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Research Article
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Gallic Acid Improves Cognitive, Hippocampal Long-term Potentiation Deficits and Brain Damage Induced by Chronic Cerebral Hypoperfusion in Rats |
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A. Sarkaki,
H. Fathimoghaddam,
S.M.T. Mansouri,
M. Shahrani Korrani,
G. Saki
and
Y. Farbood
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ABSTRACT
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Cerebral Hypoperfusion Ischemia (CHI) has important role in
neuronal damage and behavioral deficits, including memory and Long-term Potentiation
(LTP) impairment. Protective effects of Gallic Acid (GA) on memory, hippocampus
LTP and cell viability were examined in permanent bilateral common carotid artery
occlusion in rats. Animals were divided into 9 groups: Control (Cont); sham
operated (Sho); Cerebral Hypoperfusion Ischemia (CHI); CHI received normal saline
(CHI +Veh); CHI treated with different doses gallic acid (50, 100, 200 mg kg-1
for 5 days before and 5 days after CHI induction, orally); CHI treated with
phenytoin (50 mg kg-1, ip) (CHI+Phe); and sham operated received
100 mg kg-1, orally (Sho+GA100). CHI was induced by bilateral common
carotid artery occlusion (2VO). Behavioral, electrophysiological and histological
evaluations were performed. Data were analyzed by one-way and repeated measures
ANOVA followed by tukeys post-hoc
test. GA improved passive avoidance memory, hippocampal LTP and cell viability
in hippocampus and cortex of ischemic rats significantly (p<0.01). The results
suggest that gallic acid via its antioxidative and free radicals scavenging
properties attenuates CHI induced behavioral and electrophysiological deficits
and has significant protective effect on brain cell viability. Dose of 100 mg
kg-1 GA has affected the ischemic but not intact rats and its effect
was more potent significantly than phenytoin, a routine drug for ischemic subjects.
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How
to cite this article:
A. Sarkaki, H. Fathimoghaddam, S.M.T. Mansouri, M. Shahrani Korrani, G. Saki and Y. Farbood, 2014. Gallic Acid Improves Cognitive, Hippocampal Long-term Potentiation Deficits and Brain Damage Induced by Chronic Cerebral Hypoperfusion in Rats. Pakistan Journal of Biological Sciences, 17: 978-990. DOI: 10.3923/pjbs.2014.978.990 URL: https://scialert.net/abstract/?doi=pjbs.2014.978.990
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Received: December 05, 2013;
Accepted: February 13, 2014;
Published: March 29, 2014
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INTRODUCTION
One of common pathophysiological states associated with central nervous system
is chronic cerebral hypoperfusion that frequently occurs in conditions such
as vascular dementia and Alzheimer's disease (Ozacmak et
al., 2007). Hypoperfusion brain injury is caused by the interruption
of cerebral blood flow leading to both acute and delayed degeneration of brain
cells (Xu et al., 2009a). Oxidative stress plays
an important role in animal models of brain ischemia (Horecky
et al., 2011). Reactive Oxygen Species (ROS) formation represents
the first key step to initiate oxidative damage (Silva-Adaya
et al., 2008). Oxidative stress is defined as an imbalance between
cellular antioxidant capacity and ROS (Kasparova et al., 2005).
Focal disturbance of blood flow after brain ischemia involves increase of extracellular
glutamate (Liu et al., 2010). Activation of
glutamate receptors after cerebral hypoperfusion increases excitotoxicity and
neuronal damage (Saransaari and Oja, 2010).
Vascular endothelial nitric oxide may play a critical role in spatial memory
function during cerebral brain hypoperfusion and can result in spatial memory
impairment (De La Torre and Aliev, 2005). Chronic cerebral
hypoperfusion (CHI) caused progressive and long-lasting cognitive deficits (Tohda
et al., 2004), perturbation in the memory and exacerbate cognitive
impairment in rat (Choi et al., 2011b).
