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American Journal of Life Science Researches
www.worldofresearches.com
100 Jan, 2015
© 2014, World of Researches Publication
Am. J. Life. Sci. Res. Vol. 3, Issue 1, 100-111, 2015
ISSN: 2332-0206 (Online) ISSN: 2375-7485 (Print)
Neuroprotective Efficacy of lipoic acid in Acrylamide-
Induced Neuropathy in Rats: Behavioral and
Histopathological evidence
Rashed R. Rashed and Hossam G. Tohamy
Department of Animal Husb. and Animal Wealth Develop. Fac. of Vet. Medicine
Alex. Univ. Egypt.
Department of Pathology Faculty of Veterinary Medicine Alexandria University.
Egypt.
*Corresponding Author: Rashed R. Rashed
Email: rashed.ragab@aleux.edu.eg.
INTRODUCTION
Many chemicals with broad industrials, pharmaceutical and agricultural
application produce a neurotoxic syndrome in humans and experimental animals
involving weight loss, skeletal muscle weakness and ataxia1, 2and multifocal
Abstract: The primary objective of this investigation was to assess the neuroprotective efficacy
of lipoic acid in an acrylamide (ACR) neuropathy model in rats. To this end, albino males rat were
given 50 mg ACR in drinking water, with or without lipoic acid in the diet for four weeks. A group
of untreated controls was also included in the study. All ACR-treated animals exhibited
progressive neurotoxicity as judged by landing feet spread distance and learning ability (take
along time to solve the maze). While among lipoic acid co-administrated, lipoic acid didn't
prevent the effect of ACR but it slightly decreased the severity and delayed the appearance of
signs of ACR toxicity . ACR treatment decreased significantly the time spend feeding, drinking
frequencies, sitting time, walking and running frequencies and scratching frequencies while
increased significantly time spend lying. Moreover, ACR treatment increased frequencies of
exploration . From pathological point of view, this study revealed brain lesions in rats treated
with ACR alone and ACR with lipoic acid. The cerebrum lesions were characterized by the
presence of pyknotic neuron, central chromatolysis, satellitosis, neuronophagia and finally focal
gliosis. The cerebellum of rats treated with ACR alone exhibited congestion of blood vessel and
pyknotic purkinje cells while in rats received ACR and lipoic acid showed mild pyknotic purkinje
cells.
Keywords: Neuroprotective, Efficacy, lipoic acid, Acrylamide-Induced Neuropathy, Rats,
Behavioral, Histopathological evidence.
ORIGINAL ARTICLE Received 9 Oct. 2014 Accepted 14 Dec. 2014
Neuroprotective Efficacy of lipoic acid in Acrylamide-Induced …
neurofilamentous swelling and eventual degenerations beginning from the distal
ends of peripheral nerve axons have been traditionally thought as hallmark
morphological features of acrylamide (ACR)-induced neuropathy3 . The initial
target of ACR appears to be the nerve terminals in both central and peripheral
nervous systems, resulting in autonomic, behavioral, sensory, motor
disturban es4. Mechanisms underlying the diverse neurotoxicity remain 7
controversial. approaches to reducing its toxic effects should be established.
Morphologic studies have suggested that these functional effects are associated
with distal axon injury in central and peripheral nervous systems. This type of
toxic neuropathy and is characterized by multifocal swelling of distal axon regions
and eventual retrograde axon degeneration with sparing of more proximal
sections . ACR monomer considered to be prototypical among chemicals that 1
produce distal axonopathy found that all ACR treated animals exhibited hind 5,6
limb splay, ataxia and muscle weakness with a progressive increase in gait scores
and a progressive decrease in weight studied the efficacy of eugenol and 7
isoeugenol in ACR induced neuropathy in rats and found that rats receiving ACR a
lone developed progressive gait abnormalities during the experimental period.
