti-AChE activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Patel, M.B., and Amin, D. (2012). Sphaeranthus indicus flower derived constituents exhibits synergistic effect against acetylcholinesterase and possess potential antiamnestic activity. J. Complement. Integr. Med., 9. source

      Not checked in the free run.

  • Findingcitation

    Volatile oil from Plectranthus aegyptiacus leaves exhibited AChE inhibitory activity with IC50 = 8 ± 0.6 mg/mL.

    “The oil was observed to exhibit AChE inhibitory activity with an IC50 = 8 ± 0.6 mg/mL, which can be helpful in the treatment of AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Christianah, 2018, Acetylcholinesterase inhibitory effect and characterization of the essential oil of Plectranthusa egyptiacus (Forssk.) C. Chr. growing in Nigeria, Med. Aromat. Plants

      Not checked in the free run.

    • Rests on an assumption: In vitro AChE inhibition by a sesquiterpene is sufficient to indicate potential for treating AD or improving learning and memory.
  • May combine two claims. 62
  • Classified as probably not a substantial claim. 22
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The review's analysis found that 12 compounds out of 58 reviewed sesquiterpenes had IC50 < 9 μM and can be considered potential candidates for improving learning and memory.

    “After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9 μM and can be considered as potential candidates for the improvement of learning and memory.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: An IC50 below 9 μM is an appropriate threshold for considering a sesquiterpene a potential candidate for improving learning and memory.
    • Rests on an assumption: In vitro AChE inhibition by a sesquiterpene is sufficient to indicate potential for treating AD or improving learning and memory.

  • May combine two claims.

    Findingcitation

    Gynura bicolor leaf oil inhibited AChE with IC50 = 85 μg/mL and stem oil with IC50 = 92 μg/mL; leaf oil is a stronger inhibitor than stem oil.

    “The leaf oil inhibited the AChE with IC50 = 85 µg/mL), On the other hand, stem oil showed the same inhibition with IC50 = 92 μg/mL. It indicated the leaf oil as a stronger inhibitor of AChE activity than the stem oil.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Miyazawa, 2016, Chemical composition, aroma evaluation, and inhibitory activity towards acetylcholinesterase of essential oils from Gynura bicolor DC, J. Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Amberboin and lipidiol are better inhibitors of AChE and BChE than galanthamine (IC50 = 3 ± 0.2 μM for AChE and 47 ± 1 μM for BChE).

    “The results clearly stated that the two isolated sesquiterpene lactones are the better inhibitors of AChE and BChEas compared to the reference, galanthamine (IC50 = 3 ± 0.2 μM and 47 ± 1 μM for AChE and BChE, respectively).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Elsebaia, 2018, Amberboin and lipidiol: X-ray crystalographic data, absolute configuration and inhibition of cholinesterase, Phytochem. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    For Acorus calamus rhizomes, IC50 values for alcoholic extract, essential oil, β-asarone, and α-asarone were 182 ± 17 μg/mL, 11 ± 0.8 μg/mL, 3 ± 0.02 μM, and 46 ± 3 μM, respectively.

    “The IC50 values for alcoholic extract, essential oil, and two chief constituents of oil, i.e., β-asarone (11) and α-asarone (12) were reported as 182 ± 17 μg/mL, 11 ± 0.8 μg/mL, 3 ± 0.02 μM, and 46 ± 3 μM, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Mukherjee, 2007, In vitro acetylcholinesterase inhibitory activity of the essential oil from Acorus calamus and its main constituents, Planta Medica source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Four sesquiterpene lactones from Amberboa ramosa had AChE IC50 values: Amberin 17 ± 0.01, Amberbin-A 9 ± 0.2, Amberbin-B 0.9 ± 0.02, and Amberbin-C 1 ± 0.08 μM.

    “Their IC50 (μM) for AChE inhibition was reported as 17 ± 0.01, 9 ± 0.2, 0.9 ± 0.02 and 1 ± 0.08 for sesquiterpene lactones Amberin (37), Amberbin-A (38), Amberbin-B (39), and Amberbin-C (40), respectively”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Ibrahim, 2013, Acetyl and butyryl cholinesterase inhibitory sesquiterpene lactones from Amberboaramosa, Chem. Cent. J. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The dihydro derivative of turmerone from Peltophorum dasyrachis oil is the most potent AChE inhibitor with IC50 = 82 ± 0.2 μM, followed by volatile oil with IC50 = 83 ± 3 μg/mL.

    “Di hydro derivative of turmerone is most potent with IC50 at 82 ± 0.2 μM, followed by volatile oil (IC50 = 83 ± 3 μg/mL).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Fujiwara, 2010, Acetylcholinesterase inhibitory activity of volatile oil from Peltophorum dasyrachis Kurz ex Bakar (yellow batai) and bisabolane-type sesquiterpenoids, J. Agric. Food Chem. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Artemisinin and chrysosplenetin from Artemisia annua inhibited AChE by 72% and 80% at 0.1 mg/mL with IC50 of 104 μM and 73 μM, respectively.

    “The crude extract with artemisinin and chrysosplenetin showed the inhibition of AChE activity by 72% and 80% at 0.1 mg/mL with IC50 of 104 µM and 73 µM.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Duan, 2001, Immunosuppressive sesquiterpene alkaloids from Tripterygium wilfordii, J. Nat. Prod. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    M. myristica oil inhibited AChE and BChE with IC50 205 ± 0.06 μg/mL and 178 ± 0.02 μg/mL, with 79% and 89% inhibition, respectively.

    “M. myristica elicited stronger inhibition for AChE and BChE with IC50 of 205 ± 0.06 µg/mL and 178 ± 0.02 µg/mL with 79% and 89% inhibition”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Olawuni, 2018, In vitro anti-cholinesterase and cognitive enhancing properties of essential oils from Piper nigrum L. and Monodora myristica (Gaertn) dunal, Int.J. Pharmacol. Toxicol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Long-term exposure to chloroform extract of Alpinia oxyphylla fruits improved cognitive abilities, increased GSH-px, decreased AChE, MDA, and Aβ, and overturned microglia activation, neuronal acidophilia degeneration, and cortex and hippocampus nuclear condensation.