GA (2, 3 ,4-trihydroxybenzoic acid) is a natural phenolic compound which finds
application in chemical industries such as dye-making, the tanning of leather
and organic synthesis (Qi et al., 2009). It
also has a wide range of biological activities such as antioxidant, anti-inflammatory,
anti-microbial and anti-cancer. The free GA content of plants is very low, at
a level which could not meet the demands of chemical industry (Kratz
et al., 2008b). The synthetic n-alkyl esters of GA, also known as
gallates, especially propyl, octyl and dodecyl gallates, are widely employed
as antioxidants by food and pharmaceutical industries (Kratz
et al., 2008a). GA has strong anti tyrosines activity (Kim,
2007) and protects the brain by improving antioxidant capacity and reducing
inflammation in a rat model of permanent brain hypoperfusion (Mansouri
et al., 2013).
Phenytoin is an anticonvulsant that has been used successfully to treat epilepsy
for many years, but its potential as a mood stabilizer has only recently been
evaluated in a controlled manner. Phenytoin up-regulates the expression of genes
related to glutamate neurotransmission (Mariotti et al.,
2010). On the other hand, phenytoin is known to interact with the voltage-dependent
Na+ channels responsible for action potential generation and has
positive effect on dura healing (Ergun et al., 2011).
Chronic cerebral hypoperfusion, induced by 2VO, is related to neurological disorders
and contributes to cognitive decline (He et al.,
2012).
The aim of present study was to evaluate the effects of GA on memory, hippocampal
long-term potentiation (LTP) and cell viability in rats with cerebral hypoperfusion/ischemi.
MATERIALS AND METHODS
Animals: Adult male Wistar rats (250-300 g) were obtained from the central
animal house of the Shahrekord University of Medical Sciences, Shahrekord-Iran).
They were maintained in a temperature-controlled room (21±2°C), on
a 12/12 h light/dark cycle and with food and water available ad libitum. Animals
were randomly divided into 9 experimental groups with 14 in each as following:
(1) Control (Cont) (2) Sham-operated (Sho) (3) With Cerebral Hypoperfusion Ischemia
(CHI) in which bilateral common carotid arteries were occluded (4) CHI received
normal saline (2 mL kg-1, orally) (5-7) CHI received different doses
gallic acid (CHI+GA50-200) (8) CHI received 50 mg kg-1, i.p. phenytoin
(CHI+Phe) (Wu et al., 1989) (9) sham operated
received 100 mg kg-1 GA (Sh+GA100) orally as positive control group.
All procedures were done in accordance with the guides for the care and use
of laboratory animals adopted by National Institute of Health and with the Federation
of Iranian Societies for Experimental Biology.
Experimental design: GA administration was started 5 days before surgery
to make CHI and continued for 5 consecutive days after CHI induction. On 5th
day the 2VO surgery was applied. The treatment schedule and the intervals for
estimation of various parameters have been presented in Fig. 1.
Permanent cerebral hypoperfusion induction: Permanent cerebral hypoperfusion
was induced by occlusion of the bilateral common carotid arteries (2VO) by ligation
with silk threads and cutting (Xu et al., 2012)
under appropriate anesthesia with ketamine/xylazine (50/5 mg kg-1)
(Roohbakhsh et al., 2007). A neck ventral midline
incision was made and the common carotid arteries were then exposed and gently
separated from the vagus nerve. The sham operated animals underwent a similar
surgery but vessel ligation was excluded.
Neurological evaluation: Behavioral assessment such as sensorimotor
tests were done to prove the ischemic brain damage in all groups of animals
5 days after the operation by an examiner who was blind to the type of surgical
procedure. It consisted of six tests developed and described by (Garcia
et al., 1995) with some modifications. The scores assigned to each
rat at the end of the examination is the sum of the six tests scores. Each animal
with summation score at least 3 for all six tests assign as CHI model in this
study.
