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Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in Rats

Authors:
  • Faculty of Pharmacy Al-Azhar University
  • Modern university for technology and information

Abstract and Figures

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that leads to memory loss. It is characterized by deposition of Beta-amyloid peptides (Aβ), accumulation of neurofibrillary tangles and cell loss. Social isolation may exacerbate memory deficits. The risk of cognitive decline and the onset of AD may be lower by maintaining social connections and keeping mentally active. The relationship between frequent social activity and enhancing cognitive functions has been established. Objective: Study the influence of complete social isolation for a long period on biochemical and histopathological changes as well as DNA fragmentation in the brain of normal rats. In addition, investigate the possible interaction between social isolation and development of AD using isolation-associated AD rat model. Methods: Four groups of rats were used; 2 groups socialized and 2 isolated for four weeks. One of each socialized and isolated groups were served as control and the other served as AD groups and injected by ALCl3 (70 mg/kg, IP) every day during four weeks of isolation or socialization. Isolated rats were housed individually in cages covered with black plastic while socialized rats were randomly paired and housed in transparent covered cages. Biochemical changes in the brain as acetyl cholinesterase (ACHE), Aβ, brain derived neurotrophic factor (BDNF), monoamins (Dopamine, Serotonin, Norepinephrine), inflammatory mediators (TNF-α, IL-1β), oxidative parameters (MDA, SOD, TAC) and DNA fragmentation were estimated for all groups. Histopathological changes in the brain were also evaluated. Results: Complete social isolation for a long period resulted in brain neurological damage indicated by significant increase in Aβ, ACHE, MDA, TNF-α, IL-1β as well as decreases in SOD, TAC, BDNF, and monoamines and confirmed by histopathological changes in different brain regions. Brain neurological damage was more severe in isolation-associated AD than in socialized condition. Isolation also enhanced the DNA fragmentation induced by AD. Conclusion: Complete social isolation for a long period induces brain neuronal degenerations. It represents a risk factor especially when associated with AD; it increases DNA fragmentation and enhances the severity of AD development. Thus, socialization is advised especially with AD to avoid worsen or deterioration of the disease.
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Volume 6 • Issue 2 • 1000230
Brain Disord Ther, an open access journal
ISSN: 2168-975X
Research Article Open Access
Brain Disorders & Therapy
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ISSN: 2168-975X
Ali et al., Brain Disord Ther 2017, 6:2
DOI: 10.4172/2168-975X.1000230
Keywords: Alzheimer’s disease; Social isolation; Neuronal
degeneration; Socialization; Rats
Introduction
Alzheimer’s disease (AD) represents the most important problem
in aged population. It is the most common form of dementia and
causes progressive loss of cognitive function together with behavioral
dysfunction [1,2]. ere is no eective treatment for preventing
the neuronal death or memory impairment and cognitive decline
characterizing this progressive neurodegenerative disease [3,4]. Indeed,
the risk of AD development can be lowered by keeping mental activity
and maintain strong social connections during aging. However, the
underlying mechanisms of the relationship between frequent social
activity and better cognitive function are still unclear [4-6].
Severe and/or chronic stress has negative impact on the brain
structure as well as on learning and memory process [3,7,8]. Both
AD and mental stress can impair cognitive function in animals and
humans [9,10]. Mental stress can elevate excitatory amino acid and
glucocorticoid (GC) levels, while there are sever age-associated loss of
hippocampal neurons and reduction in the number of corticosteroid
receptors in AD [10]. Progressive and sustained GC release can
cause hippocampal atrophy, excitotoxicity and neurotoxicity [8,10].
Consequently, exposure to stress forms an additional deleterious
eect on the brain of AD patients and can exacerbate AD-induced
impairment of learning and memory. It is worthy to note that the
concurrent incidence of AD and stress is increased with advancing age
[11,12].
*Corresponding author: Azza A Ali, Head of Pharmacology and Toxicology
Department, Faculty of Pharmacy, Al-Azhar University, Cairo, 253, Tagamoa 3, Local
7, New Cairo-11835 Egypt, Tel: +2 01061905439; E-mail: azzamoro@gmail.com
Received April 28, 2017; Accepted May 12, 2017; Published May 20, 2017
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social
Isolation as a Risk Factor in Development of Alzheimer’s Disease in Rats. Brain
Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Copyright: © 2017 Ali AA, et al.. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Abstract
Background: Alzheimer’s disease (AD) is a neurodegenerative disease that leads to memory loss. It is characterized
by deposition of Beta-amyloid peptides (Aβ), accumulation of neurobrillary tangles and cell loss. Social isolation may
exacerbate memory decits. The risk of cognitive decline and the onset of AD may be lower by maintaining social
connections and keeping mentally active. The relationship between frequent social activity and enhancing cognitive
functions has been established.
Objective: Study the inuence of complete social isolation for a long period on biochemical and histopathological
changes as well as DNA fragmentation in the brain of normal rats. In addition, investigate the possible interaction
between social isolation and development of AD using isolation-associated AD rat model.
Methods: Four groups of rats were used; 2 groups socialized and 2 isolated for four weeks. One of each socialized
and isolated groups were served as control and the other served as AD groups and injected by ALCl3 (70 mg/kg, IP)
every day during four weeks of isolation or socialization. Isolated rats were housed individually in cages covered with
black plastic while socialized rats were randomly paired and housed in transparent covered cages. Biochemical changes
in the brain as acetyl cholinesterase (ACHE), Aβ, brain derived neurotrophic factor (BDNF), monoamins (Dopamine,
Serotonin, Norepinephrine), inammatory mediators (TNF-α, IL-1β), oxidative parameters (MDA, SOD, TAC) and DNA
fragmentation were estimated for all groups. Histopathological changes in the brain were also evaluated.
Results: Complete social isolation for a long period resulted in brain neurological damage indicated by signicant
increase in Aβ, ACHE, MDA, TNF-α, IL-1β as well as decreases in SOD, TAC, BDNF, and monoamines and conrmed by
histopathological changes in different brain regions. Brain neurological damage was more severe in isolation-associated
AD than in socialized condition. Isolation also enhanced the DNA fragmentation induced by AD.
Conclusion: Complete social isolation for a long period induces brain neuronal degenerations. It represents
a risk factor especially when associated with AD; it increases DNA fragmentation and enhances the severity of AD
development. Thus, socialization is advised especially with AD to avoid worsen or deterioration of the disease.
Study on Social Isolation as a Risk Factor in Development of Alzheimers
Disease in Rats
Azza A Ali1*, Mona G Khalil2, Hemat A Elariny1 and karema Abu-Elfotuh1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
Social interaction is central to human well-being and can improve
both mental and physical health; it can reduce risk of cognitive
impairment and development of dementia [13-15]. Social isolation (SI)
which means the absence or insucient contact with others is harmful
to both physical and mental development [16,17]. especially for elderly
[18,19]. It represents the major source of mental or psychosocial stress
and is associated with the increased prevalence of neurological diseases
[20]. It also exacerbates the risk of morbidity and mortality as well as
the onset of many neuropsychological disorders [20-23]. Moreover, it
is considered as risk factor for age-related cognitive deterioration and
dementia [24]. e inuences of SI on the development of AD may
be through the production of Aβ peptide and phosphorylation of tau
[17,25]. Furthermore, SI increases oxidative stress and inammatory
reaction [26] while inhibits antiinammatory responses [27], synaptic
plasticity [28] and myelination [29]; all of these mentioned mechanisms
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in
Rats. Brain Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Page 2 of 10
Volume 6 • Issue 2 • 1000232
Brain Disord Ther, an open access journal
ISSN: 2168-975X
β-amyloid (Aβ) content, acetylcholine esterase (ACHE) activity and
brain derived neurotrophic factor (BDNF). Oxidative stress markers
{malondialdehyde (MDA), superoxide dismutase (SOD), total
antioxidant capacity (TAC)}, inammatory mediators {tumer necrosis
factor-alpha (TNF-α), Interleukin 1β (IL-1β)}, brain monoamins
{Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT)} as well as
DNA fragmentation were also estimated for all groups. In additions,
specimens from the brain tissue from dierent groups were taken for
histopathological examination.
