ARTICLE
Auteur(s) : Benjamin Buaud1,2, Carole
Boue1, Nicole Combe1, Paul
Higueret2, Véronique
Pallet2
1ITERG – Département Nutrition Santé; Université
Bordeaux 1, Avenue des Facultés, 33405 Talence
2Unité de Nutrition et Neurosciences, Universités
Bordeaux 1 et 2; Université Bordeaux 1, Avenue des Facultés, 33405
Talence
Introduction
Brain is a tissue rich in lipids (about 50-60 percent of its dry
weight). Cerebral membranes are especially rich in n-6 and n-3
PUFAs; arachidonic (20:4 n-6, AA) and docosahexaenoic acids (22:6
n-3, DHA) are their main representatives. These PUFAs are
specifically present in membrane phospholipids such as
phosphatidylethanolamine (PE).
According to literature [1], AA and DHA play fundamental roles,
notably the second which is essential for structure and functional
development of brain during prenatal and early life.
Since several years, the involvement of PUFAs in brain
functioning is well studied. For instance, some studies performed
in rodents fed with variable and controlled contents of n-6 and n-3
PUFAs evidenced an influence of PUFAs on cognitive processes [2,
3]. It emerges that decreased cerebral amounts of DHA resulting
from dietary n-3 deficiency are associated with impaired cognitive
function such as decreased learning performances and disorders of
memory and attentiveness. In addition, data obtained in human
[review in 4] reported that some neurological disorders (autism,
schizophrenia, depression) could be related to a membrane PUFA
deficiency.
Multiple roles have been described for PUFAs within the central
nervous system (CNS) [5]. In addition to their impact on the
membrane biophysical properties (with consequences on membrane
fluidity, ionic transport and interaction with membrane proteins),
and their involvement in regulation of neurotransmitter release and
synthesis of biologically active oxygenated derivatives, PUFAs
could have also a transcriptional action. To modulate nuclear
receptor-mediated transcription of genes [6], the nuclear receptors
responsive to fatty acids (PPAR, peroxisome proliferator-activated
receptors) have to form a functional transcriptional unit upon
heterodimerization with RXR (retinoid X receptor), one of the
nuclear receptors of retinoids.
Vitamin A and retinoic acid (RA), its most potent natural
metabolite, play a significant role within the CNS, not only during
brain development but also in the function of the mature brain
[7-9]. In brain, RA controls, via its nuclear receptors RAR
(retinoic acid receptor) and RXR, the expression of genes involved
in synaptic plasticity, memory [10] and cognitive processes [11].
Among RA target genes, there are those coding for two identified
neuron-specific protein kinase substrates implicated in molecular
mechanisms underlying synaptic plasticity and memory formation: the
neurogranin or RC3 [12] and the neuromodulin or GAP43 [13]. These
two proteins are expressed on both sides of the synaptic cleft and
are considered as good markers of dendrite spine density.
In this context, we hypothesized that a modification of the
bioavailability of the nuclear modulators that are PUFA (by
establishing a n-3 PUFA deficiency), could induce modifications of
nuclear receptor (RAR and RXR) expression patterns. These modified
profiles were described in our laboratory as able to cause
modifications of the expression of genes involved in synaptic
plasticity (RC3 and GAP43) with consequences on the synaptic
plasticity state. Alterations of this state have been described as
responsible, at functional level, for disorders of memory
performances.
Thus, the retinoid nuclear receptor (RAR and RXR) expression and
that of neuromodulin and neurogranin were measured in striatum, a
brain area involved in memory processes. Levels of mRNA and
proteins were respectively measured by real time RT-PCR and western
blot analysis. At last, plasma, red blood cell membrane and brain
fatty acid patterns were investigated.
Materials and methods
Experimental protocol
Our study was performed with male rat pups at weaning (Wistar),
randomly divided into two experimental groups designated as n-3
adequate (n = 22) and n-3 deprived (n = 20) diets. The first group
received a n-3 PUFA adequate diet which consisted of a mixture of
peanut and rapeseed oils in the same proportions (50/50, v/v). The
18:2n-6/18:3n-3 (LA/ALA) ratio amounted to 5 and was conformed to
the current French recommendations. The second group fed a
α-linolenic acid (18:3 n-3) deficient diet, made of peanut oil; the
LA/ALA ratio was equivalent to 232. In the two diets, lipids
represented 5% of the ration and globally exhibited the same
proportions of SFA, MUFA and PUFA (table
1). All animals were fed and given water ad libitum. Each
rat was weighed three times weekly; food intake was recorded daily.