Among rats receiving the spine active principles the onset of gait abnormalities
were delayed band occurred from week 3 onwards indicating their protective
effect. However after 4 weeks, all ACR treated rats developed characteristic
symptoms such as foot splay, twisting hind limbs, difficulty in ambulation and
increase landing foot spread distance. The pattern and strength of synaptic
connections are widely believed to code memory traces. Long-term potentiation
of synaptic strength (LTP) is correlated with behaviorally relevant memory
function: reductions in LTP cause memory impairments , whereas increases in 8,9
LTP are associated with enhancement of learning and memory . However, 10,11,12
the ability to store new information in neural networks depends on the degree of
plasticity of synaptic connections, as well as the number of available connections.
Therefore, number of synapses should be critical for learning and memory too.
Indeed, loss of synapses is correlated with age-dependent memory decline in
rats. , while hormones and neuropeptides, such as estrogen , 13,14,15 16
neurotophins insulin/IGF , and ghrelin , increase synaptic density and 17 , 18,19 18
improve memory. Diet, in conjunction with environmental factors, has a crucial
role in shaping brain cognitive capacity . Therefore, searching for dietary 20
components that can increase the number and plasticity of synapses might yield
new strategies to enhance learning and memory functions.
MATERIALS AND METHODS
This experiment was carried out in the laboratory animal unit of the
department of animal husbandry and animal wealth development, faculty of
veterinary medicine, Alexandria University, Egypt, during the period from
February to March 2014.
Animals : 36 male albino rats obtained from department of forensic
medicine, faculty of veterinary medicine, Alexandria University, Egypt, and
Rashed and Tohamy, 2015
102 January 2015
average weight about 160gm were randomly divided into 4 equal groups and
distributed as 9 rats/cage. The first group control group and the second received
50mg acrylamide/kg body weight. In drinking water, the third received 50mg
acrylamide in drinking water and lipoic acid in basal diet and the fourth group
received lipoic acid in basal diet. Acrylamide was dissolved at the concentration of
0.02% (w/v; corresponding to 2.8mM) in distilled water for administrations' and
lipoic acid was given at dose 0.5% (wt/wt) mixed into basal diet. Animals were
housed in open system door and provided with galvanized wire cage batteries
(55×45×30 cm/cage) and 14 -16 h of light/day. Daily temperature was ranged
between 16 to 25o C and 50 to 60% relative humidity. Food was provided ad-
libtium with commercial pelted diet contained the following nutrients. Crude
protein 16.3%, Crude fiber 3.5%, Fat 6.8%. Rats fed the ration from feeding trough
and drinking water from water trough.
Behavioral tests:
I. Behavioral observations : Animals were identified by using color paint on
their back and the behavioral observation were carried out during day light,
using focal sample according to and the behavior patterns recorded are: 21
A. Ingestive behavior: A.1.Feeding:(min/hr.): The time spent (min.) by rats in
eating food. A.2. drinking:( freq/hr.): Frequency of taking water from water
trough.
B. Resting behavior: B.1.Lying :( min/hr.): The time spent (min) by rats in a
lying or sleeping. B.2.sitting up :( min/hr.): Either idles standing or doing
some maintenance activities.
C. Movement activities: C.1: Walking :( freq/hr.): Slow symmetrical gait taking
one step or more. C.2. running :( freq/hr.): Fast movement by the rat.
D. Body care behaviors: D.1.Scratching :( freq/hr.): Include friction of head
and/or shoulder region by hind feet. D.2. Licking: (freq/hr): licking of the body by
their tongue.
E. Investigatory behavior :( freq/hr): In investigatory behavior the rats
explore the surrounding environment by sniffing feeding and water troughs,
walls, floor or others.
II. Behavioral index:
II.1. Landing foot spread distance (LFSD): LFSD was measured as the fourth
digit of the hind limbs of the rats was colored with ink and dropped from a
height 30 cm in a horizontal position. The distance between the fourth
digits of each hind limb on landing was measured. The procedure was
repeated three times for each rat and the average was recorded. The
mean± SE was calculated for each group.
II.2. learning ability: ability to solve maze II.2.1. The Morris water maze is a 9
large round tub of opaque water with powdered milk) with two small
hidden platforms located 1-2cm under water's surface. The rat is placed on
a start platform. The rat swims around until it finds the other platform to
Neuroprotective Efficacy of lipoic acid in Acrylamide-Induced …
stand on. External cues, such as patterns or the standing researcher, are
placed around the pool in the same spot every time to help the rat learn
where the end platform is. The researcher measures how long it takes for a
rat to find hidden plat form.