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Fig. 1: |
Design of experimental protocols. BR: Brain removing for histological
and molecular studies |
Spontaneous activity: The animal was observed for 5 min in its normal
environment. The rats activity was assessed by its ability to approach
all four walls of the cage. Scores were given as following: score 3, rat moved
around, explored the environment and approached at least three walls of the
cage; score 2, slightly affected rat moved about in the cage but did not approach
all sides and hesitated to move, although it eventually reached at least one
upper rim of the cage; score 1, severely affected rat did not rise up at all
and barely moved in the cage and score 0, rat did not move at all.
Symmetry in the movement of four limbs: The rat was held in the air
by the tail to observe symmetry in the movement of the four limbs. Scores were
given as following: score 3, all four limbs extended symmetrically; score 2,
limbs on left side extended less or more slowly than those on the right; score
1, limbs on left side showed minimal movement and score 0, forelimb on left
side did not move at all.
Forepaw outstretching: The rat was brought up to the edge of the table
and made to walk on forelimbs while being held by the tail. Symmetry in the
outstretching of both forelimbs was observed while the rat reached the table
and the hind limbs were kept in the air. Scores were given as following: score
3, both forelimbs were outstretched and the rat walked symmetrically on forepaws;
score 2, left side outstretched less than the right and forepaw walking was
impaired; score 1, left forelimb moved minimally and score 0, left forelimb
did not move.
Climbing: The rat was placed on the wall of a wire cage. Normally the
rat uses all four limbs to climb up the wall. When the rat was removed from
the wire cage by pulling it off by the tail, the strength of attachment was
noted. Scores were given as following: score 3, rat climbed easily and gripped
tightly to the wire; score 2, left side was impaired while climbing or did not
grip as hard as the right side and score 1, rat failed to climb or tended to
circle instead of climbing.
Body proprioception: The rat was touched with a blunt stick on each
side of the body and the reaction to the stimulus was observed. Scores were
given as following: score 3, rat reacted by turning head and was equally startled
by the stimulus on both sides; score 2, rat reacted slowly to stimulus on left
side and score 1, rat did not respond to the stimulus placed on the left side.
Response to vibrissae touch: A blunt stick was brushed against the vibrissae
on each side; the stick was moved toward the whiskers from the rear of the animal
to avoid entering the visual fields. Scores were given as following: score 3,
rat reacted by turning head or was equally startled by the stimulus on both
sides; score 2, rat reacted slowly to stimulus on left side and score 1, rat
did not respond to stimulus on the left side.
The score given to each rat at the completion of the evaluation is the summation
of all six individual test scores. The minimum neurological score is 3 and the
maximum is 18.
Passive avoidance test: The passive avoidance apparatus (Shuttle box)
consisted of two illuminated/darken compartments. The cognitive test was performed
at 8:00-11:00 am. The rat was placed in the lighted compartment while a guillotine
door was opened and allowed to explore into both compartments for 5 min. After
10 min the rat was placed in the lighted compartment again facing away from
the closed guillotine door and ten seconds later the door was raised and the
entering delay of rat into the darken compartment was recorded as Initial Latency
(IL). After then the guillotine door was closed and a 50 Hz square wave, 1.2
mA constant current electrical single shock was delivered to rat foot paws for
1.5 sec. On the retention test that given 24 h after the acquisition trial,
the rat was again placed into the illuminated compartment and the step-through
latency (STL) and the time spent in the darken compartment were recorded as
a measure of retention performance (Lashgari et al.,
2006). The maximum latency was 300 sec.
Electrophysiological studies
Surgery: Rats were anesthetized with intraperitoneal injection of
ketamine/xylazine (90/10 mg kg-1) and their heads mounted in a stereotaxic
device for surgery (electrode implantation and EPSP recording). A heating pad
was used to maintain the animals body temperature at 36.5±0.5°C.