Rats fed the diets during three different periods: 3, 9 and 18
weeks. At the end of each time, rats were sacrificed by
decapitation. Blood and brain were rapidly removed, and individual
brain sections (striatum) were dissected out and then stored at
– 80 °C for subsequent analysis.
Table 1 Lipid composition of n-3 PUFA adequate and
deficient diets.
|
Adequate
|
Deficient
|
|
Lipid content (g/100 g diet)
|
5
|
5
|
|
Oil composition (g/100 g diet)
|
|
|
|
Rapeseed oil
|
2,5
|
0
|
|
Peanut oil
|
2,5
|
5
|
|
Lipid contributions
|
1,25
|
1,25
|
|
SFA1 (g/day)
|
0,17
|
0,24
|
|
MUFA (g/day)
|
0,76
|
0,72
|
|
PUFA (g/day)
|
0,32
|
0,29
|
|
18:2n-6 (mg/day)
|
273
|
290
|
|
18:3n-3 (mg/day)
|
50
|
1,25
|
|
18:2n-6/18:3n-3
|
5
|
232
|
RNA extraction and reverse transcription
Total RNA was extracted from striatum by using TRIzol reagent
(Invitrogen, France) according to the manufacturer’s protocol.
Purified RNA was quantified and assessed for purity by UV
spectrophotometry. RNA samples were reverse-transcribed as
previously described [14] with minor modifications:
reverse-transcription was conducted from 1 μg of total RNA and each
target gene was co-reverse-transcribed with PPIB (cyclophilin B) as
reference gene.
Analysis of gene expression by using real-time PCR
The polymerase chain reaction (PCR) was carried out involving a
LightCycler system (Roche Diagnostics, Mannheim, Germany), and by
using LightCycler DNA Master SYBR Green according to the
manufacturer’s instructions, as previously described [15].
Forward and reverse primers sequences used were as follows: PPIB
sense 5’-GTTCTGGAAGGCATGGATGT-3’, antisense
5’-TCCCCGAGGCTCTCTCTACT-3’; RARβ sense
5’-CAGCTGGGTAAATACACCACGAA-3’, antisense
5’-GGGGTATACCTGGTACAAATTCTGA-3’; RXRβγ sense
5’-AGGCAGGTTTGCCAAGCTTCTG-3’, antisense
5’-GGAGTGTCTCCAATGAGCTTGA-3’; RC3 sense
5’-GCTCCAAGCCAGACGACGATATTC-3’, antisense
5’-CACTCTCCGCTCTTTATCTTCTTC-3’; GAP43 sense
5’-AGAAAGCAGCCAAGCTGAGGAGG-3’, antisense
5’-CAGGAGAGACAGGGTTCAGGTGG-3’.
Quantification data were analyzed using the LightCycler Relative
Quantification Software, 3.5. (Roche Diagnostics, Mannheim,
Germany). The interest of this software is illustrated in Féart et
al. [15]. In our case, the calibrator was chosen among the rats fed
the n-3 adequate diet.
Western blot analysis
Western blot analysis was performed on striatum of rats fed the two
experimental diets for 18 weeks, according to the procedure
described by Husson et al. [16] for the experiment concerning RC3
and β-actin, and as decribed by Husson et al. [17] for the
expression of GAP43. The staining intensity of protein bands was
determined using an image analyser (Quantity One, Biorad
Laboratories, USA). The relative levels of RC3, GAP43 and β-actin
proteins were determined as percent of RC3, GAP43 and β-actin
respectively of n-3 adequate rats.
Lipid analyses
Extraction of brain lipids
Total lipids of brain were extracted by using the method of Folch
et al. [18], with 20 volumes of chloroform/methanol (2/1, by vol.)
per g of tissue. Extraction was made under agitation at room
temperature; after 1 h, 0.2 volumes of KCl (0.8% in water)
were added per volume of extraction mixture. Hydroalcoolic and
chloroformic phases were separated by centrifugation. The
hydroalcoolic phase was removed and the chloroformic phase was
washed with “upper phase”. After centrifugation, the chloroformic
phase was filtered and the pellet washed with chloroform/methanol
(2/1, by vol.); then solvents were evaporated under vacuum, at room
temperature with a rotary evaporator. The lipid extract was taken
again with chloroform and filtered to obtain a chloroformic
solution. The solvent was evaporated under nitrogen and dry extract
was taken again with chloroform/methanol (2/1, by vol.). The final
solution called “Folch extract” was stored at – 20 °C.