Biochemical parameters
Determination of Aβ content: It was assessed in brain tissue
homogenate by using ELISA kit supplied by (MyBioSource, Inc.,
SanDiego, USA, Product Number MBS702915), according to the
manufacturer’s instructions.
Determination of ACHE activity: It was carried out in brain
tissue homogenate using commercially available test kit supplied by
Sigma-Aldrich Co. (St. Louis, MO, USA), Product Number MAK119,
according to the method of [32].
Determination of BDNF: It was assessed in brain tissue homogenate
by using ELISA Kit supplied by (MyBioSource, Inc., SanDiego, USA,
Product Number MBS494147), according to the method of [33].
Assessment of oxidative stress markers (MDA, SOD, TAC): Lipid
peroxidation was determined in brain tissue homogenate by estimating
the level of thiobarbituric acid reactive substances (TBARS) measured
as MDA [34]. SOD activity was achieved relying on the ability of the
enzyme to inhibit the phenazine methosulphate mediated reduction
of nitroblue tetrazolium dye [35]. e increase in absorbance at 560
nm for 5 min is measured. Finally, determination of TAC was assessed
by the reaction of antioxidants with a dened amount of exogenously
provide H2O2. e residual H2O2 was determined colourimetrically by
an enzymatic reaction which involves the conversion of 3, 5-dichloro-
2-hydroxybenzene sulphonate to a colored product [36].
Brain inammatory mediators (IL-1β, TNF-α): Determination
of TNF-α was done in brain tissue homogenate by using ELISA Kit,
Product Number (RTA00, SRTA00, PRTA00) and according to the
method of [37], determination of IL-1β was performed in brain
tissue homogenate by using ELISA Kit supplied by RayBiotech, Inc.,
USA, Product Number (ELR-IL1b) according to the manufacturer’s
instructions.
Assessment of neurochemical parameters (DA, NE, 5-HT): Rats
were sacriced rapidly by decapitation with minimum disturbance to
avoid any changes in the concentrations of brain monoamines that
may occur within few minutes [38]. Fluorometric assay of serotonins,
norepinephrine and dopamine were determined in rat’s brain according
to the method of [39].
DNA fragmentation
Apoptosis and DNA fragmentation was detected in brain tissue
sections using the kit supplied by Qiagen (Hilden, Germany). To
detect DNA fragmentation, 10 μg of each DNA was electrophoretically
fractionated on 1.5% agarose gel, stained with 0.5 μg/mL ethidium
bromide solution and destained with deionized water. Finally, the DNA
in the gel was visualized and photographed under UV light [40].
Histopathological examination of the brain
For histopathological examinations, brain specimens were
prepared and stained for light microscopy [41]. ey were xed in 10%
are involved in the pathogenesis of AD. Additionally, AD patients are
more likely to suer from SI due to cognitive and emotional impairment
especially at late stages where the loss of communication ability and the
potential neglect by society [30,31]. Although SI may contribute to the
onset of AD, better understanding of the internal interaction between
them as well as the added eect of SI on the disease development and
progression remains unclear [17]. Consequently; in order to establish
an eective therapies or interventions to delay the progression of AD,
it is necessary to determine whether SI exacerbates pathology of AD
development and progression.
In the light of what was mentioned, the present work was designed
to study the impact of SI for a long period on rat brain as regarding
changes in biochemical, histopathological and DNA fragmentation,
in addition to the possible interaction between social isolation and
development of AD using isolation-associated AD rat model.
Materials and Methods
Animals
Forty male Sprague Dawley rats, weighing 250-280 g and obtained
from e Nile Co. for Pharmaceuticals and Chemical Industries, Cairo,
Egypt were used. Animals were housed in stainless-steel cages, at a
temperature of 25 ± 1°C. Isolated rats were housed individually in cages
covered with black plastic for four weeks, while socialized rats were
randomly paired and housed in transparent covered cages. Animals
were kept under adequate environmental conditions. ey were kept
on standard diet pellets and water was given ad-libitum. e work
was conducted in accordance with the ethical guidelines of Faculty of
Pharmacy, Al-Azhar University, Egypt.
Drugs and chemicals
Aluminum chloride - hydrated (ALCl3.6H2O), was purchased from
Sigma Chemical Co. (St. Louis, MO, USA). It was freshly dissolved in
distilled water. All other chemicals and solvents were of the highest
grade-commercially available.
Experimental design
Forty rats were equally divided into 4 groups (10 rats/each), rats
were classied and IP injected every day during four weeks as follows:
Control socialized group
Rats received normal saline (1 ml/kg), randomly paired and housed
in transparent covered cages.
AD socialized group
Rats received ALCl3 (70 mg/kg), randomly paired and housed in
transparent covered cages.
Control isolated group
Rats received normal saline (1 ml/kg), housed individually in cages
covered with black plastic.
AD isolated group
Rats received ALCl3 (70 mg/kg), housed individually in cages
covered with black plastic. At the end of the four weeks; rats were
sacriced, the brain tissues were dissected and washed with ice-cold
saline. For all groups, brain tissues were either subjected for analysis
immediately or kept frozen till the time of analysis at -80°C. ey
were homogenized in saline, the homogenates were used to assess
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in
Rats. Brain Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Page 3 of 10
Volume 6 • Issue 2 • 1000232
Brain Disord Ther, an open access journal
ISSN: 2168-975X
formalin for 24 h and then washed with tap water. Serial dilutions of
alcohol (methyl, ethyl and absolute ethyl) were used for dehydration.
Specimens were cleared in xylene embedded in paran at 56ºC in
hot air oven for 24 h. Paran bees wax tissue blocks were prepared
for sectioning at 4 microns thickness by microtome. e obtained
tissue sections were collected on glass slides and deparanized. All
sections were stained with Hematoxylin & Eosin stain for the routine
histological examination.
Statistical analysis
Data are expressed as mean ± SEM and multiple comparisons were
performed using one-way ANOVA followed by Tukey Kramer as a
post hoc test. All statistical analysis and graphs were performed using
GraphPad Prism (ISI®, USA) soware (version 5).
Results
Brain β-amyloid (Aβ) content
As illustrated in (Figure 1), social isolation for a long period
resulted in brain neurological damage indicated by signicant elevation
in the brain Aβ content to 204.52% as compared to corresponding
control socialized group. Also, AD isolated group showed a
signicant elevation in the brain Aβ content to 157.5% as compared
to corresponding AD socialized group. Additionally, AD socialized
and isolated groups showed signicant elevation in brain Aβ content
to 1051.9% and 810.09% with respect to their corresponding control
groups respectively.
