vitamin e improves cognitive and functional activities in

VITAMIN E IMPROVES COGNITIVE AND FUNCTIONAL ACTIVITIES IN OLD RATS

77 June 2017 International Journal of Health and Rehabilitation Sciences Volume 6 Issue 2

ORIGINAL RESEARCH Vitamin E Improves Cognitive and

Functional Activities in Old Rats Loay Khaled Hassouneh, Salameh Al Dajah, Zead Helmi

Abudayeh, Mai Adnan Abdullah, Wadie Abed.

Loay Khaled

Hassouneh, Assistant

Prof., Faculty of Pharmacy,

Al-Isra University, ,Jordan.

Salameh Al Dajah

Associate Prof., Dept. of

Physical therapy,Al Isra

University,Jordan

Zead Helmi Abudayeh

Assistant Prof., Faculty

of Pharmacy, Al-Isra

University, Jordan.

Mai Adnan Abdullah

Lecturer, Al Balqa'a

Applied University-Al

Huson College, Jordan

Wadie Abed

Professor

Faculty of pharmacy, Middle

East University, Jordan

Corresponding Author:

Loay Khaled Hassouneh,

E-mail: [email protected].

ABSTRACT

Background: Aged humans and animals demonstrate cognitive decline.

Improvement of short-term memory performance in aged beagles with a

nutraceutical supplement containing phosphatidylserine (PS) and vitamin E

has been demonstrated.

Objectives: The purpose of the present study was to examine if alpha-

tocopherol acetate could alter PS metabolism in the hippocampus and to

improve cognitive

Materials and methods: Intragastric administration of alpha-tocopherol

acetate to 24-month-old rats for 14 days.

Results: Increase of newly synthesized PS level in the hippocampus of

experimental animals as compared with control rats. At the same time, there

was a decrease in [14C] phosphatidylcholine (PC) content in the hippocampus

of experimental rats with respect to controls. The changes in phospholipids

levels was seen in the hippocampus of experimental animals due to alpha-

tocopherol acetate administration were associated with increased number of

active avoidances and decreased latent period of avoidances on acquisition of

a conditioned reflex in a shuttle box.

Conclusion: The data which was obtained in the work provide evidence

that alpha-tocopherol acetate is a powerful modulator of phospholipids

metabolism in the hippocampus and its function at old age.

Keywords: Aging, Hippocampus, Vitamin E, Phosphatidylcholine,

Phosphatidylserine, Cognitive Function.



Introduction

Phospholipids are not only

important components of biological

membranes but participate actively in cell

signaling. PS is the major acidic phospholipid

of nerve cell membranes and plays an

exclusively important role in supporting

neural functions1. PS has been shown to

participate in the regulation of

acetylcholine, dopamine, and noradrenaline

release at old age2. Its role in signal

transduction became evident after the

opening that PS acts as a binding site for the

protein kinase C in the plasma membranes

and as a regulator of diacylglycerol kinase, c-

Raf-1 protein kinase, and nitric oxide

synthase1. It is important that protein kinase

C is a critical component of memory and

learning. Moreover, PS promotes neuronal

survival and facilitates serine threonine

kinase Akt signaling. Significant changes of

the asymmetrical positioning of PS in the

plasma membranes of synaptosomes and

the expression of proapoptotic proteins

have been found in the brains of patients

with Alzheimer’s disease and impaired

cognitive functions4. The prominent

decrease of PS content has been observed in

the hippocampus of rats during aging5. The

PS level decreased by 50% in the

hippocampus of the 24-month-old animals

and by 80% in the brain region of the 30–32-

month-old animals as compared with the

adults. Administration of exogenous PS to

aged rats promotes the formation of

synapses, dendrites, and surface receptors

of nerve cells in different parts of the

brain6 and improves the cognitive functions

of aged animals7. The dietetic fish oil mimics

an exogenous PS action on PS content in the

hippocampus of old animals5. Both, the n-3

polyunsaturated fatty acids (PUFA)-enriched

diet and exogenous PS addition increased

the PS level in the hippocampus of the 24-

month-old rats. Increased PS concentration

in the membrane initiates the interaction of

the PH domain of the kinase Akt with the

plasma membrane, facilitates translocation

and phosphorylation of Akt and thus

promotes cell survival8. Both, the

antiapoptotic effect of n-3 PUFA and Akt

translocation are sensitive to n-3 PUFA-

induced PS accumulation, strongly

suggesting that the antiapoptotic effect of

n-3 fatty acids depends on its ability to

accumulate PS in neuronal membranes. The

ability of dietetic fish oil is to nullify the age-

dependent disturbances of the PS turnover

as well as hippocampus function suggests

the critical PS role in cognitive function

decline during normal physiological aging.