Isolation of brain phosphatidylethanolamine (PE)
Solvent of “Folch extract” was evaporated to dryness under a stream
of nitrogen. Lipids were taken up in an appropriate volume of
chloroform/methanol (2/1, v/v). Total phospholipids of brain were
separated by thin layer chromatography (TLC) with using plates
pre-coated with 0,35 mm silica gel 60H (Merck, France). A
volume of “Folch extract” was deposed on silica gel; the solvent
system used for separation was a mixture of
chloroform/methanol/acetic acid/water (75/45/12/6, by vol). After
migration and revelation by DCF (0.2% in ethanol), the silica gel
area corresponding to PE was visualized under U.V. (254 nm),
removed from the TLC plate and transferred in a glass tube for
preparation of fatty acid methyl esters.
Preparation of fatty acid methyl esters (FAME)
Total fatty acids of brain PE were methylated according to the
method of Morrison and Smith [19]. 1mL of boron trifluoride
methanol solution (14%; w/v) (SigmaChemical Co.) was added to the
silica gel area corresponding to PE in a glass tube, maintained for
20 min at 90°C after closing. After addition of 1 mL of
NaOH (5N), FAME obtained were extracted three times with 2 mL
of hexane. Hexanic phases were concentrated, washed with 1 mL
of water and stored at – 20 °C.
Plasma lipids
Total fatty acids of plasma were methylated according to the method
of Lepage and Roy [20]. 2 mL of methanol/benzene (4/1, v/v)
were added to 400 μL of plasma. Then, under agitation and at
0 °C, 200 µL of acetyl chlorure were added, and this mix
was maintained for 1 hour at 100 °C in a closed tube. To stop
the reaction, 5 mL of Na2CO3 6% (w/v)
were added to the mixture. After centrifugation, the upper phase
containing FAME was removed and stored at – 20 °C.
Analyses of FAME
Analyses of total FAME were carried out on gas chromatograph
equipped with a flame-ionization detector and a split injector. A
fused-silica capillary column (BPX 70, 60 m × 0.25 mm i.d.,
0.25 μm film; SGE, France) was used with H2 as a
carrier gas (inlet pressure : 1 bar). The split ratio was 1:70. The
column temperature was programmed from 150 C to 200 °C at
1.5 °C/min for 25 min, then from 200 °C to
225 °C at 20 °C/min and held at 225 °C until
completion of the analysis (20 min). The injection port and
the detector were maintained at 250 and 280 °C respectively.
The gas chromatography (GC) peaks were integrated using a SP 4400
integrator (Spectra Physics, San Jose, CA). Identification of each
fatty acid methyl ester was made by comparison of retention time of
authentic standards (Sigma Chemical Co.).
Statistical analysis
Values are given as means and standard errors of the mean (SEM).
The statistical significance of differences between means was
calculated by ANOVA followed by Student’s t-test (P < 0.05)
using Statgraphics Plus 5.1. software.
Results and discussion
Retinoic acid nuclear receptor expression
The retinoic acid nuclear receptor expression was studied in the
striatum of rats fed the deficient diet for 3, 9 and 18 weeks.
In comparison with animals of the adequate group, animals fed
the deficient diet exhibited i) after 3 weeks, no significant
variation of expression of any nuclear receptors ; ii) after 9
weeks, a strongly decreased expression of RARβ (– 28.2%, p
< 0.001); iii) after 18 weeks, no significant variation of RARβ
expression.
Data have shown in many animal tissues that retinoid signaling
pathway was susceptible to fatty acid supply [21] and consequently
to the level of activity of their signaling pathway. So the
deficient diet could lead to a decrease of the expression of
retinoid receptors, as observed after 9 weeks, which would indicate
a hypoactivity of the retinoid signaling pathway.
Synaptic plasticity marker expression (table
2)
The expression of neurogranin (RC3) and neuromodulin (GAP43) was
investigated at the mRNA and protein levels. The n-3 deprived rats
displayed i) after 3 and 9 weeks, no different RC3 and GAP43 mRNA
contents between the two experimental groups; ii) after 18 weeks, a
decreased expression of the two synaptic plasticity markers: – 14%
(at mRNA level) and –18% (at protein level) for RC3; – 24% (at
protein level) for GAP43.
Considering the involvement of RARβ in the regulation of RC3 and
GAP43 expression, the lack of decreased expression of these two
synaptic plasticity markers after 9 weeks is difficult to explain.
This result suggests a possible regulation of RC3 and GAP43
expression by another signaling pathway as it has been reported by
Guadano-Ferraz et al. [22] about the transcriptional induction of
RC3 by thyroid hormone. Concerning the difference of expression
between GAP43 mRNA and protein, Namgung and Routtenberg [23] have
previously suggested a post-transcriptional regulation of this
synaptic plasticity marker.