Brain Acetylcholine Esterase (ACHE) activity
As shown in Figure 2, social isolation for a long period induced
brain neurological degeneration as indicated by signicant elevation
in the brain ACHE activity to 136.82% as compared to corresponding
control socialized group. Also, AD isolated group showed a signicant
elevation in the brain ACHE activity to 150.1% as compared to
corresponding AD socialized group. Additionally, AD socialized and
isolated groups showed signicant elevation in brain ACHE activity
to 405.9% and 445.26% with respect to their corresponding control
groups respectively.
Brain Derived Neurotrophic Factor (BDNF)
As illustrated in (Figure 3), social isolation for a long period
resulted in brain neurological damage indicated by a signicant
reduction in the brain BDNF to 96.7% as compared to corresponding
control socialized group. Also, AD isolated group showed a signicant
reduction in the brain BDNF to 51.9% as compared to corresponding
AD socialized group. Additionally, AD socialized and isolated groups
showed signicant reduction in brain BDNF to 63.9% and 34.3% with
respect to their corresponding control groups respectively.
Brain Oxidative Stress Markers (MDA, SOD, TAC)
As shown in Figures 4a, 4b and 4c, social isolation for a long period
resulted in brain neurological degeneration as indicated by a signicant
elevation in brain MDA content to 188.4% as compared to the
corresponding control socialized g roup. Also, AD isolated group showed
a signicant elevation in the brain MDA content to 113.0% as compared
to corresponding AD socialized group. Additionally, AD socialized and
isolated groups showed also signicant elevation in brain MDA content
to 1842% and 1104.9% with respect to their corresponding control
groups respectively. Moreover, social isolation induced signicant
Control socialized
Control isolated
AD socialized
AD isolated
0
10
20
30
a
b,c
c
Beta amyloid
(ng/g tissue)
Data expressed as Mean ± SEM (n=10).
Signicant difference at p<0.05 between:
a: Control isolated and socialized.
b: AD isolated and socialized.
c: AD and the corresponding control either socialized or isolated.
Figure 1: Effect of social isolation on brain β-amyloid (Aβ) content in normal and
Alzheimer’s disease rat model.
C
ontrol socialized
Control isolated
AD socialized
AD isolated
0
20
40
60
80
a
c
b,c
ACHE
(ng/g tissue)
Data expressed as Mean ± SEM (n=10).
Signicant difference at p<0.05 between:
a: Control isolated and socialized.
b: AD isolated and socialized.
c: AD and the corresponding control either socialized or isolated.
Figure 2: Effect of social isolation on brain acetylcholine esterase (ACHE)
activity in normal and Alzheimer’s disease rat model.
C
ontrol socialized
Control isolated
AD socialized
AD isolated
0
50
100
150
a
c
b,c
BDNF
(ng/g tissue)
Data expressed as Mean ± SEM (n = 10).
Signicant difference at p<0.05 between:
a: Control isolated and socialized.
b: AD isolated and socialized.
c: AD and the corresponding control either socialized or isolated.
Figure 3: Effect of social isolation on brain derived neurotrophic factor (BDNF)
in normal and Alzheimer’s disease rat model.
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in
Rats. Brain Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Page 4 of 10
Volume 6 • Issue 2 • 1000232
Brain Disord Ther, an open access journal
ISSN: 2168-975X
reduction in brain SOD and TAC to 70.4% and 77.03% respectively
as compared to the corresponding control socialized group. Also, AD
isolated group showed a signicant reduction in brain TAC to 76.6% as
compared to the corresponding AD socialized group. Additionally, AD
socialized and isolated groups showed signicant reduction in brain
SOD activity to 19.8% and 16.1% as well as in brain TAC to 37.6% and
37.4% respectively with respect to their corresponding control groups.
Brain Inammatory Mediators (IL-1β, TNF-α)
As illustrated in Figures 5a and 5b, social isolation for a long period
induced brain neurological degeneration indicated by signicant
elevation in brain IL-1β and TNF-α to 122.2% and 124.21% respectively
as compared to corresponding control socialized group. Also, AD
isolated group showed signicant elevation in brain IL-1β and TNF-α
to 105.9% and 109.04% respectively as compared to corresponding
AD socialized group. Additionally, AD socialized and isolated groups
showed signicant elevation in brain IL-1β to 482.4% and 418.2% as
well as in TNF-α to 480.2% and 421.5% respectively with respect to
their corresponding control groups.
Brain neurochemical parameters
As shown in Figures 6a, 6b and 6c, social isolation for a long period
resulted in brain neurological changes as indicated by the signicant
reduction in brain DA, NE and 5-HT to 85.9%, 88.23% and 85.84%
respectively as compared to their corresponding control socialized
group. Also, AD isolated group showed signicant reduction in brain
DA, NE and 5-HT to 50.9%, 86.33% and 52.8% respectively as compared
to corresponding AD socialized group. Additionally, AD socialized and
isolated groups showed signicant reduction in brain DA to 35.9%,
21.24% and in NE to 30.6%, 29.9% as well as in 5-HT to 41.4%, 25.4%
respectively with respect to their corresponding control groups.
DNA fragmentation
By agarose gel electrophoresis, DNA isolated from control socialized
brain tissues did not show any DNA fragmentation (Figure7, Lane c).
However, control isolated as well as AD either socialized or isolated
groups (Figure7, Lanes 1-3) showed characteristic DNA fragmentation
or laddering as which was found in the model (M) laddering shape.
Histopathological alterations in the brain
Histopathological alterations in the brain specimens from dierent
treated groups are shown in Figures 8A-8D and Table 1. Brain specimens
from control socialized rats showed normal histological structure of
hippocampus. On the other hand, brain specimens of control isolated
and AD socialized groups showed focal nuclear pyknosis as well as
degeneration in the neuronal cells of cerebral cortex associated with
atrophy in some neurons of the substantia nigra but no histopathological
alteration in the hippocampus as well as in the striatum. However, brain
specimens of AD isolated group showed marked pathological changes
indicated by nuclear necrosis and degeneration in cerebral cortex
associated with focal gliosis. It is worthy to note that, hippocampus
as well as neurons of the fascia dentate, striatum and substantia nigra
in isolation-associated AD rat model showed nuclear pyknosis and
Control socialized
Control isolated
AD socialized
AD isolated
0
50
100
150
a
cb,c
MDA
(nmol/g tissue)
4a. Malondialdehyde (MDA) content
Control socialized
Control isolated
AD socialized
AD isolated
0
1
2
3
4
5
a
cc
SOD
(U/g tissue)
4b. Superoxide
dismutase (SOD) enzyme activity
Control socialized
Control isolated
AD socialized
AD isolated
0
10
20
30
40
50
a
cb,c
TAC
(µmol/ g tissue)
4c. Total antioxidant capacity (TAC)
Data expressed as Mean ± SEM (n=10).
Signicant difference at p<0.05 between:
a: Control isolated and socialized.
b: AD isolated and socialized.
c: AD and the corresponding control either socialized or isolated.
Figure 4: (a, b, c) Effect of social isolation on brain oxidative stress markers
(MDA, SOD, TAC) in normal and Alzheimer’s disease rat model.