2.2: Plus Maze: Rat was allotted individually to the center of the maze and
measure the time elapsed to the closed arm and the time elapsed to reach the
open arm and the frequencies in the close and the open arm for each rat in 3
minutes.
III. Pathological indication: The tissues were fixed in 10% buffered formalin
solution and embedded in paraffin. Tissue sections of 3 -5 µm thickness
were stained with hematoxylin and eosin. The slides were then evaluated
under light microscope.
1.3: Statistical analysis:
The behavioral were analyzed by Statistical Analysis System , Nested 22
design analysis of variance. b-The leg splay and the time elapsed in both
plus and water maze were analyzed using Statistical analysis system .The 22
frequencies in closed and open arms of plus maze and the scores of
pathological were analyzed using wilcoxon scores (rank sums) for variables
frequencies.
RESULTS
Table 1: Showing the effect of acrylamide with or without lipoic acid on behavior of rats.
Treatment feeding Min/hr Drinking
Freq/hr
Sitting up Min/hr
Control 17.89±2.90a 1.05± 0.15a 34.74±2.69a
Acrylamide 12.80±2.00b 0.03±0.01b 15.60±2.10c
Acrylamide+lipoi
c
11.20±2.37b 0.24±0.09b 22.80±2.37b
lipoic 12.60±1.16b 0.24±0.09b 33.00±1.85a
Treatment Lying Min/hr Walking Freq/hr Running Freq/hr
Control 7.47±1.16b 4.37±0.65a 0.58±0.13a
Acrylamide 31.60±3.04a 0.08±0.01b 0.00±0.00b
Acrylamide+lipoi
c
26.08±3.17a 0.80±0.18c 0.08±0.06bc
lipoic 14.40±1.81b 2.88±0.43b 0.28±0.09b
Treatment Licking Freq/hr Scratching Freq/hr Exploration other
Freq/hr
Control 1.32±0.23a 1.58±0.31a 0.16±0.08a
Acrylamide 0.56±0.13b 0.24±0.09b 0.00±0.00b
Acrylamide+lipoi
c
0.08±0.06c 0.24±0.09b 0.08±0.06ab
lipoic 0.16±0.08c 0.52±0.15b 0.04±0.03ab
Treatment Exploration cage
Rashed and Tohamy, 2015
104 January 2015
Freq/hr
Control 0.37±0.10a
Acrylamide 0.40±0.13a
Acrylamide+lipoi
c
0.00±0.00b
lipoic 0.16±0.08ab
All values are means ±SE, n=9
Values with different letters at the same raw are significantly different at (p<0.05)
Table 1 shows the effect of acrylamide on behavior of male rats as the control
group has the highest feeding time and significantly more than acrylamide treated
rats while the lowest feeding time observed in acrylamide + lipoic acid group.
Moreover, addition of acrylamide in water decreases significantly drinking
frequencies than control groups. As the sitting up time increased in control and
lipoic acid groups it decreased in both acrylamide and acrylamide + lipoic acid
groups on contrast the lying time increased in acrylamide and Acrylamide+ lipoic
acid groups due to neurotoxic effect of acrylamide and muscle weakness lead the
rat unable to stand so taking resting time in lying position.
The number of walking and running frequencies were found to be decreased
significantly in both acrylamide and acrylamide + lipoic than control and lipoic
acid groups this because neurotoxic effect and muscles weakness and the gait
inability to support body weight, dragging hind limbs, inability to rear.
Licking was higher in control group followed by acrylamide treated group
while the lowest frequencies observed in acrylamide + lipoic acid groups, on
contrast scratching frequencies decreased in both acrylamide and acrylamide +
lipoic acid groups. However other exploration was lower in control group on
contrast the cage exploration was higher in ACR group followed by control group
and the lowest observed in ACR+ lipoic acid group
Table 2 : Effect of acrylamide with or without lipoic acid on learning ability and landing leg
spread distance of rats.