    “Long term exposure to chloroform extract improved the cognitive abilities while performing the behavioral tasks, increased the glutathione peroxidase (GSH-px) activities, decreased the acetylcholinesterase (AChE), malondialdehyde level (MDA), and β-amyloid (Aβ), and ultimately overturned the microglia activation, neuronal acidophilia degeneration, and cortex and hippocampus nuclear condensation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Shi, S.H., Zhao, X., Liu, B., Li, H., Liu, A.J., Wu, B., Bi, K.S., and Jia, Y. (2014). The effects of sesquiterpenes-rich extract of Alpinia oxyphylla Miq. on amyloid-𝛽-induced cognitive impairment and neuronal abnormalities in the cortex and hippocampus of mice. Oxidative Med. Cell. Longev. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Petroleum ether fraction of Sphaeranthus indicus had AChE inhibitory potential with IC50 of 37 mg/mL, and extract at 10 mg/kg per orally in mice considerably inverted cognitive damages caused through the passive avoidance test (p < 0.05).

    “It was observed that petroleum ether fraction was the only portion with AChE inhibitory potential with an IC50 of 37 mg/mL and the extract at a dose of 10 mg/kg, per orally. in mice considerably inverted the cognitive damages caused through the passive avoidance test (p < 0.05).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Patel, M.B., and Amin, D. (2012). Sphaeranthus indicus flower derived constituents exhibits synergistic effect against acetylcholinesterase and possess potential antiamnestic activity. J. Complement. Integr. Med., 9. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Salvia chionantha essential oil showed moderate AChE and BChE activity, 57 ± 2% and 41 ± 9%, respectively.

    “Similarly, the greenish-yellow color essential oil from the Salvia chionantha moderate AChE and BChE activity, i.e., 57 ± 2% and 41 ± 9%, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Tel, 2010, Chemical composition of the essential oil and hexane extract of Salvia chionantha and their antioxidant and anticholinesterase activities, Food Chem. Toxicol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    P. nigrum oil inhibited AChE (75%) and BChE (85%) with IC50 = 0.3 ± 0.02 μg/mL and 223 ± 0.002 μg/mL, respectively.

    “whereas the P. nigrum oil inhibited the AChE (75%) and BChE (85%) with IC50 = 0.3 ± 0.02 µg/mL and 223 ± 0.002 µg/mL, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Olawuni, 2018, In vitro anti-cholinesterase and cognitive enhancing properties of essential oils from Piper nigrum L. and Monodora myristica (Gaertn) dunal, Int.J. Pharmacol. Toxicol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Turmerone is a competitive inhibitor of AChE, whereas its dihydro derivative is a non-competitive inhibitor.

    “Moreover, the Turmerone was analyzed to be a competitive inhibitor of AChE, whereas the dihydro derivative is the non-competitive inhibitor of this enzyme.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Fujiwara, 2010, Acetylcholinesterase inhibitory activity of volatile oil from Peltophorum dasyrachis Kurz ex Bakar (yellow batai) and bisabolane-type sesquiterpenoids, J. Agric. Food Chem. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Amberboin and lipidiol from Volutaria abyssinica inhibited AChE with IC50 = 0.8 ± 0.03 μM and 0.5 ± 0.01 μM, respectively.

    “Docking study of both compounds confirms the affinity of them towards the active sites of AChE, which indicated inhibitory activity against AChE at IC50 = 0.8 ± 0.03 µM and 0.5 ± 0.01 µM, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Elsebaia, 2018, Amberboin and lipidiol: X-ray crystalographic data, absolute configuration and inhibition of cholinesterase, Phytochem. Lett. source

      Not checked in the free run.

    • Rests on an assumption: Molecular docking scores predict binding affinity and AChE inhibitory activity.

  • May combine two claims.

    Findingcitation

    Three eremophilane sesquiterpenes from Aquilaria sinensis inhibited AChE: compound 5 had IC50 = 275 ± 5 μM, compound 6 had IC50 = 491 ± 4 μM, and neopetasane had IC50 = 158 ± 4 μM.

    “Isolated compounds were found out to be 7-β-H-9-(10)-ene-11,12-epoxy-8-oxoeremophilane (5) (48 ± 2% inhibition at 50 mg/mL with IC50 = 275 ± 5 µM); 7α-H-9(10)-ene-11,12-epoxy-8-oxoeremophilane (6) with 31 ± 1% inhibition at 50 mg/mL with IC50 = 491 ± 4 µM); neopetasane (7) (62 ± 1% inhibition at 50 mg/mL with IC50 = 158 ± 4 µM).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Yang, 2014, Fragrant agarofuran and eremophilane sesquiterpenes in agarwood ‘Qi-Nan’ from Aquilaria sinensis, Phytochem. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Essential oil from Myrciaria floribunda exhibited AChE inhibitory potential with IC50 = 0.08 μg/mL, attributed to higher binding affinity of δ-cadinene and γ-cadinene with docking scores -7.35 and -6.77.

    “The oil exhibited the AChE inhibitory potential with IC50 = 0.08 μg/mL, and this activity is attributed to the higher binding affinity of δ-cadinene and γ-cadinene (oil constituents) toward AChE as predicted by the docking score of –7.35 and –6.77, respectively [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Holanda, 2020, Chemical composition and acetylcholinesterase inhibitory potential, in silico, of Myrciaria floribunda (H. West ex Willd.) O. Berg fruit peel essential oil, Ind. Crops Prod. source

      Not checked in the free run.

    • Rests on an assumption: Molecular docking scores predict binding affinity and AChE inhibitory activity.

  • May combine two claims.

    Findingcitation

    Umbelliprenin and feselol from Heptaptera cilicica inhibited AChE with IC50 = 6 ± 0.03 μM and 1 ± 0.01 μM, respectively, and BChE with IC50 = 10 ± 0.24 μM and 1 ± 0.19 μM, respectively.