Control socialized
Control isolated
AD socialized
AD isolated
0
50
100
150
a
c
b,c
IL-1B
(Pg/ g tissue)
5a.Interleukin 1β (IL-1β)
Control socialized
Control isolated
AD socialized
AD isolated
0
50
100
150
a
c
b,c
TNF
(Pg/ g tissue)
5b. Tumor necrosis factor-alpha (TNF-α)
Data expressed as Mean ± SEM. (n=10)
Signicant difference at p<0.05 between:
a: Control isolated and socialized.
b: AD isolated and socialized.
c: AD and the corresponding control either socialized or isolated.
Figure 5: (a, b): Effect of social isolation on brain inammatory mediators (IL-
1β, TNF-α) in normal and Alzheimer’s disease rat model.
Control socialized
Control isolated
AD socialized
AD isolated
0
20
40
60
80
a
c
b,c
Dopamine
(ng/g tissue)
6a. Dopamine (DA)
Control socialized
Control isolated
AD socialized
AD isolated
0
200
400
600
800
a
cb,c
NE
(nmol/g tissue)
6b. Norepinephrine (NE)
Control socialized
Control isolated
AD socialized
AD isolated
0
5
10
15
a
c
b,c
5-HT
(ng/g tissue)
(6c) Serotonin (5-HT)
Data expressed as Mean ± SEM (n=10).
Signicant difference at p < 0.05 between:
a: Control isolated and socialized.
b: AD isolated and socialized.
c: AD and the corresponding control either socialized or isolated.
Figure 6: (a, b, c) Effect of social isolation on brain monoamines (DA, NE,
5-HT) in normal and Alzheimer’s disease rat model.
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in
Rats. Brain Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Page 5 of 10
Volume 6 • Issue 2 • 1000232
Brain Disord Ther, an open access journal
ISSN: 2168-975X
and nucleic acids [45]. Chronic stress has been proposed as a risk factor
in AD progression [46].
Results of the present study showed that SI for a long period
resulted in brain neurological damage indicated by signicant elevation
in the brain Aβ content as compared to control socialized group. These
findings are in agreement with [46] but the exact mechanism of how
C
Figure 7: Effect of social isolation on DNA fragmentation (DNA ladder) in
normal and Alzheimer’s disease rat model. (Lane M: DNA Marker with 100 bp;
Lane 1: Control isolated; Lane 2: AD socialized; Lane 3: AD isolated; Lane C:
Control socialized).
A
Figure 8A: Representative photomicrograph (magnication 40 X) of brain
section stained by Hematoxylin–Eosin: Section taken from brain of control
socialized group showed normal histological structure of the hippocampus (hp).
B2
B3
B1
B5
B4
Figure 8B: (B1-B5) Representative photomicrographs (magnication 40 X)
of brain sections stained by Hematoxylin–Eosin: Sections taken from brain
of control isolated group showed focal nuclear pyknosis and degeneration
in the neuronal cells of cerebral cortex (B1), atrophy in some neurons of the
substantia nigra (B2) but no histopathological alteration in the hippocampus
(B3, B4) as well as in the striatum (B5).
degeneration with congestion in the blood vessels. Consequently, it is
clear that the severity of brain neurological damage induced by social
isolation was more pronounced in AD rats.
Discussion
e impact of Aluminum (AL) on neural tissues is well known
[42] It has been implicated in the etiology of AD; excessive AL intake
leads to accumulation of Aβ in the brain and over expression of
β-amyloid precursor protein (APP) [43]. e neurotoxicity of Aβ is
strongly related to oxidative stress which plays an eective role in the
pathogenesis of AD [44]. e generation of reactive oxygen species
(ROS) causes damage of neuronal membrane as well as lipids, proteins
C5
C4
C3
C2
C1
Figure 8C: (C1-C5) Representative photomicrographs (magnication 40 X) of
brain sections stained by Hematoxylin–Eosin: Section taken from brain of AD
socialized group showed normal histological structure in the striatum (C1) while
showed nuclear pyknosis and degeneration in the neurons of cerebral cortex
(C2) and hippocampus (C3, C4). Atrophy was observed in some neurons of the
substantia nigra (C5).
D1
D3
D2
D6
D5
D4
Figure 8D: (D1-D6) Representative photomicrographs (magnication 40 X) of
brain sections stained by Hematoxylin–Eosin: Section taken from brain of AD
isolated group showed nuclear necrosis and degeneration in cerebral cortex
(D1) associated with focal gliosis (D2). Hippocampus as well as neurons of
the fascia dentate, striatum and substantia nigra showed nuclear pyknosis and
degeneration with congestion in the blood vessels (D3, D4, D5, D6).
Histopathological
alterations
Control
socialized
Control
isolated
AD
socialized
AD
isolated
Degeneration
and pyknosis in
hippocampus neurons
- - - +++
Eosinophillic plaque
formation in striatum - - - +++
Gliosis - - - +++
Focal nuclear
pyknosis and
degeneration in
neuronal of cerebral
cortex
-+ ++ +++
Atrophy in some
neurons of the
Substantia nigra
-+ + +++
+++ Severe ++ Moderate + Mild - Nil
Table 1: Effect of social isolation on the severity of brain histopathological
alterations in normal and Alzheimer's disease rat model.
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in
Rats. Brain Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Page 6 of 10
Volume 6 • Issue 2 • 1000232
Brain Disord Ther, an open access journal
ISSN: 2168-975X
SI led to Aβ increase is not clear. Social isolation leads to oxidative stress
[20,47] which in turn can stimulate β- and γ-secretase activity [25,48]
resulting in Aβ elevation and cognition decline. Social isolation can
also aggravate the inammatory processes [49,50]. In the present study,
Aβ content was elevated in the brain of both socialized and isolated
rats but isolated rats showed signicant increase in Aβ content than
socialized one. Several lines of evidence suggest that oxidative stress
has been proposed to facilitate Aβ secretion [51]. Accumulation of Aβ
in cellular compartments interferes with normal cell function [52] and
promotes cellular changes. It is suggested that Aβ plays a major role
in AD development and progression [53] Additionally, the correlation
between the beginning of cognition decline with Aβ levels and stress
promotes APP processing along the amyloidogenic pathway has
been established [46,54] and resulting in the exacerbation of AD-like
neuropathology [11,25].
Brain aging is characterized by memory decits and cognitive
decline that could be the result of oxidative stress and impaired
cholinergic function. Studies have been also highlight that various
stresses as SI can lead to cholinergic dysfunction [55]. In the brain,
the cholinergic neurotransmission system plays an essential role in
learning and memory. It is terminated by acetylcholine hydrolysis via
ACHE; this enzyme is important in maintaining the normal function
of the nervous system and participates in the underlying processes
of AD [56,57]. e activity of ACHE has been shown to be elevated
in brain of aluminum- treated animals [58]. e elevation of ACHE
activity may be due to neurotoxic eect on the plasma membrane
which caused by increased lipid peroxidation. Changes in plasma
membranes may inuence the integrity and the functions of cholinergic
system. Consequently, lipid membrane is a decisive factor in aecting
ACHE and results in learning and memory decits [57,59]. It is worthy
to note that ACHE inhibitors are used for the symptomatic treatment
of patients with AD. e present study examined the eect of social
isolation on brain cholinergic functions since ACHE activities inuence
cognitive performance [60,61]. e results of the present study showed
that social isolation for a long period induced signicant elevation in
the brain ACHE activity as compared to control socialized group which
was evidenced to be paralleled to impairment on learning and memory
as mentioned above. It is well known that individuals with more social
engagement have a reduced rate of cognitive decline with aging [62].