Regarding the consequences of such results, if we consider some
bibliographic data showing that RC3 knockout mice have impaired
synaptic plasticity and spatial learning [24], and as well as that
decreased GAP43 expression was associated with reduced neuronal
plasticity and learning [25], we can suppose that the n-3
deficiency could lead to similar cognitive alterations.
Table 2 Influence of the deficient diet on the mRNA and
protein expression (% expression/n-3 adequate diet) of neurogranin
and neuromodulin in striatum.
|
|
3 weeks
|
9 weeks
|
18 weeks
|
|
RC31
|
mRNA
|
98,18 ± 4,55
|
94,85 ± 6,19
|
86,21 ± 3.5*
|
|
protein
|
ND2.
|
ND2.
|
82.03 ± 12.91***
|
|
GAP431
|
mRNA
|
90,82 ± 6,12
|
92,93 ± 4,04
|
108,33 ± 2,08
|
|
protein
|
ND2
|
ND2
|
76,42 ± 10,45*
|
Effects of the deficient diet on plasma and brain PE fatty acid
composition
Plasma polyunsaturated fatty acid composition (table 3)
The plasma n-6 and n-3 PUFA composition of rats fed the deficient
diet changed all along the study; these modifications consisted in
i) an important decrease (– 80%) of the total n-3 PUFA proportions,
for α-linolenic acid (18:3 n-3) as much as for long-chain
derivatives (eicosapentaenoic 20:5 n-3, docosapentaenoic 22:5 n-3,
and docosahexaenoic 22:6 n-3 acids); ii) a slight increased
percentage (+10%) of total n-6 PUFAs, specially arachidonic (20:4
n-6) and docosapentaenoic (22:5 n-6) acids. Nevertheless, the
linoleic acid (18:2 n-6) proportion was diminished, despite the
same supply of both experimental diets. This suggests that this
fatty acid is used for synthesis of the n-6 long-chain derivatives
(20:4 and 22:5), because of the natural competition phenomenon
between n-6 and n-3 fatty acids towards enzymes of the fatty acid
metabolism; in the deficient group, preference is given to the n-6
fatty acids.
At the same time, we studied the total fatty acid composition of
red blood cell membranes, as described previously [26]. This
membrane model gives indications about the incorporation ability of
dietary fatty acids into cell membranes. The same patterns as those
observed in plasma were obtained for n-6 and n-3 PUFAs.
The study of the plasma total fatty acid composition is of very
particular interest because it is an indicator of fatty acids
usable by brain [27]. Some authors [28] reported that low plasma
DHA content was a significant risk factor for the development of
Alzheimer disease and appeared to be common in cognitive impairment
with aging. Others [29], in epidemiological studies, evidenced in
old subjects, that a higher proportion of n-6 PUFAs and a lower n-3
PUFA content in erythrocyte membrane were associated with a greater
risk of cognitive decline, diverse neuropsychiatric and
neurodegenerative diseases.
Table 3 Influence of the deficient diet on plasma
polyunsaturated fatty acid composition (% of total fatty acids).
|
3 weeks
|
9 weeks
|
18 weeks
|
|
Polyunsaturated fatty acids1
|
Adequate
|
Deficient
|
Adequate
|
Deficient
|
Adequate
|
Deficient
|
|
18:2 n-6
|
12,33 ± 0,29
|
11,24 ± 0,36*
|
12,31 ± 0,22
|
10,78 ± 0,25***
|
13,33 ± 0,33
|
12,02 ± 0,35*
|
|
20:4 n-6
|
22,98 ± 0,74
|
27,39 ± 1,03*
|
19,76 ± 0,85
|
22,31 ± 0,31*
|
18,72 ± 0,57
|
21,76 ± 0,72**
|
|
22:5 n-6
|
0,09 ± 0,01
|
1,82 ± 0,12***
|
0,07 ± 0,01
|
1,32 ± 0,12***
|
0,06 ± 0,01
|
1,41 ± 0,13***
|
|
Total n-6 PUFA
|
36,31 ± 0,72
|
41,67 ± 0.74***
|
32,96 ± 0,75
|
35,55 ± 0,44*
|
33,27 ± 0,67
|
36,52 ± 0,61**
|
|
18:3 n-3
|
0,7 ± 0,05
|
0,04 ± 0.00***
|
0,87 ± 0,04
|
0,06 ± 0,01***
|
0,68 ± 0,03
|
0,03 ± 0,00***
|
|
20:5 n-3
|
0,66 ± 0,05
|
0,03 ± 0.00***
|
0,75 ± 0,07
|
nd2***
|
0,59 ± 0,04
|
nd.2***
|
|
22:5 n-3
|
0,54 ± 0,04
|
0,09 ± 0,01***
|
0,49 ± 0,04
|
0,06 ± 0,01***
|
0,43 ± 0,02
|
0,09 ± 0,01***
|
|
22:6 n-3
|
3,43 ± 0,11
|
0,84 ± 0,04***
|
2,98 ± 0,11
|
0,55 ± 0,03***
|
2,56 ± 0,07
|
0,8 ± 0,02***
|
|
Total n-3 PUFA
|
5,33 ± 0,10
|
1,00 ± 0.005***
|
5,09 ± 0,09
|
0,66 ± 0.02***
|
4,27 ± 0,09
|
0,72 ± 0,03***
|
Brain phosphatidylethanolamine polyunsaturated fatty acid
composition (table 4)
Phosphatidylethanolamine (PE), with phosphatidylcholine, is the
most abundant phospholipid in rat cerebral membranes but especially
the richest in DHA.