    “The compounds showed potential inhibitory activity against AChE (IC50 = 6 ± 0.03 μM and 1 ± 0.01 μM, respectively) and BChE (IC50 = 10 ± 0.24μM and 1 ± 0.19 μM, respectively) and established the plant as an emerging source in AD treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Guvenalp, 2017, Cholinesterase inhibition and molecular docking studies of sesquiterpene coumarin ethers from Heptapteracilicica, Rec. Nat. Prod. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Valenc-1(10),3(4),11,(12)-trien-2-one from Juniperus chinensis exhibited butyrylcholinesterase inhibition with IC50 = 68 μM, compared with berberine IC50 = 19 μM.

    “This compound exhibited significant butyrylcholinesterase activity with the IC50 = 68 μM when compared to the positive control, berberine (IC50 = 19 μM)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Jung, 2017, Sesquiterpenoids from the heartwood of Juniperus chinensis, Nat. Prod. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In APPswe/PS1E9 double-transgenic mice, middle and high dose groups of Volvalerenic acid K had improved AChT activity in brain tissues and significantly decreased AChE activity, causing increased learning memory.

    “The results of the study showed that, in mice (APPswe/PS1E9 double-transgenic mouse) from middle and high dose groups, the AChT (acetylcholine transferase) activity had been improved in the brain tissues, while the AChE activity was significantly decreased causing an increase in the learning memory.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Chen, 2016, Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo, Fitoterapia source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Volvalerenic acid K from Valeriana officinalis var. latifolia improved learning and memory abilities of mice, with in vitro IC50 = 0.16 μM.

    “It was observed that the Volvalerenic acid K (8) improved the learning and memory abilities of mice, with IC50 = 0.16 µM in vitro.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Chen, 2016, Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo, Fitoterapia source

      Not checked in the free run.

    • Rests on an assumption: In vitro AChE inhibition by a sesquiterpene is sufficient to indicate potential for treating AD or improving learning and memory.

  • May combine two claims.

    Findingcitation

    (E)-β-caryophyllene (31%) and bicycle germacrene (8%) are major sesquiterpenoids in Gynura bicolor leaf oil.

    “GC–MS analysis confirmed the presence of (E)-β-caryophyllene (31%) and bicycle germacrene (8%) as the major sesquiterpenoids from the Gynura bicolor DC leaves oil.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Miyazawa, 2016, Chemical composition, aroma evaluation, and inhibitory activity towards acetylcholinesterase of essential oils from Gynura bicolor DC, J. Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Pterosinone from Pteridium aquilinum has mild inhibitory activity against acetylcholinesterase and butyrylcholinesterase with IC50 = 88 μM and 73 μM, respectively.

    “Pterosinone was reported to have mild inhibitory activity against acetyl and butyl cholinesterase enzymes with IC50 = 88 μM and 73 μM, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Choi, 2018, (−)-Pteroside N and pterosinone, new BACE1 and cholinesterase inhibitors from Pteridium aquilinum, Phytochem. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    AChE inhibition can help maintain normal ACh-mediated neurotransmission in a healthy brain and could prevent the occurrence or slow the progression of AD.

    “AChE inhibition can help in maintaining the normal neurotransmission mediated by ACh in a healthy brain and could prevent the occurrence or slow down the progression of AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Poor cholinergic transmission at the synapse is one of the main reasons behind the progression and occurrence of AD.

    “The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Reduction in substrate concentration (AChE) by cholinesterase inhibitors may affect Aβ plaque formation and justify the use of ChEi as multi-target therapy for AD.

    “Moreover, the reduction in substrate concentration (AChE) by these inhibitors may affect the Aβ plaque formation and thus justify the use of ChEi as multi-target therapy for AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Various sesquiterpene lactones seem to be promising AChE inhibitors and helpful in improving the equilibrium between excitatory and inhibitory neuronal potential, and thus can be used in possible management of AD.

    “In the light of the above-cited examples, various SLs (Figure 3) seem to be promising acetylcholinesterase inhibitors and helpful in improving the equilibrium between the excitatory and inhibitory potential of neurons and thus can be used in the possible management of AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In vitro AChE inhibition by a sesquiterpene is sufficient to indicate potential for treating AD or improving learning and memory.

  • May combine two claims.

    Premisecitation

    Ferula communis population from Sardinia has two chemotypes: one contained prenylated 4-hydroxycoumarins that are toxic, while the second demonstrated therapeutic activity due to sesquiterpene coumarin ethers.

    “One of the chemotypes contained prenylated 4-hydroxycoumarins, which are toxic while the second one demonstrated therapeutic activity because of the presence of the SC ethers [127,128].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [127] Iranshahi, 2009, Sesquiterpene coumarins from the fruits of Ferulabadrakema, Pharm. Biol. source

      Not checked in the free run.

    • cites [128] Guangzhi, 2015, Two new sesquiterpene coumarins from the seeds of Ferulasinkiangensis, Phytochem. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Alpinia oxyphylla ameliorates learning and memory deficits by attenuating oxidative stress, regulating microglia activation, and neuronal acidophilia degeneration to reinforce cholinergic functions.

    “It was concluded that the Alpinia oxyphylla ameliorates the learning and memory deficits by attenuating the oxidative stress, regulating the activation of the microglia, and degeneration of the neuronal acidophilia to reinforce the cholinergic functions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Shi, S.H., Zhao, X., Liu, B., Li, H., Liu, A.J., Wu, B., Bi, K.S., and Jia, Y. (2014). The effects of sesquiterpenes-rich extract of Alpinia oxyphylla Miq. on amyloid-𝛽-induced cognitive impairment and neuronal abnormalities in the cortex and hippocampus of mice. Oxidative Med. Cell. Longev. source

      Not checked in the free run.

    • Rests on an assumption: In vitro AChE inhibition by a sesquiterpene is sufficient to indicate potential for treating AD or improving learning and memory.

  • May combine two claims.

    Premisecitation

    During late stages of AD, AChE concentration decreases significantly (up to 45%) and BuChE is enhanced (up to 40-90%).