Moreover, the rate of memory decline eectively doubles with SI [63].
On the contrary to the present study, a previous study did not show
the change in ACHE between socialized and isolation-reared mice [64].
Results of the present study showed that ALCl3 signicantly
increased ACHE activity of both socialized and isolated rats, but
isolated rats showed more pronounced increase than socialized
one. These findings are in agreement with previous results stated
that AL exposure increased ACHE activity and leads to pathological
deterioration related to the etiology of AD [65,66] ese results could
be attributed to the ability of AL to alter the blood brain barrier and
produce changes in the cholinergic neurotransmission [67]. Besides
the fact that AL is a cholinotoxin, its neurotoxicity could be attributed
to an additional mechanisms as induction of oxidative stress or
disarrangement of the cell membrane caused by the associated increase
in lipid peroxidation [42,68].
It is known that the onset and severity of AD symptoms can vary
dramatically among patients even with similar plaque burden [20,69].
Moreover, individuals with larger social networks have greater cognitive
function [70]. It is suggested that larger brains have more neural matter
that can be lost before manifestation of clinical symptoms of aging
[71,72]. Indeed, social engagement has been linked to larger brain
volumes [73] and individuals who engage in aliative interaction are
less liable to develop AD and dementia. It is possible that SI exacerbates
the oxidative stress-mediated damage; reduce the available brain
reserve, increases inammation and allowing clinical symptoms of
neuropathology to manifest at earlier stages [74,75].
On the other hand, BDNF is a key protein in maintenance as well as
survival of neurons [76,77] and inuences learning and memory [78].
Brain of patients with AD exhibits low expression of BDNF [79,80]. In
the current study, we examined the eect of SI on neurogenesis, it was
found that neurogenesis was signicantly reduced in isolated group as
compared to social ized one. It is quite evident that neurogenesis can
improve brain function in AD [16,81]. In this study, BDNF levels were
decreased in the isolated group. Decreased BDNF levels have been
linked to faster cognitive decline and poor memory performance in
AD [82]. These findings are in agreement with other studies which
showed that SI resulting in a signicant reduction in BDNF levels in
the hippocampus when compared to paired housed rats [49,83,84].
Furthermore, social isolation can cause apoptosis of hippocampal cells
and memory decline [85]. us, preventing social isolation can improve
neurogenesis, inhibit memory deterioration and reduce cognitive
decits in AD patients. On the contrary to the present study, BDNF
has been implicated in the pathophysiology of anxiety disorders [86,87]
and there is augmentation in the expression of BDNF in cerebral cortex
of mice aer social isolation [88,89].
Results of the present study showed that injection of ALCl3 decrease
BDNF in both socialized and isolated rats but isolated rats showed
more signicant decrease than socialized rats. These findings are in
agreement with other results [90,91] e BDNF has been shown to
be decreased in the hippocampus of AD patients and it is suggested that
a loss of BDNF may contribute to the progressive atrophy of neurons in
AD. It is also possible that social isolation may reduce the protection
of the brain against AD-related damage as mentioned before [92,93].
In the current study, it has been demonstrated that SI increased
oxidative damage in the brain via enhanced lipid peroxidation
measured as MDA accompanied with depletion of endogenous
antioxidants SOD and TAC level in the brain tissue as compared to
control socialized group. These findings are in agreement with other
results that linked the short and long term SI with the generation of
oxidative stress in the brain [94,95]. Moreover, reactive oxygen species
are implicated in the pathogenesis of CNS damage; there are lines of
evidence indicating the underlying pathological consequences of stress
in the tissues by enhancement of lipid peroxidation [96]. Additionally,
previous study suggested that chronic treatment with the antioxidant
helped to reverse SI- induced oxidative damage, thus supporting the
idea that SI inuences AD pathology [20,54].
Results of the present study also showed that ALCl3 increased MDA
and decreased SOD and TAC in socialized rats. However, isolated rats
showed a signicant increase in MDA and decrease in TAC as compared
to socialized rats. Oxidative stress and synaptic damage are known to
be important factors in the pathogenesis of AD and are contributed to
Aβ generation and neurobrillary tangles formation [53,97,98]. e
production of ROS can be indirectly evaluated by analyzing MDA. It is
well known that oxidative stress and cognitive dysfunction are strongly
linked and antioxidants that modulate ROS are considered to play a
major role in improving learning and memory decits, moreover SOD
can prevent diseases linked to oxidative stress. As previously mentioned,
AL alters physiological and biochemical behavior of the living organism
and implicated in the increased brain MDA level [99]. It has been
Citation: Ali AA, Khalil MG, Elariny HA, Abu-Elfotuh K (2017) Study on Social Isolation as a Risk Factor in Development of Alzheimer’s Disease in
Rats. Brain Disord Ther 6: 230. doi: 10.4172/2168-975X.1000230
Page 7 of 10
Volume 6 • Issue 2 • 1000232
Brain Disord Ther, an open access journal
ISSN: 2168-975X
demonstrated that AL exposure increases ROS production in dierent
brain areas [66]. It also causes impairment of the antioxidant defense
system that may lead to oxidative [58,68] and attacks almost all cell
components including membrane lipids producing lipid peroxidation
[67,100]. us, oxidative stress could be one of the main contributing
factors for AL-induced CNS disorders [66,101]. e obtained data
revealed also a signicant inhibition in the activities of SOD and TAC
in the brain tissue of socialized rats and of TAC of isolated rats treated
with ALCl3. These findings are in harmony with the study of [102]
as regarding lower SOD with AL exposure which may attribute to the
altered conformation of SOD molecule as a result of AL-SOD complex
formation. Also, AL-intoxicated rats showed a decrease in brain TAC.
Long term exposure to oxidative stress due to AL exposure leads to
exhaustion of antioxidative enzymes [66]. In addition, Aβ can induce
oxidative stress with increased production of hydrogen peroxide and
lipid peroxides in neurons. Finally, oxidative stress plays an important
role in the development and progression of AD [51].
Results of the present study also showed that SI for a long period
resulted in brain neurological damage indicated by a signicant
elevation in inammatory mediators (IL-1β, TNF-α) in the brain
as compared to control socialized group. These findings are in
agreement with [26] who found that SI increases oxidative stress and
inammatory reaction. Also, [49] reported that rats subjected to SI
showed elevate IL-1ß protein levels in the hippocampus. Furthermore,
inammatory markers associated with isolation can be increased in
AD patients [103] together with increased the rate of cognitive decline
[104]. Moreover, impaired inammatory control and unregulated
inammation are highly linked to AD pathogenesis [103,105]. Also,
IL-1 plays an important role in the process of neuroinammation and
in the pathogenesis of AD through its inhibition on other inammatory
factors such as TNF-α and IL-1β [106]. In addition, TNF-α is one of the
major proinammatory response regulators in the brain [107]. Previous
study ndings showed that TNF-α could increase the neurotoxicity and
resulted in cellular damage [108]. It is worthy to note that, cognitive
decline in can be improved by TNF-α inhibition [109]. is would
explain the increase in IL1β and TNF-α observed in the AL treated rats
in present work.