Vitamin E is a well-known singlet

oxygen quencher and antioxidant, and a

modulator of lipid metabolism. There are a

number of potential mechanisms by means

of which vitamin E supplementation can

change levels of phospholipids in cell

membranes. Vitamin E has been shown to

influence on gene expression and modulate

the activities of a number of enzymes

involved in signal transduction, including

phospholipase A29 and diacylglycerol

kinase10. Recently, it has been

demonstrated that alpha-tocopherol and

gamma-tocopherol regulate the sphingolipid

metabolism in the liver and hippocampus

of old rats11,12.Alpha-tocopherol

supplementation nullified the age-

dependent disturbances of sphingomyelin

(SM) turnover linked to the increased state

of oxidative stress in the liver at old age11.

Alpha-tocopherol, as well as gamma-

tocopherol, targeting the neutral and acid

sphingomyelinases (SMase) activities and

key enzyme of sphingolipid synthesis de

novo, serine palmitoyltransferase,

normalized the content of pro-apoptotic and

pro-inflammatory lipid ceramide in the aged

isolated hepatocytes. Besides, alpha-

tocopherol or N-acetylcysteine (NAC)

administration to old rats prevented

ceramide accumulation and increased SM

levels in the hippocampus of 24-month-old

rats12. The oxidative stress-induced

ceramide accumulation in the keratinocytes,

neurons, and astrocytes can be blocked by a

pretreatment of cells with the vitamin E,

too13, 14, 15, and 16. Taking into account the

close metabolic relationship between PS and

sphingolipids (Meyer and Groot, 2003) and

the fact that PS administration to old rats

significantly decreased the neutral SMase-

dependent ceramide production in the

hippocampus of 24-month-old animals5 and

improved acquisition and retention of

passive and active avoidance tasks in aged

Wistar rats17

The aim of this study was to

investigate the effects of alpha-tocopherol

on PS content and cognitive and functional

activities of old animals. Alpha-tocopherol

could ameliorate the age-dependent decline

of cognitive and functional activities of old

animals. Manipulating of the PS level in the

hippocampus of the aged animals with

alpha-tocopherol could be a strategy to

improve learning and memory abilities.

Material and Methods

Experiments on rats were carried

out according to the International

Principles of the European Convention for

the Protection of Vertebrate Animals

Used for Experimental and Other

Scientific Purposes (Strasbourg, 1985) and

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Meyer%20SG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22de%20Groot%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus



National General Ethical Principles for

Experiments on Animals (Ukraine, 2001). In

the experiments 24-month-old male Wistar

rats (n = 20) weighing 450-480 g were used.

The rats which had a free access to a

standard chow diet and drinking water add

libitum were divided into two groups. Rats

of vitamin E-treated group were fed with

the alpha-tocopherol acetate (100 mg/100 g

body weight) intragastrically daily for 14

days. Control 24-month-old rats were fed

with corn oil. Prior to experiment the

animals were starved overnight. Their hippo

campuses were obtained 24 hours after the

last alpha-tocopherol treatment and used

for lipid analysis as described below.

Conditioned active avoidance reflex (CAAR)

induced by pain stimulation was studied as

described below.

Functional activities of Experimental

Animals

Conditioned active avoidance reflex induced

by pain stimulation was studied in 24-

month-old rats trained in a shuttle chamber

with two sections and an electrified floor, as

described in (Babenko and Semenova,

2011)5. Electric bulb (30 W) switching on 5

sec before application of unconditioned

electrical pain stimulation of the limbs (0.8

to 1 mA current was supplied via the

electrode-equipped floor alternately in one

section or another) served as a conditioned

stimulus. Passages of the animals from one

section of the chamber to another caused

by light switching were interpreted as

conditioned reflex phenomena when the

latency of such locomotors reaction was

shorter than 5 sec. The daily training session

for each animal included 30 presentations of

the conditioning signal with randomized

intervals from 30 to 90sec. Training lasted

until the rat demonstrated a clear

realization of CAAR (nine passages in

response to 10 presentations of the

conditioning signals). We daily recorded the

number of conditioned reflex avoidances

and unconditioned reactions within the

training session, measured the delays of

these reflexes (sec), and also estimated the

total duration of the learning period (until

reaching the selected criterion of

reproducibility).

Phospholipids synthesis

Tissue samples were incubated in

Krebs–Ringer bicarbonate buffer (pH 7.4)

with the addition of 0.1 % albumin for 90

min at 37°С in the presence of

[14С]H3COONa (10 µCi/ml). After inclusion

of the label, tissues were washed in

bicarbonate buffer (pH 7.4) with 0.1%

albumin and used for lipid extraction and

separation as described below.