    “However, during the late stages of AD, the concentration of AChE decreases significantly (upto 45%) and BuChE is enhanced (upto 40–90%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Arendt, 1992, Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease resemble embryonic development—A study of molecular forms, Neurochem. Int. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Essential oils containing sesquiterpenoids are more effective inhibitors of AChE than oils containing monoterpenoids, and mixtures dominated by monoterpenoids show weaker inhibition than mixtures dominated by sesquiterpenoids.

    “The essential oils containing sesquiterpenoids in comparison to the oils containing monoterpenoids were found to be more effective inhibitors of AChE activity, and the same is the case of mixtures where it ruled by monoterpenoids showed weaker inhibition than the mixture dominated by sesquiterpenoids.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ACh temporarily sequesters to the PAS through π-cation interaction between tryptophan on the enzyme surface and the quaternary amine of ACh.

    “The ACh temporarily sequesters to the PAS through π-cation interaction between tryptophan on enzyme surface and quaternary amine of ACh.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Dvir, 2010, Acetylcholinesterase: From 3D structure to function, Chem. Biol. Interact. source

      Not checked in the free run.

    • cites [28] Li, 2016, Implications of GABAergic neurotransmission in Alzheimer’s disease, Front. Aging Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stigmene A and Stigmene B isolated from Stigma maydis waste are macrocarpene type sesquiterpenes.

    “Qi et al. [138] investigated the waste produced of Stigma maydis (maize) industry and isolated macrocarpene type sesquiterpenes compounds, namely Stigmene A and Stigmene B”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Qi, 2018, Sesquiterpenes from stigma maydis (Zea mays) as a crop by-product & their potential neuroprotection and inhibitory activities of Aβ aggregation, Ind. Crops Prod. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Compounds 52-57 isolated from aerial parts of Maytenus disticha and seeds of Maytenus boaria exhibited AChE inhibitory activity with IC50 values of 0.1-0.4 mg/mL.

    “The compounds and their AChE inhibitory potential of (IC50 in mg/mL) were found to be, 1-α,2-α,6,8α-tetraacetoxy-9-benzoyloxy-15-hydroxy agarofuran (52) (0.1 ± 0.01)”
    • Also stated in: § 2.3. Miscellaneous Sesquiterpenes · plain
      “1-α-acetoxy-6-β, 9-β-difuroyloxy-4-β-hydroxy- β-agarofuran (56) (0.4 ± 0.04), and 6-β,8-α-diacetoxy-9-β-furoyloxy-1-α-hydroxy-β-agarofuran(57) (0.3 ± 0.02).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Astudillo, 2008, Inhibition of acetylcholinesterase activity by dihydro-β-agarofuran sesquiterpenes isolated from Chilean Celastraceae, Zeitschriftfür Naturforschung

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A tetrahedral intermediate forms at CAS by reaction between the oxygen atom of the acetyl group of ACh and the serine-histidine-glutamate residue of the enzyme through a covalent bond.

    “Later, a tetrahedral intermediate forms at CAS (at the deeper gorge of enzyme) by a reaction between the oxygen atom of the acetyl group of ACh and serine–histidine–glutamate residue of the enzyme through a covalent bond (Figure 1) [27,28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Dvir, 2010, Acetylcholinesterase: From 3D structure to function, Chem. Biol. Interact. source

      Not checked in the free run.

    • cites [28] Li, 2016, Implications of GABAergic neurotransmission in Alzheimer’s disease, Front. Aging Neurosci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Farnesol, caryophyllene, and α-humulene significantly alter intracellular signaling parameters of inflammation.

    “Moreover, the active constituents of different essential oils such as farnesol, caryophyllene, and α-humulene significantly alter the various intracellular signaling parameters of inflammation [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Andrade, 2015, Sesquiterpenes from essential oils and anti-inflammatory activity, Nat. Prod. Commun.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Halting expression of NF-κβp65 could reduce production of β-amyloid (Aβ), resulting in enhancement of cholinergic transmission at synapse.

    “Halting the expression of this factor could reduce the production of β-amyloid (Aβ), which results in enhancement of cholinergic transmission at the synapse.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Khalil, M.N., Choucry, M.A., El Senousy, A.S., Hassan, A., El-Marasy, S.A., El Awdan, S.A., and Omar, F.A. (2019). Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin. PLoS ONE, 14. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    AChE mainly has two active sites, the peripheral anionic site (PAS) and the catalytic active site (CAS), for binding acetylcholine.

    “The enzyme mainly has two active sites, peripheral anionic site (PAS) and catalytic active site (CAS), for the binding of substrate, i.e., acetylcholine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Huperzine-A can enhance cognitive abilities and task switching functions rapidly in people suffering from AD.

    “and can enhance cognitive abilities and task switching functions rapidly in people suffering from AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Gul, 2019, Huperzine: A response to cognitive impairment and task switching deficits in patients with Alzheimer’s disease, J. Chin. Med. Assoc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The potency of bilobalide decreases with increasing GABA concentrations, indicating competitive antagonism.

    “The potency level of bilobalide decreased with increasing GABA concentrations indicating a module of competitive antagonism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Huanga, 2003, Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2Ƴ2L GABAA receptors, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Nootkatone might play a role as a potent therapeutic agent in treating AD and neuroinflammation via improvement in cholinergic transmission, clearing amyloid-β-peptide, and reducing oxidative stress.

    “This study indicated that the compound, nootkatone, might play a role as a potent therapeutic agent in treating AD and neuroinflammation via improvement in cholinergic transmission, clearing amyloid-β-peptide, and reducing oxidative stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Wanga, 2018, Nootkatone, a neuroprotective agent from AlpiniaeOxyphyllae Fructus, improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer’s disease, Int. Immunopharmacol. source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of AD translate to humans.

  • May combine two claims.

    Premisecitation

    Stigmene A and Stigmene B inhibit Aβ aggregation, with percentage decrease in Aβ aggregation of 82.9 ± 2.52% and 70.1 ± 3.01%, respectively, compared with positive control 69.8 ± 1.55%.

