Possible Preventive Effect of Donepezil and Hyoscyamoside by Reduction of Plaque Formation and Neuroinflammation in Alzheimer’s Disease

Fatemeh Heidari Soureshjani, Majid Kheirollahi, Parichehreh Yaghmaei, Fattah Sotoodehne jadnematalahi


Background: Alzheimer disease (AD) is the most common age‑dependent dementia. The complex natural accumulation of amyloid beta (Aβ) precursor protein in hippocampus neurons is regarded as the earliest pathological feature of AD, although there are cholinergic assumptions and effective inflammation in AD. In this animal experimental study, we evaluated the preventive effect of hyoscyamoside (Hyo) and donepezil (Dz) on plaque formation and improvement of neurogenic inflammation in AD rats.

Methods: Dz was prepared and Hyo (steroidal saponin) was isolated from Hyoscymus niger. Then, Wistar rats divided into five groups including negative and positive controls, AD, Dz, and Hyo treatment groups based on the drug exposure and their behavioral alternation was examined using Morris water maze (MWM) test. Bielschowsky staining was used to detect the nerve fibers. Serum levels of interleukin (IL)‑4 and IL‑6 were evaluated by ELISA. The RNA expression of cyclin‑dependent kinase CDK11-P58 in peripheral blood lymphocytes was performed using quantitative PCR.

Results: The MWM test showed significant changes in time the models spent to find the hidden platform. The Hyo treatment group showed a notable speed change (P < 0.01). The histopathological analysis of the hippocampal tissue revealed the inhibition of Aβ formation in the treatment groups. The treatment groups had a significant decline in the serum level of IL‑6, and the IL‑4 serum level was increased in the Hyo and Dz treated groups. The expression levels of CDK11-P58 was significantly decreased in the treatment groups.

Conclusions: In sum, the therapeutic effects of Hyo is comparable with that of Dz in AD rats by suppressing neuroinflammation. Thus, these compounds could be considered as a preventive agent in the AD therapy.


Alzheimer disease; amyloid beta‑protein; donepezil; hyoscyamoside; neurogenic inflammation

Full Text:



St George‑Hyslop PH, Petit A. Molecular biology and genetics

of Alzheimer’s disease. C R Biol 2005;328:119‑30.

Hebert LE, Scherr PA, Beckett LA, Albert MS, Pilgrim DM,

Chown MJ, et al. Age‑specific incidence of Alzheimer’s disease

in a community population. JAMA 1995;273:1354‑9.

Kirouac L, Rajic AJ, Cribbs DH, Padmanabhan J. Activation

of Ras‑ERK signaling and GSK‑3 by amyloid precursor

protein and amyloid beta facilitates neurodegeneration

in Alzheimer’s disease. eNeuro 2017;4. doi: 10.1523/


Buee L, Bussiere T, Buee‑Scherrer V, Delacourte A,

Hof PR. Tau protein isoforms, phosphorylation and role

in neurodegenerative disorders. Brain Res Brain Res Rev


Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F,

Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease.

Lancet Neurol 2015;14:388‑405.

Craig LA, Hong NS, McDonald RJ. Revisiting the cholinergic

hypothesis in the development of Alzheimer’s disease. Neurosci

Biobehav Rev 2011;35:1397‑409.

Bajic V, Stanojevic B, Zivkovic L, Cabarkapa A, Perry G,

Arendt T, et al. Cyclin dependent kinase 11, neuroinflammation

and Alzheimer’s disease: A review. J Clin Cell Immuno


Wyss‑Coray T. Inflammation in Alzheimer disease: Driving force,

bystander or beneficial response? Nat Med 2006;12:1005‑15.

Pope C, Karanth S, Liu J. Pharmacology and toxicology of

cholinesterase inhibitors: Uses and misuses of a common

mechanism of action. Environ Toxicol Pharmacol 2005;19:433‑46.

Mohamed T, Yeung JC, Vasefi MS, Beazely MA, Rao PP.

Development and evaluation of multifunctional agents for

potential treatment of Alzheimer’s disease: Application to

a pyrimidine‑2,4‑diamine template. Bioorg Med Chem Lett


Banjari I, Marček T, Tomić S, Waisundara VY. Forestalling the

epidemics of Parkinson’s disease through plant‑based remedies.

Front Nutr 2018;5:95‑103.

Tohda C, Yang X, Matsui M, Inada Y, Kadomoto E, Nakada S,

et al. Diosgenin‑rich yam extract enhances cognitive function:

A placebo‑controlled, randomized, double‑blind, crossover study

of healthy adults. Nutrients 2017;9:pii: E1160.

Li J, Shi J, Yu X , Sun J, Men Q, Kang T. Chemical and

Pharmacological Researches on Hyoscyamus niger Chinese

Herbal Med 2011;3:117-26.

Kim JE, Go J, Koh EK, Song SH, Sung JE, Lee HA, et al.

Diosgenin effectively suppresses skin inflammation induced by

phthalic anhydride in IL‑4/Luc/CNS‑1 transgenic mice. Biosci

Biotechnol Biochem 2016;80:891‑901.

Ahmed T, Enam SA, Gilani AH. Curcuminoids enhance memory

in an amyloid‑infused rat model of Alzheimer’s disease.

Neuroscience 2010;169:1296‑306.

Khalil WK, Roshdy HM, Kassem SM. The potential therapeutic

role of Fenugreek saponin against Alzheimer’s disease:

Evaluation of apoptotic and acetylcholinesterase inhibitory

activities. J App Pharm Sci 2016;6:166‑73.

Astuti SM. Determination of saponin compound from Anredera

cordifolia (Ten) steenis plant (Binahong) to potential treatment

for several diseases. J Agric Sci 2011;3:224‑32.

Nedova I. Structure of steroidal glycosides from the seeds of

Hyoscyamus niger L. and their biological activity. CZU Bio

Chem 2008;581.19:8-25.

Tabet N. Acetylcholinesterase inhibitors for Alzheimer’s disease:

Anti‑inflammatories in acetylcholine clothing. Age Ageing


Shal B, Ding W, Ali H, Kim YS, Khan S. Anti‑neuroinflammatory

potential of natural products in attenuation of Alzheimer’s

disease. Front Pharmacol 2018;9:548‑64.

Huell M, Strauss S, Volk B, Berger M, Bauer J. Interleukin‑6

is present in early stages of plaque formation and is restricted

to the brains of Alzheimer’s disease patients. Acta Neuropathol


Gambi F, Reale M, Iarlori C, Salone A, Toma L, Paladini C,

et al. Alzheimer patients treated with an AchE inhibitor show

higher IL‑4 and lower IL‑1 beta levels and expression in

peripheral blood mononuclear cells. J Clin Psychopharmacol


Lee HG, Casadesus G, Zhu X, Castellani RJ, McShea A,

Perry G, et al. Cell cycle re‑entry mediated neurodegeneration

and its treatment role in the pathogenesis of Alzheimer’s disease.

Neurochem Int 2009;54:84‑8.