Results of the present study also showed that ALCl3 signicantly
elevate inammatory mediators (IL-1β, TNF-α) in the brain of
isolated rats more than socialized rats. It has been speculated that this
inammatory response associated with the presence of neuritic plaques
is secondary to accumulation of Aβ and is involved in neuronal damage
and in the progression of AD [110]. Aggregation of Aβ can activate
microglia and induces the production of dierent factors as nitric oxide
(NO), ROS, chemokines and proinammatory cytokines (TNF-α, IL-
1β) that promote neuronal death [111,112]. On the other hand, stress
and inammatory mediators enhance the production of APP and
restricts the generation of its soluble fraction which provides neuronal
protection [113,114].
Long period of SI also resulted in brain neurological changes
as indicated by a signicant reduction in brain monoamins (DA,
NE, 5-HT) as compared to control socialized group. These findings
are in agreement with other studies [20,115] which stated that
SI decreases noradrenergic and serotonergic neurons in the brain.
Frontal cortex and hippocampus of animals have been damaged by
SI leading to abnormal function of neurotransmission [116,117].
Additionally, previous studies have reported that SI elicits a variety of
behavioral abnormalities which may be attributed to deciency in the
brain neurotransmitters as NE, 5-HT or DA [118-120]. It is worthy to
mention that higher 5-HT levels were observed in socialized rats; this
nding is consistent with the postulation that increased utilization of
5-HT during SI cannot be compensated by an increase in its synthesis,
thus leading to depressive-like behaviors [121,122]. It is well known
that, 5-HT together with BDNF can facilitate the maintenance and the
formation of synapses in CNS [121]. In addition, 5-HT increases BDNF
expression while BDNF ensures neuron survival of 5-HT [122,123]. On
the other hand, socialization improves BDNF and induces higher levels
of 5-HT [122,124]. Previous reports demonstrated that isolated animals
showed NE depletion which could account for the observed depressive-
like behaviors [122,125]. Additionally, SI in rats can alter dopamine
concentrations in the cortex and in other brain regions [126,127].
Results of the present study also showed that injection of ALCl3
to both socialized and isolated rats signicantly decrease brain
monoamins (DA, NE, 5-HT) but isolated rats showed more pronounced
reduction than socialized rats. These findings are in agreement
with other studies [128,129], they found that these neurotransmitters
are signicantly decline with AD. It is also conrmed that, AL
neurotoxicity are linked, to deciencies of these neurotransmitters. It
is well known that, altered production of neurotransmitters produces
severe neurological illness [130].
Finally, the occurrence of DNA fragmentation is demonstrated
by gel electrophoresis. Labeled DNA isolated from control isolated,
AD socialized and isolated groups induced characteristic DNA
fragmentation which is characteristic of apoptotic cell degeneration,
these ndings are in agreement with the opinion of [131] In addition,
histopathological examinations have conrmed the biochemical results
and showed that brain specimens of control isolated and AD socialized
groups showed focal nuclear pyknosis as well as degeneration in the
neuronal cells of cerebral cortex associated with atrophy in some
neurons of the substantia nigra but no histopathological alteration
in the hippocampus as well as in the striatum. Additionally, brain
specimens of AD isolated group showed marked pathological changes
as indicated by nuclear necrosis and degeneration in cerebral cortex
associated with focal gliosis. Finally, Hippocampus, neurons of the
fascia dentate, striatum and substantia nigra showed nuclear pyknosis
and degeneration with congestion in the blood vessels. ese ndings
conrm the other measured biochemical parameters and are in
harmony with other studies concerning some of these measurements
[17,100,132].
Conclusion
Social isolation for a long period causes severe brain neurological
degenerations as indicated by the biochemical and the histopathological
changes as well as DNA fragmentation; these degenerations are more
pronounced in isolation-associated AD rat model than socialized ones.
Accordingly, SI can be identied as a risk factor in AD development.
Consequently, socialization is advised especially with AD to avoid
severe progression of the disease.
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... In animals, social isolation (via individual housing) has been shown to exacerbate memory deficits and promote cognitive decline by increasing systemic inflammation [135,136], oxidative stress [135], neuroinflammation [137], and A␤ levels [135,137], and by decreasing BDNF levels and neurogenesis [135,138,139]. ...
... In animals, social isolation (via individual housing) has been shown to exacerbate memory deficits and promote cognitive decline by increasing systemic inflammation [135,136], oxidative stress [135], neuroinflammation [137], and A␤ levels [135,137], and by decreasing BDNF levels and neurogenesis [135,138,139]. ...
... In animals, social isolation (via individual housing) has been shown to exacerbate memory deficits and promote cognitive decline by increasing systemic inflammation [135,136], oxidative stress [135], neuroinflammation [137], and A␤ levels [135,137], and by decreasing BDNF levels and neurogenesis [135,138,139]. ...
Article
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A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.
... The disease is clearly diagnosed by the presence of extracellular amyloid β (Aβ) peptide deposits in the form of plaques as well as intracellular neurofibrillary tangles in postmortem brains [2]. Increased Al ingestion can lead to Aβ deposition in central nerve cells and over-expression of the β-amyloid precursor protein, therefore it can be seen as a possible etiological factor in AD [3]. There is a direct relationship between Aβ and oxidative stress. ...
... Aβ is known to cause increased production of reactive oxygen species (ROS) which can lead to the destruction of neuronal membrane, proteins, lipids, and nucleic acids and induces membrane lipid peroxidation and also damage mitochondria, which can lead to further enhanced production. Subsequently, oxidative stress is thought to play a powerful role in the pathogenesis of AD [3,4]. Also, the brain tissue has a low antioxidant concentration and contains a lot of unsaturated fatty acids which are especially vulnerable to free radical attacks [5]. ...
... Also, the brain tissue has a low antioxidant concentration and contains a lot of unsaturated fatty acids which are especially vulnerable to free radical attacks [5]. Also, administration of AlCl 3 significantly elevates inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL-1β), secondary to Aβ aggregation which is involved in neuronal damage and AD progression [3]. Therefore, antioxidant and anti-inflammatory substances can play a fundamental part in the prevention and treatment of AD [5]. ...
Article
Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is exacerbated by social isolation (SI) and protein malnutrition (PM). Antioxidants, physical and mental activities (Ph&M) can maintain cognitive functions and protect against dementia. Objective To investigate the impact of Epigallocatechin-3-gallate (EGCG), Vitamin E (VE), Vitamin C (VC), and Selenium (Se), in enhancing the potential effect of Ph&M versus SI&PM as risk factors in the progression of AD in rats. Methods Aluminum chloride (70 mg/kg, I.P for 5 weeks) was used to induce AD in rats that either normally fed or socially isolated and protein malnourished (SI&PM). Simultaneously, rats were weekly exposed to Ph&M either alone or in combination with EGCG (10 mg/kg, I.P), VC (400 mg/kg, P.O), VE (100 mg/kg, P.O), and Se (1 mg/kg, P.O). Results The combination protocol of EGCG, VE, VC, and Se together with Ph&M significantly increased brain monoamines, superoxide dismutase (SOD), total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) in AD, SI&PM and SI&PM/AD groups. Additionally, this regimen significantly mitigated brain acetylcholine esterase (ACHE), β-amyloid (Aβ), Tau protein, β-secretase, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and Interleukin 1β (IL-1β) as well as DNA fragmentation. These biochemical findings were supported by the histopathological examinations of brain tissue. Conclusion The combination protocol of antioxidants with Ph&M activities mitigated SI&PM-induced progressive risk of AD.