    “It was observed that (%) decrease in Aβ aggregation was found more in the case of Stigmene A (82.9 ± 2.52%) and Stigmene B (70.1 ± 3.01%) when compared against a positive control, (69.8 ± 1.55%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Qi, 2018, Sesquiterpenes from stigma maydis (Zea mays) as a crop by-product & their potential neuroprotection and inhibitory activities of Aβ aggregation, Ind. Crops Prod. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PAS of AChE has affinity toward the Aβ peptide, and binding of this protein to the enzyme promotes amyloid fibrogenesis and converts non-amyloidogenic Aβ to amyloidogenic form.

    “PAS of AChE also reported to have an affinity toward the peptide of Aβ and the binding of this protein to enzyme promotes the amyloid fibrogenesis and converts the non-amyloidogenic form of Aβ to amyloidogenic form [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Valenzuela, 2006, Dual binding site acetylcholinesterase inhibitors: Potential new disease-modifying agents for AD, J Mol. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bilobalide has an IC50 of 4.6 ± 0.5 μM at α1β2γ2L GABA_A receptors against GABA neurotransmitter, comparable to picrotoxinin (2.4 ± 0.5 μM) and bicuculline (2.0 ± 0.1 μM).

    “The bilobalide IC50 (4.6 ± 0.5 μM) was reported as comparable to conventional antagonists of GABA receptors, picrotoxinin (2.4 ± 0.5 μM) and bicuculline (2.0 ± 0.1 μM) at α1β2γ2LGABAA receptors against GABA neurotransmitter.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Huanga, 2003, Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2Ƴ2L GABAA receptors, Eur. J. Pharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nerolidol reduces damage to biomolecules (DNA, protein, lipids) due to elevated reactive oxygen species in cells.

    “Sesquiterpene such as nerolidol was reported to reduce the damage to biomolecules (DNA, protein, lipids) due to elevated levels of reactive oxygen species in cells [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Chan, W.K., Tan, L.T.H., Chan, K.G., Lee, L.H., and Goh, B.H. (2016). Nerolidol: A sesquiterpene alcohol with multi-faceted pharmacological and biological activities. Molecules, 21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Huperzine-A shows reversible AChE inhibitory activity with IC50 = 22 μM.

    “This natural compound showed reversible AChE inhibitory activity (IC50 = 22 μM)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Gul, 2019, Huperzine: A response to cognitive impairment and task switching deficits in patients with Alzheimer’s disease, J. Chin. Med. Assoc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NF-κβp65 upregulates expression of inflammatory cytokines and genes related to oxidative stress and BACE-1, responsible for production of β-amyloid.

    “This factor upregulates the expression of inflammatory cytokines and genes related to oxidative stress and BACE-1 (B-site APP Cleaving Enzyme), responsible for the production of β-amyloid [141,142].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [141] Shi, 2016, Upstream regulators and downstream effectors of NF-κB in Alzheimer’s disease, J. Neurol. Sci. source

      Not checked in the free run.

    • cites [142] Srinivasan, 2015, Significance of NF-κB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis, Expert Opin. Ther. Targets source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bilobalide amplifies GABA levels in cerebral cortex and hippocampus of mice and enhances neuronal excitability in hippocampus through blockade of GABAergic neurotransmission, correlated with learning and memory motions.

    “Bilobalide amplified the levels of GABA in the cerebral cortex and hippocampus of mice; in addition, bilobalide also enhanced the neuronal excitability in hippocampus sites through the blockade of GABAergic neurotransmission, which is directly correlated with the learning and memory motions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Huanga, 2003, Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2Ƴ2L GABAA receptors, Eur. J. Pharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cholinesterase inhibitors such as galantamine and rivastigmine mainly bind to the peripheral site competitively and reversibly, spare ACh at the synapse, and help improve cholinergic transmission.

    “Cholinesterase inhibitors (ChEi) such as galantamine and rivastigmine mainly bind to the peripheral site in a competitive and reversible manner and spare the ACh at the synapse and thus help in the improvement of cholinergic transmission [31,32].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Heinrich, 2010, Galanthamine from galanthus and other amaryllidaceae—Chemistry and biology based on traditional use, Alkaloids Chem. Biol. source

      Not checked in the free run.

    • cites [32] Thomsen, 1990, Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo, Life Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Huang et al. investigation established Huperzine-A as a reversible, selective, potent, and finely tolerated inhibitor of acetylcholinesterase which can considerably improve memory and learning deficit in persons suffering from Alzheimer's disease.

    “Huang et al. [3] investigation about the compound provided a marked base for the establishment of this compound as a reversible, selective, potent, and finely tolerated inhibitor of acetylcholinesterase which can considerably improve the memory and learning deficit in the persons suffering from Alzheimer’s disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Huang, 2013, Natural products as sources of new lead compounds for the treatment of Alzheimer’s disease, Curr. Top. Med. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARD, HDS, and PDA showed considerable effect on oxidative stress and enhanced memory power in animals that received Aβ-42 infusion.

    “The above-stated SLs compounds showed a considerable effect on oxidative stress and enhanced the memory power in animals that received Aβ-42 infusion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Amoah, 2015, Inhibitory effect of sesquiterpene lactones and these squiterpene alcohol aromadendrane-4β, 10α-diol on memory impairment in a mouse model of Alzheimer, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    ARD, HDS, and PDA, constituents of H. brasiliense, are efficient in inhibiting cognitive deficits of animals and may be used in treating AD.

    “This study confirmed that ARD, HDS, and PDA, the constituents of H. brasiliense, are efficient in inhibiting the cognitive deficits of animals and may be used in treating AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Amoah, 2015, Inhibitory effect of sesquiterpene lactones and these squiterpene alcohol aromadendrane-4β, 10α-diol on memory impairment in a mouse model of Alzheimer, Eur. J. Pharmacol. source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of AD translate to humans.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    This could be the possible rationale for inclusion of these herbs as food supplements for AD.

    “Hence, this could be the possible rationale for the inclusion of these herbs as food supplements for AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Mancuso, 2012, Natural substances and Alzheimer’s disease: From preclinical studies to evidence based medicine, Biochimica Biophysica Acta (BBA) Mol. Basis Dis. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In recent years, treatment paradigm for AD is moving toward alleviating inflammation associated with development of this disease.

