الفهرس 
Alzheimer’s DiseaseOnly 14 pages are availabe for public view
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Abstract
Alzheimer’s disease (AD) is a complex disease in which a single monofunctional ‘targeted’ drug is uneffective
for management. Hybrid drugs that impact multiple targets simultaneously are better at controlling
such complex disease systems. Hybrid agents were synthesized through the combination of the
steroid moiety with curcumin molecule. Also novel curcumin analogues containing promising heterocyclic
nucleus fused to the essential pharmacophoric feature of the curcumin moiety, were synthesized.
The aim of the present study was extended to elucidate the efficacy of these novel synthesized compounds
in the regression of AD induced in adult female albino rats. The results revealed that treatment
of AD groups with compounds 3, 5, 8c or rivastigmin experienced significant increase in brain Ach, GSH,
paraoxenase and BCL2 levels with respect to untreated group associated with significant decrease in
brain AchE activity, urinary 8-OHG level, serum Caspase-3 level and brain P53 level relative to the
untreated group. Immunohistochemical investigation revealed that the selected treatments caused
marked increase in ChAT positive cells. These findings were documented by the histological investigation
of the brain tissue. The activity of tested compounds showed gradual increase from compound b followed
by compound 8c then compound 5. The anti-cholinesterase potential, anti-oxidant properties and antiapoptotic
activity are responsible for the anti-Alzheimer’s disease potential of these compounds.
2015 Elsevier Inc. All rights reserved.
1. Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder, responsible for over 50% of all cases of dementia, which
affects up to 5% of people over 65 years, while its prevalence
increases to more than 20% of those over 80 years [1]. AD is currently
a major public health problem and will presumably be the
most important disorder of this century in developed/developing
countries. Sustained efforts have been made in the last decade to
determine the etiopathogenesis of AD, and to carry out its early
diagnosis and therapeutic control. Currently, there is no drug
thereby that provides definite solution for curing Alzheimer’s
disease. The pharmacological treatment conventionally used to
maintain cognitive functions of patients consist of two classes of
drugs, the acetyl cholinesterase inhibitors (AchEI) and the glutamate
modulators [2].
There is a growing body of evidence indicating that oxidative
damage may contribute to AD pathogenesis before amyloid beta
(Ab) accumulation in the brain [3]. Several studies have consistently
shown the presence of lipid, protein, and DNA oxidation
products in the brain of AD patients [4]. Also, increases in brain
levels of 8-hydroxyguanosine (8-OHG), an oxidized nucleoside,
have been detected early in AD [5]. Furthermore, reduced antioxidant
enzyme activity has been shown in AD brain [6]. Treatment
with antioxidants has been suggested to be an alternative
approach for slowing disease progression whereas oxidative damage
may be responsible for the cognitive and functional decline
observed in AD [7].
Tacrine and Trozamicol are heterocyclic drugs available for
Alzheimer’s disease based on the cholinergic approach. Many analogues
of Tacrine and Trozamicol have been prepared which retain
the pharmacologically rich heterocyclic moiety [8]. Also, many
new heterocyclic compounds were synthesized as AchEI [9]. The
investigation of new modified steroid derivatives condensed with
http://dx.doi.org/10.1016/j.steroids.2015.06.003
0039-128X/ 2015 Elsevier Inc. All rights reserved.
Abbreviations: Ach, acetylcholine; AchE, acetylcholinesterase; acetyl-CoA, acetyl
coenzyme; AchEI, acetyl cholinesterase inhibitors; AD, Alzheimer’s disease; Ab,
amyloid beta; AR, androgen receptor; BCL-2, 2B-cell lymphoma; b.wt., body weight;
ChAT, choline acetyl transferase; DHEA, dehydroepiandrostane; DMSO, dimethylsulfoxide;
GABA, c-aminobutyric acid; GSH, glutathione reduced; 8-OHG,
8-hydroxy guanosine; MAP, mitogen activated protein; P53, tumor protein; ROS,
reactive oxygen species; TLC, thin layer chromatography.
⇑ Corresponding author at: Hormones Department, National Research Centre,
12622 Dokki, Giza, Egypt. Tel.: +20 2 33872607; fax: +20 2 33370931.
E-mail address: gamalae@hotmail.com (G.A. Elmegeed).
1 Affiliation ID: 60014618.
Steroids 101 (2015) 78–89
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