... CA1 is the zone that is most sensitive and vulnerable to various insults and oxidative stress [7] . Increased oxidative stress underlay the adverse effects of SI that raise concern about antioxidants administration [8] . Melatonin (MT) is a hormone secreted from the pineal gland with a regulatory and neuroprotective function. ...
... That might be related to the recovery state of the tissue and decline in degeneration process. Co-administration of MT resulted in a sig increase in SOD and TAC levels and decrease MDA level due to its antioxidant effects [8] . Dopamine expression in the current study was sig increased in SI + MT group compared to other groups, in contrary to many authors who concluded that SI resulted in increased dopamine expression compared to socialized animals, but still with unclear mechanism [35] . ...
... Acetylcholine and ACHE neuro-transmittors are a key factor in learning and memory and maintaining the nervous system [37] . This finding is in agreement with previous study who studied the relation between ACHE decline and decrease brain function, memory and learning ability [8] . On the contrary to this finding, no sig change in ACHE between socialized and isolation-reared mice were noticed [38] . ...
... Furthermore, impaired social memory in AD patients may lead to patients developing apathy toward social engagement and can result in a preference for introversion. Due to the importance of social interaction for cognition and mental health (reviewed in: Berkman et al., 2000;Leser and Wagner, 2015), social isolation caused by AD could further worsen disease progression (Wilson et al., 2007;Ali et al., 2017). Currently, there is no cure or effective treatment available due to the limited understanding of the pathological mechanisms underlying AD. ...
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Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer’s disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear. In this study, we used local injections of AAV virus containing a dominant-negative (DN) Rac1 under the control of CaMKIIα promoter and found that the reduction of Rac1 hyperactivity in ventral hippocampal excitatory neurons improves social recognition memory in APP/PS1 mice. Expression of DN Rac1 also improves long-term potentiation, a key synaptic mechanism for memory formation. Our results suggest that overactivation of Rac1 in hippocampal excitatory neurons contributes to social memory deficits in APP/PS1 mice and that manipulating Rac1 activity may provide a potential therapeutic strategy to treat social deficits in AD.
... Depression originated from loneliness and social disconnection is a strong risk factor for AD and CVD in human beings [75][76][77][78]. The pathomechanisms responsible for the increased incidence of AD and CV dysfunction in depressive patients are poorly understood. ...
Article
Depression is a risk factor for Alzheimer’s (AD) and cardiovascular diseases (CVD). Therefore, depression treatment restricts its deteriorating effects on mood, memory and CV system. Fluoxetine is the most widely used antidepressant drug, it has neuroprotective effect through its antioxidant/anti-inflammatory properties. The current study investigated for the first-time the cross link between depression, AD and CVD besides, role of fluoxetine in mitigating such disorders. Depression was induced in rats by social isolation (SI) for 12 weeks, AlCL3 (70 mg/kg/day, i.p.) was used to induce AD which was administered either in SI or normal control (NC) grouped rats starting at 8th week till the end of the experiment, fluoxetine (10 mg/kg/day, p.o) treatment also was started at 8th week. SI and AD showed a statistically significant deteriorated effect on behavioral, neurochemical and histopathological analysis which was exaggerated when two disorder combined than each alone. Fluoxetine treatment showed protective effect against SI, AD and prevents exacerbation of CVD. Fluoxetine improved animals’ behavior, increased brain monoamines, BDNF besides increased antioxidant defense mechanism of SOD, TAC contents and increased protein expression of Nrf2/HO-1 with significant decrease of AChE activity, β-amyloid, Tau protein, MDA, TNF-α, IL1β contents as well as decreased protein expression of NF-kB, TLR4, NLRP3 and caspase1. It also showed cardioprotective effects as it improved lipid profile with pronounced decrease of cardiac enzymes of CK-MB, troponin and MEF2. In conclusion, fluoxetine represents as a promising drug against central and peripheral disorders through its anti-inflammatory/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways.
... Surprisingly, a meta-analysis of the association between social support-social integration and neuroinflammation has shown that inflammatory cytokines were significantly reduced in the social support group (Uchino et al., 2018). In addition, social interaction significantly reduced the activity of IL-1β and TNF-α in a rat model with AD (Ali et al., 2017). These results reveal that increased emotional or social interaction alleviates the neuroinflammatory response. ...
Article
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Alzheimer’s disease (AD) is an irreversible neurodegenerative brain disorder with aggregation of amyloid-beta (Aβ) and tau as the pathological hallmarks. AD is the most common form of dementia and is characterized by a progressive decline of cognition. The failure of pharmacological approaches to treat AD has resulted in an increased focus on non-pharmacological interventions that can mitigate cognitive decline and delay disease progression in patients with AD. Animal-assisted intervention (AAI), a non-pharmacological intervention, improves emotional, social, and cognitive dysfunction in patients with neurodegenerative diseases. In particular, AAI is reported to mitigate the effects of cognitive impairment in patients with AD. Despite the positive effects of AAI on cognitive dysfunction in patients with AD, there have been no studies on how AAI affects AD-related pathologies. This review postulates potential neurological mechanisms of emotional or social interaction through AAI in countering AD-related pathologies, such as Aβ deposition, tau hyperphosphorylation, neuroinflammation, and impaired adult hippocampal neurogenesis (AHN), and proposes insights for future research by organizing accumulated previous evidence.
... The role of social isolation in increasing various oxidative stress markers have been studied before and demonstrated. The authors of an animal model of Alzheimer's indicated a significant elevation in brain MDA content to 188% as compared to the corresponding control socialized group [34]. ...
Article
Full-text available
While animal models for schizophrenia, ranging from pharmacological models to lesions and genetic models, are available, they usually mimic only the positive symptoms of this disorder. Identifying a feasible model of chronic schizophrenia would be valuable for studying the possible underlying mechanism and to investigate emerging treatments. Our hypothesis starts from the observation that combining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like features; thus, it could probably be used as the first model of chronic schizophrenia that emphasizes the characteristic of having a multifactorial etiology. By the means of this study, we investigated the effects of ketamine administration combined with isolation in inducing schizophrenia-like symptoms in male albino rats and the brain reactive oxygen species levels. Our results showed that the number of lines crossings in the open field test, the number of open arm entries in the elevated plus maze, and the spontaneous alternations percentage in the Y-maze were significantly lower in the ketamine + isolation group compared to both the control and ketamine + social housing group (p < 0.05). Furthermore, the ketamine + isolation intervention significantly increased the MDA levels and decreased the GPx levels both in the hippocampus and the cortex of the rats. In addition, our premise of creating a model capable of exhibiting both positive and negative symptoms of schizophrenia was also based on adding the aripiprazole treatment to a group of rats. Therefore, we compared the ketamine + social isolation group with the ketamine + social isolation + aripiprazole group in order to attempt to discover if the antipsychotic drug would significantly decrease the potential positive schizophrenia-like symptoms induced by social isolation and ketamine. Given that we obtained significant results, we cautiously presume that this might be an important step in developing our animal model capable of illustrating both positive and negative symptoms of schizophrenia. This study could be a first step towards the creation of a complex animal model capable of exhibiting the multifactorial origin and manifestation of schizophrenia.