    “In recent years, the treatment paradigm for AD is moving toward alleviating the inflammation associated with the development of this disease [163,164].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Karunaweera, 2015, Plant polyphenols as inhibitors of NF-κB induced cytokine production—A potential anti-inflammatory treatment for Alzheimer’s disease?, Front. Mol. Neurosci. source

      Not checked in the free run.

    • cites [164] Carrillo, 2016, The roles of inflammation and immune mechanisms in Alzheimer’s disease, Alzheimers Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The above-cited compounds may potentially be used as moieties in building a better multi-target anti-AD drug for possible prevention and treatment of AD.

    “The above-cited compounds may potentially be used as moieties in the building of a better multi-target anti-AD drug for possible prevention and treatment of AD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In vitro AChE inhibitory activity of sesquiterpenes predicts clinical efficacy in Alzheimer's disease.
    • Rests on an assumption: Findings from animal models of AD translate to humans.

  • May combine two claims.

    Interpretationcitation

    Mere possession of significant IC50 for AChE should not be the criteria for selection of a compound for anti-Alzheimer potential because evaluation of cholinesterase inhibition potential of compounds with carbonyl group by in vitro methods such as Ellman reagent could produce false positive.

    “However, mere possession of significant IC50 (for AChE) should not be the criteria for the selection of a compound for anti-Alzheimer potential. Because the evaluation of cholinesterase inhibition potential of compounds, with carbonyl group, by in vitro methods such as Ellman reagent could produce the false positive [149].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Rhee, 2003, Qualitative determination of false-positive effects in the acetylcholinesterase assay using thin layer chromatography, Phytochem. Anal. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Extracts of Ginkgo biloba and Nardostachys jatamansi are reported to contain sesquiterpenes such as Bilabolide and Jatanolides/Jatamansone as main ingredients.

    “The extracts of these herbs are reported to contain sesquiterpenes such asBilabolide and Jatanolides/Jatamansone as main ingredients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Nowadays, paradigm for AD management has shifted toward management of neuroinflammation by novel compounds.

    “Nowadays, the paradigm for AD management has shifted toward the management of neuroinflammation by novel compounds.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    12 compounds out of total 58 sesquiterpenes were reported to possess IC50 < 9 μM and can be considered as potential candidates for improvement of learning and memory.

    “Critically analyzing the literature, it has been found that 12 compounds out of total 58 sesquiterpenes were reported to possess IC50 < 9 µM and can be considered as potential candidates for the improvement of learning and memory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Memory enhancement by Nardostachys jatamansi extract could be a result of facilitation of cholinergic transmission in the brain because the extract showed potential against scopolamine-induced impairment.

    “It was concluded that memory enhancement could be a result of the facilitation of cholinergic transmission in the brain becausethe extract showed potential against scopolamine-induced impairment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Joshi, 2006, Nardostachysjatamansi improves learning and memory in mice, J. Med. Food source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent clinical studies have shown that AChE inhibitors significantly alleviate Alzheimer's symptoms and also lessen rates of related mortality.

    “Recent clinical studies have shown that the AChE inhibitors significantly alleviate Alzheimer’s symptoms and also lessen the rates of related mortality [154].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Castells, 2017, Discontinuation, efficacy, and safety of cholinesterase inhibitors for Alzheimer’s disease: A meta-analysis and metaregression of 43 randomized clinical trials enrolling 16 106 patients, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical studies prove the neuroprotective role of Ginkgo biloba and Nardostachys jatamansi herbs due to reduction in neuronal damage by free radicals and restoration of calcium homeostasis.

    “Preclinical studies prove the neuroprotective role of these herbs due to reduction in neuronal damage by free radicals and restoration of calcium homeostasis [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Mancuso, 2012, Natural substances and Alzheimer’s disease: From preclinical studies to evidence based medicine, Biochimica Biophysica Acta (BBA) Mol. Basis Dis. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    Exploration of novel sesquiterpenes for expression of NF-κβp65 could be a target for scientists for management of neurodegenerative disorders such as AD.

    “Hence, the exploration of novel sesquiterpenes for the expression of NF-κβp65 could be a target for scientists for the management of neurodegenerative disorderssuch asAD.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Karunaweera, 2015, Plant polyphenols as inhibitors of NF-κB induced cytokine production—A potential anti-inflammatory treatment for Alzheimer’s disease?, Front. Mol. Neurosci. source

      Not checked in the free run.

    • cites [164] Carrillo, 2016, The roles of inflammation and immune mechanisms in Alzheimer’s disease, Alzheimers Dement. Transl. Res. Clin. Interv. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Jatanolides, Jatamansone, and Jatamansic acid are main sesquiterpene alkaloids isolated from Nardostachys jatamansi and are helpful in cognitive disorders as they improve learning and memory.

    “The Jatanolides, Jatamansone, and Jatamansic acid are the main sesquiterpene alkaloids isolated from the Nardostachys jatamansi, which are helpful in cognitive disorders as they improve the learning and memory supremacy of a person [145,146].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [145] Balmus, 2017, Main plant extracts’active properties effective on scopolamine-induced memory loss, Am. J. Alzheimers Dis. Dement. source

      Not checked in the free run.

    • cites [146] Joshi, 2006, Nardostachysjatamansi improves learning and memory in mice, J. Med. Food source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For proper functioning of neurons, there should be a critical balance between excitatory and inhibitory neurotransmitters.

    “Furthermore, it has been established that for the proper functioning of neurons, there should be a critical balance between the excitatory and inhibitory neurotransmitters [155,156,157,158].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [155] Kehrer, C., Maziashvili, N., Dugladze, T., and Gloveli, T. (2008). Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia. Front. Mol. Neurosci., 1. source

      Not checked in the free run.

    • cites [156] Cummings, 2009, Alterations in cortical excitation and inhibition in genetic mouse models of Huntington’s disease, J. Neurosci. source

      Not checked in the free run.

    • cites [157] Sun, 2009, Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal model of Alzheimer’s disease, Cell Stem Cell source

      Not checked in the free run.