The bipolar metal wire recording and stimulating microelectrodes were positioned
in the granular cells of DG (tungsten wire, CFW, USA) with stereotaxic coordination
of AP= -3.8 mm from bregma; ML= -2.3 mm; DV= -3.5 mm from dura (Paxinos
and Waston, 2006) and Perforant Pathway (PP) (stainless steel; 0.125 mm
diameter, Advent Co., UK) at AP: -7.5 from bregma, ML: -4, DV: -3.9 mm from
the dura, respectively (Roohbakhsh et al., 2007).
Implantation of electrodes at the correct position was determined by fEPSP recording
(Lashgari et al., 2006) and histological verification
at the end of experiments.
Electrophysiological recordings and LTP induction: The field potential
recordings were obtained in the granular cells of the DG following stimulation
of the PP. Test stimuli were delivered to the PP every 30 sec. Electrodes were
positioned to elicit a maximal field Population Spike (PS) and field excitatory
post synaptic potential (fEPSP). The PS amplitude was measured as the difference
of voltage between the peak of the first positive wave and the peak of the first
negative deflection. The slope of fEPSP was measured as the maximum slope between
initial point of fEPSP and the first positive peak of wave in order to measure
synaptic efficacy. Extracellular field potentials were amplified (1000x); band
pass filtered between 0.1Hz-3kHz, digitized and recorded, after then analyzed
with using potentialize software (Science Beam Co. Version 1.107, Iran). LTP
was induced by using high-frequency stimuli (HFS) protocols of 400 Hz (10 bursts
of 20 stimuli, 0.2 ms stimulus duration, 10 sec interburst interval) at a stimulus
intensity that evoked a PS amplitude of approximately 80% of maximum response.
All potentials employed as baseline before and after HFS were evoked at a stimulus
intensity which produced 40% of its maximum amplitude by input/output (I/O)
curve with different intensities for LTP recording. Both fEPSP and PS were recorded
in the periods of 5, 15, 30, 45 and 120 min after the HFS in order to determine
any changes in the synaptic response of DG neurons (Lashgari
et al., 2006).
Histology: At the end of electrophysiological evaluations rats were
deeply anesthetized with chloral hydrate (350 mg kg-1) and perfused
transcardially by 200 mL of normal saline followed by 600 mL of 4% paraformaldehyde
solution. The brains were removed and immersion-fixed in 5% paraformaldehyde
solution for 10 days. Afterward, each brain was dehydrated in graded ethanol
solutions and embedded in paraffin. Coronal serial sections with 5 μm thickness
were cut. Ten sections including hippocampal formation and cerebral cortex were
selected by random systemic sampling from each animal and stained by hematoxylin-eosin.
The cytoarchitectonic borders of granular layer of DG were defined according
to standard cytoarchitectonical criteria. The granular layer of hippocampus
in both hemispheres was studied under a light microscope (BX51, Olympus, Japan)
coupled to a digital camera (objective lensx100; Olympus, Japan). The magnification
was calculated by an objective micrometer. For counting of dark neurons on each
section, at least ten microscopic fields were selected by uniform systematic
random sampling in granular layer of hippocampus. Glial cells were distinguished
from neurons based on their nuclear shape, size, cytoplasm location and characteristic
staining (Nazem et al., 2012).
Statistical analysis: Data were expressed as Mean±SEM of mean
and processed by SPSS ver.17. Data from the behavioral and electrophysiological
experiments were analyzed by one-way and two-way Analysis of Variance (ANOVA)
with repeated-measures for lesion and treatments as independent variables and
session as the repeated measure. All analyses were followed by post hoc Tukeys
test. P-value less than 0.05 considered to be statistically significant. The
symbols * and # mean differences with sham operated and cerebral hypoferfusion/ischemia
groups, respectively.
RESULTS
No differences were seen between control (Cont) and sham operated (Sho) groups
during analyzing the all parameters. So, the other groups were compared only
with Sho group in all experiments.