... Therefore, there is a significant relationship between stress and yawning, and since social isolation is also stressful, social isolation is associated with yawning [9]. Social isolation for a long period causes severe brain neurological degenerations as indicated by the biochemical and the histopathological changes as well as DNA fragmentation [10]. Neurobiological mechanisms underlying the altered brainderived neurotrophic factor (BDNF) expression as well as the involvement of signaling pathways downstream of BDNF in chronically isolated animals [11]. ...
Article
A sample of 80 Male rats (21-day post weaning) were chosen, and were put for 6 weeks in separate cages with black plastic buffers. Eight rats were put in one group of 8 rats in a single cage (the control group) and the rest were put in individual cages: one male rat in each cage. In group 1 or the control group (social conditions) 8 rats were put in one cage. They received saline carrier and their yawning behavior was recorded for 60 minutes. Group 2 (n=8; in separate cages) (social isolation conditions) received no treatment with serotonin and dopamine agonist and antagonist and were kept in separate cages with one rat in each cage. Their yawning behavior was also recorded for 60 minutes. Group 3 (n=8; in separate cages) included the rats that received Apomorphine (dopamine agonist) at a dose of 0.08 mg/kg via subcutaneous injection (SC), and their yawning behavior was recorded for 60 minutes. Rats in group 4 (n=8; in separate cages) received serotonin agonist (m-CPP) at a dose of 0.5 mg/kg via subcutaneous injection, and their yawning behavior was recorded for 60 minutes. Group 5 (n=8; in separate cages) included rats that received Serotonin Antagonist (Mianserin) at a dose of 0.2 mg/kg via subcutaneous injection, and their yawning behavior was recorded for 60 minutes. Group 6 (n=8; in separate cages) included rats receiving dopamine antagonist (haloperidol) at a dose of 0.1 mg/kg via Intraperitoneal (IP) injection, and their yawning behavior was recorded for 60 minutes. Group 7 (n=8; in separate cages) included rats receiving Serotonin antagonist (Mianserin) at a dose of 0.2 mg/kg via subcutaneous injection 15 minutes before injection of apomorphine (dopamine agonist) and their yawning behavior was recorded for 60 minutes. Rats in group 8 (n=8; in separate cages) received dopamine antagonist (haloperidol) at a dose of 0.1 mg/kg via intraperitoneal injection (IP) 15 minutes before the injection of serotonin agonist (m-ccp), and their yawning behavior was recorded for 60 minutes. Rats in group 9 (n=8; in separate cages) received Apomorphine (dopamine agonist) at a dose of 0.08 mg/kg and Serotonin agonist (m-CPP) injected subcutaneously (SC) at a dose of 0.5 mg/kg and their yawning behavior was recorded for 60 minutes. Group 10 (n=8; in separate cages) included rats that received dopamine antagonists (haloperidol) at 0.1 mg/kg via intraperitoneal injection (IP) and antagonist serotonin (Mianserin) at 0.2 mg/kg injected subcutaneously and their yawning belabor was recorded for 60 minutes. Dopamine agonist (apomorphine) and serotonin antagonist (Mianserin) induce yawning in the social conditions and injection of haloperidol (dopamine antagonist) before serotonin agonist (m-ccp) reduces yawning in social conditions. Yawning is different in social conditions and social isolation conditions. Using Meta-Chlorophenylpiperazineserotonin (serotonin agonist), Mianserin (serotonin antagonist), apomorphine (dopamine agonist), haloperidol (dopamine antagonist) the role of serotonin and dopamine in yawning, fear, erection etc. can be investigated as a model for human studies.
... Further in the current study, IR increased hippocampal MDA, TNFα, IL6 and decrease in SOD as compared to the SR group, which is endorsed by previous studies [4,52,53]. It is previously reported that the early increase of oxidative stress likely triggered the stress response by activation of sympathetic nervous system and HPA-axis [4] leading to activation of ADRβ by NE and increasing the production of pro-inflammatory cytokines such as IL-6, which promotes a pro-inflammatory response and major elevation of cortisol [5]. ...
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Alzheimer's disease (AD) is a neurodegenerative disease characterized by gradual declines in social, cognitive, and emotional functions, leading to a loss of expected social behavior. Social isolation (SI) has been shown to have adverse effects on individual development, growth, as well as health and aging. Previous experiments have shown that SI causes an early onset of AD-like phenotypes in young APP/PS1 mice. However, the interactions between SI and AD still remain unknown. Seventeen-month old male APP/PS1 mice were either singly housed or continued group housing for 3 months. Then, AD-like pathophysiological changes were evaluated by using behavioral, biochemical and pathological analyses. Isolation housing further promoted cognitive dysfunction and Aβ plaque accumulation in the hippocampus of aged APP/PS1 mice, associated with increased γ-secretase and decreased neprilysin expression. Furthermore, exacerbated hippocampal atrophy, synapse and myelin associated protein loss, and glial neuroinflammatory reactions were observed in the hippocampus of isolated aged APP/PS1 mice. The results demonstrate that SI exacerbates AD-like pathophysiology in aged APP/PS1 mice, highlighting the potential role of group life for delaying or counteracting the AD process. © The Author 2015. Published by Oxford University Press on behalf of CINP.
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Adverse early life experience is prominent risk factors for numerous psychiatric illnesses, including mood and anxiety disorders. It imposes serious long-term costs on the individual as well as health and social systems. Hence, developing therapies that prevent the long-term consequences of early life stress is of utmost importance, and necessitates a better understanding of the mechanisms by which early life stress triggers long-lasting alterations in gene expression and behavior. Post-weaning isolation rearing of rodents models the behavioral consequences of adverse early life experiences in humans and it is reported to cause anxiety like behavior which is more common in case of females. Therefore, in the present study, we have studied the impact of social isolation of young female mice for 8weeks on the anxiety like behavior and the underlying molecular mechanism. Elevated plus maze and open field test revealed that social isolation caused anxiety like behavior. BDNF, a well-known molecule implicated in the anxiety like behavior, was up-regulated both at the message and protein level in cerebral cortex by social isolation. CREB-1 and CBP, which play a crucial role in BDNF transcription, were up-regulated at mRNA level in cerebral cortex by social isolation. HDAC-2, which negatively regulates BDNF expression, was down-regulated at mRNA and protein level in cerebral cortex by social isolation. Furthermore, BDNF acts in concert with Limk-1, miRNA-132 and miRNA-134 for the regulation of structural and morphological plasticity. Social isolation resulted in up-regulation of Limk-1 mRNA and miRNA-132 expression in the cerebral cortex. MiRNA-134, which inhibits the translation of Limk-1, was decreased in cerebral cortex by social isolation. Taken together, our study suggests that social isolation mediated anxiety like behavior is associated with up-regulation of BDNF expression and concomitant increase in the expression of CBP, CREB-1, Limk-1 and miRNA-132, and decrease in the expression of HDAC-2 and miRNA-134 in the cerebral cortex.
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