    • cites [158] Gueli, 2013, Alzheimer’s disease: Amino acid levels and brain metabolic status, Neurol. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The extract of Nardostachys jatamansi also reversed aging-related amnesia, proving it as a beneficial memory restorative constituent in elderly individuals with dementia.

    “Furthermore, the extract also reversed the aging-related amnesia proving it as a beneficial memory restorative constituent in elderly individuals with dementia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Joshi, 2006, Nardostachysjatamansi improves learning and memory in mice, J. Med. Food source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of AD translate to humans.

  • May combine two claims.

    Premisecitation

    β-amyloid (Aβ) could enhance translation of GABAA receptor (at α6 subunit) by phosphorylation of mTOR and ERK in cerebellum of experimental mice, and hence an increase in inhibitory transmission at synapse affects learning and memory process.

    “It is evident that β-amyloid (Aβ) could also enhance the translation of GABAA receptor (at α6 subunit) by the phosphorylation of mTOR and ERK in the cerebellum of experimental mice [28,159,160], and hence an increase in inhibitory transmission at synapse affects the learning and memory process [161].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [28] Li, 2016, Implications of GABAergic neurotransmission in Alzheimer’s disease, Front. Aging Neurosci. source

      Not checked in the free run.

    • cites [159] Zhan, 2014, A β40 modulates GABAA receptor α6 subunit expression and rat cerebellar granule neuron maturation through the ERK/mTOR pathway, J. Neurochem. source

      Not checked in the free run.

    • cites [160] Schweizer, 2003, The γ2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses, Mol. Cell. Neurosci. source

      Not checked in the free run.

    • cites [161] Palop, 2007, Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease, Neuron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    Use of suggested herbs as nutraceuticals/dietary supplements could significantly alleviate symptoms of AD and prove highly beneficial for mankind.

    “Hence, it can also be concluded that the use of suggested herbs as nutraceuticals/dietary supplements could significantly alleviate the symptoms of AD and prove highly beneficial for mankind.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In vitro AChE inhibitory activity of sesquiterpenes predicts clinical efficacy in Alzheimer's disease.
    • Rests on an assumption: Findings from animal models of AD translate to humans.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pathophysiology of Alzheimer's disease includes degeneration of neurons at vulnerable spots in the brain such as hippocampus and cortex region.

    “Furthermore, the pathophysiology of Alzheimer’s disease includes the degeneration of neurons at vulnerable spots in the brain such as thehippocampus and cortex region [150,151,152].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [150] Selkoe, 1998, The cell biology of β-amyloid precursor protein and presenilin in Alzheimer’s disease, Trends Cell Biol. source

      Not checked in the free run.

    • cites [151] Hu, J., Liu, C.C., Chen, X.F., Zhang, Y.W., Xu, H., and Bu, G. (2015). Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoElipidation and Aβ metabolism in apoE4- targeted replacement mice. Mol. Neurodegener., 10. source

      Not checked in the free run.

    • cites [152] Stancu, I.C., Vasconcelos, B., Terwel, D., and Dewachter, I. (2014). Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism. Mol. Neurodegener., 9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ application increases concentration of AChE in cultures, and simultaneous feeding of experimental animals with farnesene significantly reduces the enzyme concentration.

    “Moreover, the Aβ application also increases the concentration of AChE in cultures and the simultaneous feeding of experimental animals with farnesene (a sesquiterpene) significantly reduces the enzyme concentration [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Mehmet, E.A., Hasan, T., and Adil, M. (2020). In vitro neuroprotective effects of farnesene sesquiterpene on Alzheimer’s disease model of differentiated neuroblastoma cell line. Int. J. Neurosci., 1–10.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The described sesquiterpenes are supposed to act as novel compounds for researchers willing to find alternatives for possible treatment of neurodegenerative diseases, i.e., Alzheimer's disease.

    “The described sesquiterpenes are supposed to act as novel compounds for the researchers willing to find some other alternatives than the existing ones for the possible treatment of neurodegenerative diseases, i.e., Alzheimer’s disease.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In vitro AChE inhibitory activity of sesquiterpenes predicts clinical efficacy in Alzheimer's disease.
    • Rests on an assumption: Findings from animal models of AD translate to humans.

  • May combine two claims.

    Interpretationcitation

    Sesquiterpenes such as Farnesene, Bilabolide, and Jatamansone were found to exert significant effect on different AD targets such as Aβ plaque, neuron excitability, and oxidative stress.

    “Moreover, the sesquiterpenes such as Farnesene, Bilabolide, and Jatamansone were found to exert a significant effect on different AD targets such as Aβ plaque, neuron excitability, and oxidative stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ethanolic extract of Nardostachys jatamansi significantly improves learning and memory in mice at 200 mg/kg and reverses scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) induced amnesia.

    “Joshi and Parle [146] studied the ethanolic extract of Nardostachys jatmansi in mice to evaluate its memory enhancing property and found it capable of significantly improving the learning and memory at a dose of 200 mg/kg and also reversed the scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) induced amnesia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Joshi, 2006, Nardostachysjatamansi improves learning and memory in mice, J. Med. Food source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Large number of formulations having extracts of Ginkgo biloba and Nardostachys jatamansi are mentioned in Table 2 and mainly prescribed as a nutraceutical for delaying symptoms (such as amnesia) of AD.

    “In addition, the large number of formulations having extracts of Ginkgo biloba and Nardostachys jatamansi are mentioned in Table 2 and mainly prescribed as a nutraceutical for delaying symptoms (such as amnesia) of AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Galliardin, a guainolide-type sesquiterpene, possesses good AChE inhibitory potential but also has significant cytotoxic properties.

    “Furthermore, the Galliardin, a guainolide-type sesquiterpene, possesses good AChE inhibitory potential, but it also has significant cytotoxic properties [123].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Hajimehdipoor, 2014, Natural sesquiterpene lactones as acetylcholinesterase inhibitors, Anais da Academia Brasileira de Ciências source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    In spite of availability of bulk knowledge related to AD, we have access only to symptomatic treatment, not to a complete cure.

    “In spite of the availability of bulk knowledge related to this progressive disorder, we have access only to symptomatic treatment, not to a complete cure.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    To be a potential candidate for Alzheimer's therapy, a compound must pass the blood-brain barrier (BBB) and should be sufficiently bioavailable in the affected area of the brain.