Sensorimotor score: Figure 2 shows the sensorimotor
scores 5 days after 2VO operation. There was significant sensorimotor impairment
in CHI rats when compared to Sho group (p<0.001). Treatment with GA started
5 days before the 2VO surgery for 10 days improved sensorimotor scores in CHI+GA100
and CHI+GA 200, while there was not any difference between them (p<0.001
vs. CHI). No significant differences were between CHI+Phe with CHI groups and
between Sho with Sho+GA100 groups, respectively.
Passive avoidance memory: The Step Through Latency (STL) in sham operated
(Sho), CHI without any treatment and CHI groups treated with GA, normal saline
or phenytoin have shown in Fig. 3.
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Fig. 2: |
Sensorimotor scores 5 days after 2VO operation in CHI group.
Treatment with GA started 5 days before the 2VO surgery for 10 days improved
sensorimotor scores in CHI+GA100 and CHI+GA 200 (p<0.001 vs. CHI). No
significant differences were between CHI+Phe with CHI groups and between
Sho with Sho+GA100 groups, respectively |
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Fig. 3: |
Mean±SEM of step down Latency (SDL) in Sham operated
(ShO), CHI, CHI+Veh, CHI+GA (50, 100 and 200 mg kg-1, orally),
CHI+Phenytoin (CHI+Phe) and Sho+GA100 groups during passive avoidance memory
(***p<0.001 vs. Sho and ### p<0.001 vs. CHI group, n = 14, one way
ANOVA followed by Tukeys post hoc test) |
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Fig. 4: |
Recorded PS (LTP) traces before (as base EPSP) and 15, 30,
45 and 120 min after high frequency stimulation (HFS, 400 Hz) in different
groups |
STL decreased significantly in CHI and CHI+Veh groups when compared with Sho
group (p<0.001). STL was significantly increased in CHI+GA100 and CHI+GA200
groups (with same effect) when compared to CHI group (p<0.001). In this case
there was no significant difference between CHI+Phe with CHI or CHI+Veh groups.
Electrophysiological results: Figure 4 shows that
recorded PS traces before and 15, 30, 45 and 120 min after high frequency stimulation
(HFS, 400 Hz) in different groups.
PS amplitude: As shown in Fig. 5, the PS amplitude
(% PS Amp) was not difference between control (Cont) and sham operated (Sho)
groups. Amp decreased significantly in CHI during all LTP recording times when
compared with sham operated group (p<0.001, Fig. 5a). PS
amplitude was improved significantly (p<0.00, Fig. 5b)
in CHI+GA100 and CHI+GA200 groups (with same effect) during all LTP recording
times when compared with CHI or CHI+Veh (CHI+GA200 group didnt show here).
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Fig. 5(a-c): |
Mean±SEM of percents of amplitude of Population Spikes
(PS) in different groups during basal fEPSP and LTP recorded from hippocampal
Dentate Gyrus (DG) at different times after High Frequency Stimulation (HFS)
to brain perforant path (PP), (a) Cont, Sho, CHI and CHI+Veh groups (b),
in Sho, CHI, CHI+GA50, CHI+GA100 and CHI+Veh groups and (c) Sho, CHI+GA100,
CHI+Phe and Sho+GA100 groups. (Repeated measures two-way ANOVA, followed
by Tukeys post hoc test, (n=14, ***p<0.001 vs. Sho group and ###
p<0.001 vs. CHI group) |
The effect of gallic acid was more effective than phenytoin as a routine drug
used in cerebral ischemic subjects to improve PS amplitude during all LTP recording
times in 2VO rats, but it was significant only during 120th recording
time (p<0.05). There was no difference between PS amplitude of Sho+GA100
and Sho group (Fig. 5c).
PS slope: As shown in Fig. 6, the PS slope has no
difference between control (Cont) and sham operated (Sho) groups. The slope
of population spikes in CHI group was significantly lower than Sho group during
all LTP recording times (p<0.001, Fig. 6a). The PS slope
in CHI group treated with 100 mg kg-1 GA (CHI+GA100) was improved
significantly when compared with CHI or CHI+Veh groups (p<0.001, Fig.