Treatment Latency to
solve water
maze
(seconds).
Latency in open
arm plus maze
at 3rd week
(seconds)
Latency in
closed arm
plus maze at
3rd week
(seconds)
Latency in
open arm
plus maze at
4th week
(seconds)
Control 6.00±0.41b 126.0± 13.16a 54.0±12.97b 114.0±8.54a
Acrylamide 12.50±1.44a 48.0±14.24b 132.0±14.2a 65.0±8.54b
Acrylamide+lipoic 10.50±0.96ab 35.6±6.96b 120.8±18.98a 18.0 ± 6.65c
lipoic 6.40±2.11b 142.6± 5.91a 37.4± 5.69b 120.8 ± 6.32a
Treatment Latency in closed arm plus maze
at 4th week seconds
Landing leg
spread
distance (cm)
Neuroprotective Efficacy of lipoic acid in Acrylamide-Induced …
Control 66.0±13.92c 6.63±0.26b
Acrylamide 115.0± 8.54b 9.75±1.26a
Acrylamide+lipoic 162.0± 6.64a 8.50±0.63a
lipoic 59.2± 6.32c 5.56±0.22b
All values are means ±SE, n=10
Values with different letters at the same raw are significantly different at (p<0.05)
Table 3: Wilcoxon scores (rank sums) for variables frequencies of acrylamide with or without
lipoic acid for open and closed arm in plus maze during the third and the fourth
week after treatment.
Treatment Freq open 3rd
week
Freq closed 3rd
week
Freq open 4th
week
Freq closed 4th
week
Control 15.50 12.80 13.60 13.80
ACR 7.00 5.50 10.20 10.60
ACR+Lipioc 8.10 12.00 4.80 8.80
Lipoic 11.40 11.70 13.40 8.80
Chi-Square 6.6981 5.2235 8.3382 3.3537
DF 3 3 3 3
Pr > Chi-
Square
0.0822 0.1561 0.0395* 0.3402
* Significantly difference from ACR treated group p≤0.05.
Learning ability: 1. Morris water maze: Rat has a well-developed central
nervous system and memory system and has the ability to solve maze so in
control group rats solve water maze in a little time 6.00± 0.41 Sec while the
longer time taken by ACR group was 12.50 ±1.44 Sec followed by ACR+ lipoic
acid group then group. 2. Plus maze: ACR treated group take a long time to
solve plus maze as the rat take a long time in the closed arm 132.0±14.2 sec
after exposure by three weeks while take short time in the open arm
48.0±14.24 sec as compared with control group 126.0± 13.16 sec in open and
54.0±12.97 sec in closed arm.
After exposure by 4 weeks the rats in lipoic + ACR spent a short period
in open arm 18.0 ± 6.65 sec and a long period 162.0± 6.64 sec in the closed arm
while in ACR treated group was 65.0±8.54 sec in open arm and 115.0± 8.54 sec
in closed arm moreover the highest time observed in open arm was for lipoic
acid 120.8 ± 6.32sec and the lowest time 59.2± 6.32 sec in closed arm. Data for
the frequencies in open and in closed arm of plus maze presented in table(3)
revealed that higher frequency in open arm was for control groups after 3 and
4 week followed by lipoic acid group and the lowest frequencies observed in
the treated ACR and ACR+ lipoic acid group.
Rashed and Tohamy, 2015
106 January 2015
Landing Foot Spread Distance (LFSD): A significant and a progressive
increase in landing feed spread distance LFSD measurement were evident
among ACR administered rats. Both ACR and ACR+ lipoic showed the LFSD
9.75±1.26cm and 8.50±0.63cm respectively while in control and lipoic groups
was 6.63±0.26cm and 5.56±0.22cm respectively.
Fig. (1): Photomicrograph of rate cerebrum treated with ACR (HE X. 250). (A) Mild
perivascular cuffing (arrows) with minor hemorrhage. (B) Shrunken, eosinophilic
cytoplasm, hyper chromatic or pyknotic nuclei and widening neuropils. (C&D) central
chromatolysis (arrow) and ghost neuron (arrow head). (E) Satellitosis around
degenerated neurons (arrow head) and neuronophagia (arrows). (F) Focal gliosis (A).