Extraction and Separation of Lipids

Extraction of lipids was performed

according to the Bligh–Dyer technique (Bligh

and Dyer, 1959). For phospholipids

separation thin-layer chromatography was

used in the systems of solvents consisting of

chloroform, methanol, acetic acid, formic

acid, and water 70:30:12:4:2 by volume).

Phosphatidylcholine (PC),

phosphatidylinositol (PI) and sphingomyelin

(SM) spots were detected in iodine vapor.

Phosphatidylserine (PS) and

phosphatidylethanolamine (PE) spots were

detected by treating chromatograms with

3% ninhydrin solution in water-saturated

butanol and identified by comparison with

standards Sigma, USA). Phospholipids

contents were estimated by the Bartlett

method (Bartlett, 1959). The gel spots

containing [4С]lipids were scraped and

transferred to scintillation vials. The

radioactivity of labeled lipids was measured

using a BETA radioactivity counter.

Statistical analysis Statistical analysis of the effect of alpha-

tocopherol acetate on the amount of newly

synthesized phospholipids in the

hippocampus of old animals, was carried out

by using the dispersion one (Newman–Keuls

test). To estimate the reproduction of the

active avoidance conditioned reflex in the

shuttle chamber, the nonparametric Mann–

Whitney test was used. The P < 0.05 was

taken as the critical significance level.

Numerical data were analyzed using

STATISTICA 6.0 software.

Results

Previous studies have been

demonstrated that hippocampal PS contents

in 24-month-old animals decrease as

compared with those in young adult rats2

The studies reported in the paper show that

administration of alpha-tocopherol acetate

to aged rats leads to increase of the newly

synthesized PS and decrease of PC contents

in the hippocampus (Fig. 1). At the same

time, there were no changes in the contents

of [14C] PE, [14C]PI, [14C]SM and total

[14C]phospholipids in the hippocampus of

experimental rats as compared with control

(165732±24377 and 160859±37894 cpm/g,

Figure 1. Effect of alpha-tocopherol acetate on

the phospholipids contents in the hippocampus

of the 24-month-old rats respectively).

Alpha-tocopherol acetate did not change

the content of PC and increase of PS level in

PC contents in the hippocampus of alpha-



tocopherol acetate-treated and control

animals were 70.9±16.4 and 60.1±8.25

nmol/mg protein, respectively. PS contents

in the hippocampus of alpha-tocopherol

acetate-treated and control rats were

40.4±4.79 and 59.9±1.87 nmol/mg protein

(p<0.05), respectively. In another set of

experiments, cognitive functions of alpha-

tocopherol acetate-treated and control 24-

month-old rats were studied. The results of

this study obtained that there were no

differences in the rats’ spontaneous activity

levels in the control and experimental

groups during adaptation to the shuttle box.

The numbers of spontaneous transfers in

the box were 6.7 ± 0.78 and 6.2 ± 0.65 in the

control and alpha-tocopherol acetate-

treated groups, respectively. However, the

number of combinations of stimuli needs to

achieve the criterion of the conditioned

active avoidance reflex in the group of

rats receiving alpha-tocopherol acetate

was significantly lower than that in control

animals (82.00 ± 7.90 and 46.51 ± 5.45 (p <

0.05),

0

5

10

15

20

days

control alpha-tocopherol acetateА

0

20

40

days

control alpha-tocopherol acetateB

Figure 2. Effects of alpha-tocopherol acetate on the

number of active avoidances (A) and latent period (B)

during acquisition of the conditioned active avoidance

reflex in the 24-month-old ratsrespectively.

The latent period of avoidance in

experimental rats treated with alpha-

tocopherol acetate decreased, while the

number of active avoidances in the shuttle

box increased on the second and third days

of the experiment as compared with

controls (Fig. 2, A, B).

Discussion

PS synthesis in rodent tissues occurs

primary via Base Exchange pathway18

(Vance, 2008). Serine incorporation into PS

through the serine Base Exchange reaction

takes place in microsomes and needs PC as

substrate. Taking into account that alpha-

tocopherol acetate increases the newly



synthesized PS content and reduced the

newly synthesized PC level, the activation of

base exchange pathway in the hippocampus

of old animals could be supposed. However,

vitamin E can induce the PC degradation19.

Vitamin E supplementation influences on

the phospholipase A2-dependent

phospholipid turnover, increasing the

contents of a variety of

lysophosphatidylcholine species in human

plasma. These data suggested that alpha-

tocopherol acetate could decrease PC

content in aged hippocampus not only due

to stimulation of base exchange reaction

and synthesis of PS, but also via PC

degradation too.

PS could be converted to PE in the

mitochondria due to phospholipid

decarboxylation. PS decarboxylase activity

has been determined in cerebral cortex,

cerebellum, retina, hippocampus and other

brain regions19, 20. Although, this pathway of

PS turnover exists in the hippocampus, the

fact that alpha-tocopherol acetate did not

change the newly synthesized contents of

[14C]PE, the contribution of PS

decarboxylation in phospholipid increase

could be excluded.