6b). Treatment ischemic groups with gallic acid 100 and 200 mg kg-1
(with same effects) improved the PS slope more power than currently medication
with 50 mg kg-1 phenytoin for brain ischemia (CHI+GA200 groups didnt
show here) (p<0.001, Fig. 6c).
PS AUC: As shown in Fig. 7, Area Under the Curve (AUC)
of Population Spike (PS) wasnt different in control and sham operated
groups while AUC in CHI group significantly decreased in comparing to sham operated
group (Sho) during all LTP recording times after HFS (p<0.001, Fig.
7a). There was no significance difference between AUC of PS in CHI, CHI+Veh
and CHI+GA50 groups. Treatment with GA 100 and 200 mg kg-1 (with
same effects) increased AUC of PS during all LTP recording times after HFS in
comparing to CHI or CHI+Veh groups (p<0.001, Fig. 7b).
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Fig. 6(a-c): |
Mean±SEM of percents of slope of Population Spikes
(PS) in different groups during basal fEPSP and LTP recorded from hippocampal
Dentate Gyrus (DG) at different times after High Frequency Stimulation (HFS)
to brain Perforant Path (PP), (a) Cont, Sho, CHI and CHI+Veh groups, (b)
Sho, CHI, CHI+GA50, CHI+GA100 and CHI+Veh groups and (c) Sho, CHI+GA100,
CHI+Phe and Sho+GA100 groups. (Repeated measures two-way ANOVA, followed
by Tukeys post hoc test, (n=14, ***p<0.001 vs. Sho group
and ### p<0.001 vs. CHI group) |
As shown in Fig. 6c there were no differences between CHI+Veh
with CHI+Phe and Sho with Sho+GA100 groups, but CHI groups treated with doses
100 and 200 mg kg-1 GA (not shown GA+200 group at here) improved
AUC of PS during 5, 15 and 30 min after HFS significantly (p<0.05, Fig.
7c). While treatment the ischemic group with phenytoin didnt change
the AUC when compared to CHI+Veh group.
Cell viability in hippocampus and cerebral cortex: The cell viability
was measured to evaluate the protective potential of GA on the cells against
oxidative stress in brain regions. As shown in Fig. 8 cell
viability level in CHI rats were found to be significantly depleted when compared
with Sho group in the hippocampus and cerebral cortex (p<0.001, Fig.
8a and b). Treatment the CHI rats with GA but not phenytoin (CHI+GA100 or
CHI+GA200) was able to raise hippocampus cells viability levels in comparing
to CHI group (p<0.05, p<0.001, Fig. 8a). Cell viability
level in CHI+GA200 significantly prevented neuronal depletion in cerebral cortex
(p<0.01, Fig. 8b).
Figure 9 shows a high number of dead neurons in CHI group
when compared with Sho (Fig. 9a, b). Treatment
the CHI rats with GA (100 or 200 mg kg-1, orally) significantly prevented
neuronal damage in both cerebral cortex and hippocampus (Fig.
9c).