    “Hence, to be a potential candidate for Alzheimer’s therapy, a compound must pass the blood-brain barrier (BBB) and should be sufficiently bioavailable in the affected area of the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Bilabolide could help in achieving equilibrium of excitatory and inhibitory transmission because it was reported as an antagonist to α1β2γ21 subunits of GABAA receptors that enhanced excitability of neurons in hippocampal slices.

    “Sesquiterpenes such asBilabolide could help in achieving the equilibrium of excitatory and inhibitory transmission because it was reported as an antagonist to α1β2γ21 subunits of GABAA receptors that enhanced the excitability of neurons in hippocampal slices [139].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Huanga, 2003, Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2Ƴ2L GABAA receptors, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Huperzine A is the only sesquiterpene alkaloid clinically established as an AChE inhibitor and received USFDA approval to manage AD.

    “Moreover, Huperzine A is the only sesquiterpene alkaloid that is clinically established as an AChE inhibitor and receivedthe approval of USFDA to manage AD.”
    Quote in the paperNot a substantial claim
78 of 78

  • The paper relies on this without support.

    An IC50 below 9 μM is an appropriate threshold for considering a sesquiterpene a potential candidate for improving learning and memory.

    “After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9 μM and can be considered as potential candidates for the improvement of learning and memory.”

  • The paper relies on this without support.

    In vitro AChE inhibition by a sesquiterpene is sufficient to indicate potential for treating AD or improving learning and memory.

    “The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol, etc.) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.”

  • The paper relies on this without support.

    Molecular docking scores predict binding affinity and AChE inhibitory activity.

    “Docking study of both compounds confirms the affinity of them towards the active sites of AChE, which indicated inhibitory activity against AChE at IC50 = 0.8 ± 0.03 µM and 0.5 ± 0.01 µM, respectively.”

  • The authors state this as an assumption.

    AChE lyses acetylcholine at a very fast rate, up to 10,000 molecules per second.

    “AChE is assumed to lyse the acetylcholine at a very fast rate (up to 10,000 molecules per second).”

  • The paper relies on this without support.

    Structural features such as double bonds at C1–10, C3–4, and C11–12 with a ketone group at C2 increase AChE inhibitory activity.

    “this property might be attributed to its structural configuration where two double bonds at C1–10 and C3–4 and C11–12with a ketone group at C2 are supposed to increase the inhibitory activity.”

  • The paper relies on this without support.

    In vitro AChE inhibitory activity of sesquiterpenes predicts clinical efficacy in Alzheimer's disease.

    “Therefore, it was observed that the agarofuran compounds isolated from the aerial parts of Maytenus disticha and seeds of Maytenus boaria have good signs for their further use in the treatment of AD or as acetylcholinesterase inhibitors.”

  • The paper relies on this without support.

    Agarofuran compounds have low toxicity.

    “It was concluded from the above-cited examples that the selective inhibitory potential of agarofuran compounds for AChE and low toxicity might lead to the development of novel therapeutic agents for possible AD management.”

  • The paper relies on this without support.

    Findings from animal models of AD translate to humans.

    “This study confirmed that ARD, HDS, and PDA, the constituents of H. brasiliense, are efficient in inhibiting the cognitive deficits of animals and may be used in treating AD.”

  • The paper relies on this without support.

    AChE inhibition is a valid therapeutic strategy that delays AD progression and relieves AD-associated symptoms.

    “Improvement in cholinergic transmission by inhibiting the AChE was considered to delay the AD progression and relieve the AD-associated symptoms.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Lipidiol and amberboin sesquiterpenes inhibit cholinesterases with an IC50 < 9 M and are potential candidates for learning and memory improvement in patients with Alzheimer's disease and possible preventive treatment for this neurodegenerative pathology.

    “Arya et al. [168] carried out an analysis of lipidiol and amberboin sesquiterpenes belonging to an important category of terpenoids found mainly in herbaceous plants and capable of causing inhibition in cholinesterases with an IC50 < 9 M, being potential candidates for learning and memory improvement in patients with AD, and possible preventive treatment for this neurodegenerative pathology.”

    From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [168]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting projections for AD prevalence by 2030

    Minor

    The abstract says the prevalence will increase by up to double, whereas the introduction projects more than 100% growth, which would exceed a doubling.

1 of 1

Cites

Flagged first, then by citations

3 of the 167 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Arya, A., Chahal, R., Rao, R., Rahman, M. H., Kaushik, D., Akhtar, M. F., Saleem, A., Khalifa, S. M. A., El-Seedi, H. R., Kamel, M., Albadrani, G. M., Abdel-Daim, M. M., & Mittal, V.
Affiliations
  • Maharshi Dayanand University (IN)
  • Guru Jambheshwar University of Science and Technology (IN)
  • Yonsei University (KR)
  • Riphah International University (PK)
  • Government College University, Faisalabad (PK)
  • Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden
  • Jiangsu University (CN)
  • Cairo University (EG)
  • Princess Nourah bint Abdulrahman University (SA)
  • Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
Corresponding author
Mittal, Vineet
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2021-02-25
Volume
11
Issue
3
Pages
350
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom11030350
PMC
PMC7996600
OpenAlex
W3133291488
Semantic Scholar
c774a72404128cca19bd1f2f1d48e529250d165d
Cited by
111
References
167
Citations by year
2026: 15 · 2025: 18 · 2024: 18 · 2023: 25 · 2022: 26 · 2021: 9
FWCI
2.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Deanship of Scientific Research at Princess Nourah bint Abdulrahman University (Fast-track Research Funding Program.)
Topics
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
Keywords
sesquiterpenes, acetylcholinesterase inhibitors, Alzheimer's disease, cholinergic neurotransmission, anticholinesterase activity, terpenoids, learning and memory, natural product drug candidates
MeSH terms
Rivastigmine, Acetylcholinesterase, Alzheimer Disease, Animals, Cholinesterase Inhibitors, Galantamine, Humans, Sesquiterpenes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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