It was well documented that

oxidative stress is a common feature of

different brain structures of aged mice and

rats21, 22. Hippocampus and frontal cortex

mitochondrial dysfunction and higher

content of oxidation products of

phospholipids and proteins has been

determined in aged rats in respect to young

animals23, 24. Dietary supplementation with

vitamin E restored the mitochondrial

respiration as well as increase complexes I

and IV and mitochondrial nitric oxide

synthase activities up to the values obtained

for 4-month-old rats. Vitamin E prevented

the increases in oxidation products and

decreases the hippocampus mitochondrial

mass in synaptic areas25. It is worth noting

that vitamin E could prevent PS oxidation

whereas other more abundant classes of

phospholipids, such as PC and PE, remained

resistant to treatments during anti-Fas-

induced apoptosis in Jurkat T cells26. These

data suggest that the alpha-tocopherol

acetate in the hippocampus of old rats could

at least partly increase PS level due to

decreased lipid oxidation.

Administration of antioxidant, such

as NAC, to 2-cyclohexene-1-one-treated rats

prevented the glutathione depletion in

striatum, hippocampus and frontal cortex

tissues and disruption of the short-term

spatial recognition memory in Y-maze test27.

NAC may protect the brain of aged mice

against glutathione depletion, and reverse

age-induced deficits in hippocampal long-



term potentiation28 and Aβ-induced

disturbances of learning and memory of

animals29. Improvement of short-term

memory performance with a nutraceutical

supplement containing phosphatidylserine

(PS) and vitamin E has been demonstrated

in aged beagles30.

Although the exact cause of age-

dependent cognitive dysfunction is not

known, several changes have been

identified, including oxidative stress,

neuroaxonal degeneration, and beta-

amyloid31. The diffuse loss of neurons

andsynapses in the neocortex, hippocampus

and other subcortical regions of the brain at

Alzheimer’s disease neuropathology32 is

associated with a ceramide

accumulation32,33. Ceramide can regulate

both the amyloid precursor protein

processing and beta-amyloid peptide

generation31.SM turnover in thestriatum,

hippocampus and frontalcortex was more

active in the agedrats than in the adult

ones2,34. Theceramideaccumulation in the

hippocampus and neocortex occurs in aging

as a consequence of neutral SMase

activation2 and can be ameliorated with the

antioxidants, NAC and alpha-tocopherol

acetate11. In addition, neutral SMase could

be inhibited with PS. PS addition to the

culture media significantly decreased the

daunorubicin-induced neutralSMase activity

and accumulation of the ceramide due to

the stimulationof PKC activity in the human

monocytic leukemia cell lines U937and HL-

6035. Based onthese results, reasonable

assumption can be made that the alpha-

tocopherol acetate prevents ceramide

accumulation in the hippocampus and

cognitive dysfunction of oldrats, at least in

part by the PS-induced SMaseinhibition.

Conclusions

In summary, the data above was

demonstrated that alpha-tocopherol acetate

is a powerful modulator of the phospholipid

turnover in the hippocampus of old rats. The

long-term treatment of old rats with the

alpha-tocopherol acetate increased the

reduced production of PS and decreased the

content of newly synthesized

phosphatidylcholine (PC) in the

hippocampus. The suggestion that alpha-

tocopherol acetate could restore the PS

turnover in the hippocampus of old animals

probably via stimulation of the Base

Exchange reaction. However, other

pathways of PS and PC turnover could be

the targets of alpha-tocopherol acetate

action in the hippocampus of old rats too.

The changes in phospholipids levels was

seen in the hippocampus of experimental

animals due to alpha-tocopherol acetate

administration were accompanied by

increases in the number of active



avoidances and decreases in the latent

period of avoidances on acquisition of a

conditioned reflex in a shuttle box. Taking

into account an extremely important role of

PS in brain functioning and results obtained

in the present work can be supposed that

alpha-tocopherol acetate ameliorates the

age-dependent decline of cognitive function

due to increase of newly synthesized PS

levels in the hippocampus.

Acknowledgments

This experimental work was

supported by the research program

“Approaches to overcome cell resistance to

physiological stimuli in animals of different

age” (State Registration No. 0106U001577,

Kharkov Karazin National University, 4,

Svobody pl., 61077 - Ukraine). At the same

time that it was supported by the faculty of

pharmacy at Isra University of Jordan.

Conflict of interest: None

Source(s) of Funding:

This work was supported by the research

program “Sphingomyelin cycle metabolites

role in the development of cells resistance

for physiological stimulus action during

aging” (State Registration No.

0111U010555).

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