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Fig. 7(a-c): |
Mean±SEM of percents of Area Under Curve (AUC) of Population
Spikes (PS) in different groups during basal fEPSP and LTP recorded from
hippocampal Dentate Gyrus (DG) at different times after High Frequency Stimulation
(HFS) to brain Perforant Path (PP) (a) Cont, Sho, CHI and CHI+Veh groups,
(b) Sho, CHI, CHI+GA50, CHI+GA100 and CHI+Veh groups and (c) Sho, CHI+GA100,
CHI+Phe and Sho+GA100 groups. (Repeated measures two-way ANOVA, followed
by Tukeys post hoc test, (n = 14, ***p<0.001 vs. Sho group
and #p<0.05 and ### p<0.001 vs. CHI group) |
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Fig. 8(a-b): |
Cell viability level of hippocampus and cerebral cortex in
different groups. Cell viability in CHI rats were found to be significantly
depleted when compared with Sho group (p<0.001, (a and b). Treatment
the CHI rats with GA but not phenytoin was able to raise cells viability
levels in hippocampus and cerebral cortex when compared to CHI group (p<0.05,
p<0.001) |
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Fig. 9(a-c): |
(a) High No. of dead neurons in CHI group (b) When compared
with Sho group and (c) Treatment the CHI rats with GA (100 or 200 mg kg-1,
orally) significantly prevented neuronal damage in hippocampus (c) |
DISCUSSION
Permanent occlusion of the common carotid arteries in rats is an established
procedure to investigate the effects of chronic cerebral hypoperfusion on brain
cognitive, electrophysiological dysfunctions and neurodegenerative processes
(Cechetti et al., 2012b). Here we have reported
that GA is effective in recovering avoidance memory deficit in rats when applied
before and after the ischemic event (Cechetti et al.,
2012a). Reduction of cerebral blood flow is an important risk factor for
dementia states and other brain dysfunctions. We demonstrate that chronic brain
hypoperfusion leads to memory impairment, brain electrophysiology, sensorimotor
disturbance, decrease spontaneous activity, loss of symmetry in the movement
of four limbs and abnormality in gait performance. Cognitive deficits were described
earlier for this experimental model and indicate the adequacy for studying vascular
dementia (Cechetti et al., 2010). It has been
suggested that the functional cognitive deficits after hypoperfusion are associated
with impairment of synaptic transmission, lower number of pyramidal neurons
and induced neurodegeneration in the hippocampal CA1 region (Cechetti
et al., 2012b). The present study indicated that GA dramatically
protected the brain against chronic brain hypoperfusion-induced deterioration
of memory in rat. Our study showed that the chronic brain hypoperfusion model
was an efficient model of neurodegenerative disorders as shown before and well
established experimental model to investigate neuronal damage and cognitive
impairment that occurs in human after CHI, ageing and Alzheimer's disease (Vicente
et al., 2009).
Cognition is a collective term for higher cortical functions such as thinking,
remembering, knowing, planning and analyzing. Cognition is crucial for a person
to become aware of his/her situation, needs and goals and meet the challenges
of daily life (Dardiotis et al., 2012). Pathophysiology
of cognitive impairment in heart failure is also the development of cerebral
abnormalities as a result of chronic hypoperfusion (Shibata
et al., 2004). Chronic cerebral hypoperfusion induces microvascular
changes that could contribute to the progression of vascular cognitive impairment
and dementia in the aging brain (Hai et al., 2013;
Marquez-Martin et al., 2012). Our results in
this experiment are consistent with previous studies that replicated memory
impairment in rats with CHI (Zhang et al., 2013).
General cognitive dysfunction were most correlated with cerebral hypoperfusion
(Yoon et al., 2012).
Hippocampus is very sensitive to ischemia and the some its subdivisions are
characterized by a low capillary density as compared with the neighboring other
subdivisions (Cavaglia et al., 2001; Farkas
et al., 2007). In other hand, on base of knowledge hippocampus plays
a crucial role in learning and memory processing. Thus it is very sensitive
to CHI in relation to other areas of brain. Our results showed that 2VO to weaken
memory and Population Spikes (PS) recorded from hippocampus DG subdivision.
Several investigations such as following reports have already established neuronal
damage due to cerebral ischemia. Neuronal cell death is caused by a serial pathophysiological
events after cerebral ischemic stroke, so called ischemic cascade
like energy failure, excitotoxicity, oxidative stress, inflammation, apoptosis
(Dahiya et al., 2010). Ischemia causes acute
necrotic death in the "core" of the ischemic area by leading to resting membrane
potential disruption and neuronal swelling (Dirnagl et
al., 1999; Saulle et al., 2002). So,
cerebral ischemia could weaken and disrupt the synaptic transition and hippocampal
PS in animals as well as humans (Squire and Zola, 1996).