Neuroprotective Efficacy of lipoic acid in Acrylamide-Induced …
Cerebrum:
Cerebrum of ACR treated rates showed moderate perivascular monocytic
aggregation (fig.1A), small shurenked pyknotic neuron with widening neuropills
(fig. 1B). Central chromatolysis where the chromatolytic cells are swollen and
rounded, rather than having the normal angulated appearance and the nucleus
becomes eccentric. Nissl granules clear from the central region of the cell body,
leaving this zone with a smooth ground-glass appearance (Fig. 1 C&D). The
cerebral cortex in ACR-intoxicated rats exhibited Perineuronal satellitosis as
surrounding small degenerated neurons, the microglia invade and phagocytize
the degenerated neurons in the process called neurophagia (fig. 1E) and focal
gliosis (fig. 1F).
Fig. (2): Photomicrograph of rate cerebellum stained with hematoxylin and eosin (HE X. 250). (A)The
histoarchitecture of the cerebellum is intact in the control rate. (B) Congestion of blood vessel (arrow) (C)
moderate to severe pyknotic Purkinje cells (arrowheads) in rates received ACR. (D) mild pyknotic purkinje
cells (arrowheads) in rate received ACR in addition Lipoic acid
Rashed and Tohamy, 2015
108 January 2015
Cerebellum:
Cerebellum of control group showed normal histology (fig. 2A). While in ACR
toxicated rats showed congestion of blood vessel (fig. 2 B) and moderate to
severe pyknotic Purkinje cells (fig. 2 C). Moreover, mild pyknotic Purkinje cells (fig.
2 D) was noticed in Lipoic acid supplemented rats
Table 4: Wilcoxon scores (rank sums) for incidence and Severity of histopathological Lesions.
Lesions Incidence and Severity of Histopathological Lesions
Treatment ACR ACR+Lipoic
Organ/ histopathological changes
pyknotic nuclei and widening
neuropils
10 (0/ 2/ 5/ 3) 10 (1/5/4/0) *
central chromatolysis
(±/+/++/+++)
10 (0/ 1/ 6 / 3) 10 (1/ 5/ 4/ 0)*
ghost neuron 10 (0/ 2/ 4/ 4) 10(3/ 4/ 3/ 0)**
Cerebrocortical satellitosis 10 (0/ 4/ 6/ 0) 10 (5/ 4/ 1/ 0)
Cerebrocortical neurophagia 10 (0/ 2/ 3 / 5) 10 (6/ 3/ 1/ 0)**
Perivascular monocytic
aggregations
10 (3/ 3 /4 / 0) 10 (5/ 3/ 2/ 0)
Cerebellum: Congestion of
blood vessels
10 (0/ 3/ 4/ 3) 10 (4/ 3/ 3/ 0)*
Pyknotic pyrkanji cells 10 (1/3 /4 / 2) 10(4/ 5/1 / 0)*
Normal (-) Mild (+) Moderate (++) Severe (+++)
*,**Significantly difference from ACR alone treated group p≤0.05, p ≤ 0.01
Number of animal examined (Minimal (±/)/ Mild (+) /Moderate (++)/ Severe (+++))
The tissues were fixed in 10 % buffered formalin solution and embedded in
paraffin. Tissue sections of 3 -5 µm thickness were stained with hematoxylin and
eosin. The slides were then evaluated under light microscope
DISCUSSION
Behavior patterns: Ataxia and hind limb muscle weakness are the primary
neurological defects associated with induction of distal axonopathy by chemicals
such as ACR . The value and effectiveness of research concerning axonopathic 5,1
mechanisms can be improved by assessment of onset, duration and magnitude of
neurological defects. Such information provides a rational basis for selection of
experimental endpoints that accurately reflect various stages of neurotoxicity and
subsequent data interpretation where establishing the path physiologic relevance
of biochemical/ molecular parameter in critical. Several neurological measures (e.g.
gait, hind limb foot splay distance) have been used as indices of developing
neurotoxicity in previous investigations, however, the change in behavior, learning
ability and using of lipoic acid as a protective agent were studied in our research.