Like in plasma, total n-6 and n-3 PUFA proportions were modified
by the deficient diet but in a different way, i) the n-6 DPA (22:5
n-6) percentage was extensively increased as the survey went (+
326% after 3 weeks and + 1002% after 18 weeks); ii) concomitantly,
the DHA proportion was diminished (– 17% and – 31%, after 3 and 18
weeks respectively).
Data of the literature mentioned that a declined brain DHA
percentage was balanced by an increase of the n-6 DPA rate in order
to maintain the membrane insaturation rate.
Thus, in the experimental conditions tested, cerebral membranes
were impoverished in DHA. Considering its involvement in brain
functioning and its ability to bind RXR [30], the loss of DHA could
have neurological consequences. This assumption is in accordance
with some results [31] that described poorer performance in spatial
tasks concomitantly to a loss of brain DHA. Others [32]
demonstrated, by studying the effects of a n-3 PUFA deprived diet
in rat, that the resulting disturbed brain PUFA metabolism
(elevated n-6 DPA and reduced DHA proportions) may be involved in
human depression, aggression, and bipolar disorder.
These data are just preliminary results of a wide work about the
effects of PUFA dietary contributions on the brain vitamin A
action. Other measures of nuclear receptor expression have to be
done in striatum and in another brain area implicated in memory
processes (hippocampus).
Table 4 Influence of the deficient diet on brain
phosphatidylethanolamine (PE) polyunsaturated fatty acid
composition (% of total fatty acids).
|
3 weeks
|
9 weeks
|
18 weeks
|
|
Polyunsaturated fatty acids1
|
Adequate
|
Deficient
|
Adequate
|
Deficient
|
Adequate
|
Deficient
|
|
18:2 n-6
|
0,28 ± 0,02
|
0,21 ± 0,01*
|
0,2 ± 0,00
|
0,17 ± 0.01***
|
0,39 ± 0,02
|
0,36 ± 0,02
|
|
20:4 n-6
|
10,35 ± 0,17
|
10,9 ± 0,21
|
9,2 ± 0,07
|
10,35 ± 0,09***
|
9,43 ± 0,09
|
10.27 ± 0.13***
|
|
22:5 n-6
|
0,91 ± 0,03
|
3,88 ± 0,12***
|
0,46 ± 0,02
|
4,16 ± 0,07***
|
0,41 ± 0,01
|
4,52 ± 0,10***
|
|
Total n-6 PUFA
|
17,56 ± 0,19
|
21,5 ± 0,35***
|
15,2 ± 0,09
|
20,98 ± 0,15***
|
15,56 ± 0,11
|
21,45 ± 0,21***
|
|
22:5 n-3
|
0,26 ± 0,01
|
0,12 ± 0,00***
|
0,23 ± 0,01
|
0,06 ± 0,00***
|
0,18 ± 0,00
|
0,04 ± 0,00***
|
|
22:6 n-3
|
17,42 ± 0,49
|
14,49 ± 0,35***
|
16,62 ± 0,31
|
12,88 ± 0.20***
|
14,91 ± 0,15
|
10,33 ± 0,20***
|
|
Total n-3 PUFA
|
17,88 ± 0,49
|
14,61 ± 0,35***
|
16,88 ± 0,31
|
12,93 ± 0,20***
|
15,09±0,15
|
10,37 ± 0,20***
|
Acknowledgments
This research was supported by Oniol, ANRT, Société Lesieur and
Conseil Régional d’Aquitaine. The authors sincerely thank Laurent
Caune (Unité Nutrition et Neurosciences) for animal care, and
Laurence Fonseca and Sabrina Serrano (ITERG, Département Nutrition
Santé) for their valuable contribution to fatty acid analyses.
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