In addition, it seems a few cells of brain will damage or die after ischemia
due to intracellular Ca+accumulation induced by activation of NMDA receptors
in important brain area. Certain studies showed that 2VO causes an increase
in the NMDA receptor density in the hippocampus and excessive Ca+2
influx through NMDA receptors is a major mechanism for neurodegeneration following
stroke and brain trauma (Shinno et al., 1997).
So, brain ischemia causes the rise in the glutamate (Glu) level in the brain
interstitial fluid (Davalos et al., 2000). Decrease
of this excess Glu may improve the consequences and outcome of ischemic conditions
(Gottlieb et al., 2003). This finding is consistent
with some previous findings (Shinno et al., 1997;
Farkas et al., 2007).
GA is a well known natural compound with potent antioxidant and free radical
scavenging abilities (Ding et al., 2012). In
nature, GA metabolites are found in two forms, methylated gallic acids form
and galloyl conjugates of catechin (Nabavi et al.,
2012). In addition to their antioxidant effects, there are numerous reports
on their other biological activities such as its anti-cancer and anti-apoptotic
potentials. Ligustilide was a neuroprotective agent for treating chronic cerebral
hypoperfusion injury, which may be attributed to its anti-apoptosis of neuron
and anti-proliferation of astrocyte both in cortex and in hippocampus of 2VO
rats (Feng et al., 2012).
So, GA likely has a protective effect against neurotoxicity due to NMDA receptors
sensitivity and excitotoxicity induced by glutamate after cerebral ischemia
that followed by ca+ influx and thereby intracellular ca+ accumulation induced
neuronal apoptosis. In other hand, GA with its antioxidative effect may oppose
with NMDA receptors activation and thereby has a protective effect for neurotoxicity
and/or excititoxicity following CHI.
Hypothesized that the cerebral injury of CHI may causes inflammation and demyelination
(Rosenberg, 2009) and excess Reactive Oxygen Species
(ROS) (Xu et al., 2009b) in the brain tissues
and has been suggested as a key pathological mechanisms of chronic cerebral
hypoperfusion. Highly adhesive glycoprotein von Willebrand factor multimer induces
platelet aggregation and leukocyte tethering on the injured vascular wall, contributing
to microvascular plugging and inflammation in brain hypoperfusion (Fujioka
et al., 2012). Previous studies shown that hippocampal, septohippocampal
or reticular thalamic nucleus lesions, have detrimental effects on performances
in many memory tasks (Karson et al., 2012) and
in this study cognition deficit, LTP reduction, attenuate cell viability in
cerebral cortex and hippocampus after CHI can be result of oxidative stress
in this parts of brain (data have not shown here). Also cognitive decline induced
by CHI could be related to dysfunction of the basal forebrain cholinergic system
and reduction of hippocampal mitogen-activated protein kinases activities (Choi
et al., 2011a). Chronic cerebral hypoperfusion is thought to induce
white matter lesions with oligodendrocyte death and myelin breakdown. There
is consistent evidence that cerebral hypoperfusion causes in memory deficits
(Cai et al., 2011). Activation of the Rho/Rho-kinase
pathway is related to the neuronal damage and the pathogenesis of the memory
impairment in CHI rats (Huang et al., 2008).
CONCLUSION
Our data show that GA could improve behavioral, electrophysiological and cell
viability of hippocampus and cerebral cortex by attenuate oxidative stress in
the hypoperfusion brain tissues. In other hand, GA is more effective than phenytoin,
a routine drug for cerebral ischemia in CHI rats. GA had no effects on behavioral,
electrophysiological properties and brain cell viability in healthy rats.
ACKNOWLEDGMENT
This article was extracted as a part of Mr. Mehrdad shahrani Korrani's Ph.D.
thesis. This research was supported by Physiology Research Center, Vice Chancellor
of Research, Ahvaz Jundishapur University of Medical Sciences, Iran (Grant No:
PRC-75). The authors would like to thank Researchers Eimani, Rafieian, hodjati,
Rabiei and Alibabaei, our colleagues in Shahrekord University of Medical Sciences
(Iran), for kindly help in technical support.
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