The results of this study suggest that rat behavior were affected by acrylamide as
the feeding time was found to be decreased in both acrylamide and acrylamide +
Neuroprotective Efficacy of lipoic acid in Acrylamide-Induced …
lipoic acid groups moreover the drinking frequency were lower in rats of both
groups. Sitting up time was also lower in both acrylamide and lipoic acid +
acrylamide groups while taking much resting time in lying position this because
acrylamide affect nerve axons and caused muscle weakness leading the rats
unable to support their bodies during sitting up so take more resting time in lying
position these results similar to those obtained by whose found that the initial 4
target of ACR appears to be the nerve terminals in both central and peripheral
nervous systems, resulting in autonomic, behavioral, sensory, motor disturbances
and muscle weakness. Movement activities (walking and running frequencies) were
higher in control and lipoic acid groups than acrylamide and acrylamide + lipoic
acid groups and the difference was significantly different as the ACR caused
progressive muscle weakness and nerve injuries resulting in motor disturbances
similar results obtained by . Licking was higher in control group followed by 4
acrylamide treated group while the lowest frequencies observed in acrylamide +
lipoic acid groups, on contrast scratching frequencies decreased in both acrylamide
and acrylamide + lipoic acid groups this because the ACR affect nerve terminals
and caused muscle weakness so the ability of rat to using hind limbs in scratching
their bodies decreased while increased using tongue in licking their bodies.
However other exploration was lower in control group on contrast the cage
exploration was higher in ACR group followed by control group and the lowest
observed in ACR+ lipoic acid group this was for ACR affect the memory system so
the rat ignore the land marks of the surrounding environment leading to increased
the exploration to investigate the surrounding environment.
Landing Hind limb Foot Splay In the present study landing hind limb foot
splay distance was also shown to be a sensitive index of developing ACR-induced
neurotoxicity. Our findings are consistent with earlier research that characterized
this neurologic end point during different ACR exposure conditions . intoxication 1
at the 50 mg/kg per day dose-rate significantly increased landing hind limb foot
splay, i.e. rats in both the exposure ACR and ACR+Lipoic exhibited initial foot
spread distances of approximately (9.75±1.26cm vs. 8.50±0.63cm respectively)
while in control group decreased to 6.63±0.26cm this results are in agreement with
the findings of . 4,7
Learning ability; Rats have a will developed memory system as they have the
ability to solve maze as in control groups rats take a shorter time to solve Morris
water maze than ACR treated group which has neurotoxic effect and caused a
nerve damage and these results emphasized that Long-term potentiation of
synaptic strength (LTP) is correlated with behaviorally relevant memory function:
reductions in LTP cause memory impairments , whereas increases in LTP are 8,9
associated with enhancement of learning and memory . However, the ability to 11,12
store new information in neural networks depends on the degree of plasticity of
synaptic connections, as well as the number of available connections. Therefore,
number of synapses should be critical for learning and memory too. Indeed, loss of
synapses is correlated with age-dependent memory decline in rats . 14,15
Pathological and histopathological changes
Rashed and Tohamy, 2015
110 January 2015
In the present study, the cerebrum of ACR treated rate showed small
shurenked pyknotic neuron with widening neuropills, Central chromatolysis is best
appreciated in large neurons of some of the brain stem nuclei, in the spinal motor
neurons, and peripheral ganglia. Cerebrocortical degenerated neuron undergo
satellitosis, neurophagia and focal gliosis. The cerebellum exhibited moderate to
severe pyknotic Purkinji cells. Finally we found that supplementation of Lipoic acid
not give the protection against ACR induced neurotoxicity but only decrease the
severity of the histopathological lesions.
Conclusions
In this study lipoic acid didn't prevent the neurotoxic effects of acrylamide but it
decreased the severity and delayed the appearance of the signs. More research are
needed to follow the neuroprotective effect of lipoic acid with a small doses of
acrylamide.
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