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Laboratoire de Physiologie de l'Environnement, Faculté de Médecine Lyon Grange-Blanche, 69373 Lyon Cedex 08, France;
*
Laboratoire de Neuropharmacologie Moléculaire UFR Laënnec, 69372 Lyon Cedex 08, France;
INRA Laboratoire de Nutrition et Sécurité Alimentaire, 78352 Jouy en Josas, France;
**
Ecole des Cadres et Techniciens de la Santé, Monastir, Tunisie; and
Laboratoire de Radiopharmacie Radioanalyse, Hôpital Neuro-Cardiologique, 69003 Lyon, France
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • melatonin • 6-sulfatoxymelatonin • DHA • phospholipids • pineal gland • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Axelrod 1974
, Reiter 1991
) via complex cellular mechanisms (Vanecek 1998
). Clinical studies have demonstrated the potential
therapeutic effects of MEL administration against behavioral disorders
[see review Nowak and Zawilska (1998)<zharvx]. MEL appears to
be an effective and safe treatment for sleep disturbances observed in
pathologic conditions such as major depression (Dolberg et al. 1998
). In humans, as in other species, MEL is secreted in a
circadian pattern with low levels during the day and high
concentrations at night (Binkley 1988
). Studies
conducted on rodents and humans indicate that the amount of MEL
secreted and consequently, the amplitude of its circadian rhythm, can
be modified by several factors such as age and nutrition; however, the
biological consequences remain unclear (Waldhauser et al. 1998
). Low levels of MEL in serum or pineal glands in old
animals and elderly humans prompted some authors to suggest a role of
MEL in delaying the aging process (Reiter 1997
).
Conversely, MEL hypersecretion appears to be extremely rare.
Numerous studies provide evidence for an essential role of the
polyunsaturated fatty acids (PUFA) in the mammalian central nervous
system. Recently, (n-3) PUFA deficiency has been linked to a number of
biological dysfunctions in humans (Maes et al. 1996
,
Martinez 1996
, Peet et al. 1998
).
Moreover, numerous studies have shown that chronic dietary
-linolenic acid [18:3(n-3)] deficiency in rats impairs performance
in various learning tasks via an alteration in monoaminergic function
(Delion et al. 1994
). Docosahexaenoic acid [DHA,
22:6(n-3)] is among the major PUFA of the (n-3) family in the pineal
glands of adult rats (Sarda et al. 1991
) localized in
the sn-2 position of membrane phospholipids. We have shown
that dietary (n-3) PUFA supplementation or deficiency affect MEL
release. Indeed, the levels of cAMP, N-acetylserotonin, a
precursor of MEL, and MEL secretion after norepinephrine or
adenosine-agonist stimulation were greater in cultured pinealocytes
from adult rats fed fish oil concentrates (Sarda et al. 1992
) or lower in (n-3) PUFA–deficient rats compared with
controls (Gazzah et al. 1993
). Conversely, in vitro DHA
supplementation of rat pinealocytes for 48 h markedly decreased
cAMP production (-50%) and then MEL production (-50%)
(Delton-Vandenbroucke et al. 1996
, Zaouali-Ajina et al. 1998
). Furthermore, the fatty acid (FA) composition of
the rat pineal gland reflected the differences in the dietary fat
source. There was a reciprocal replacement of the (n-6) PUFA by (n-3)
PUFA in the pineal glands from rats fed a fish oil diet. Conversely, in
rats fed an 18:3(n-3)–deficient diet, the pineal gland contained a
reduced proportion of (n-3) PUFA, which was accompanied by high levels
of docosatetraenoic acid [22:4(n-6)] and docopentaenoic acid
[22:5(n-6)] (Sarda et al. 1991
).
These data suggest that the dietary fat, especially a high level of
DHA, may modulate the pineal gland activity in terms of MEL synthesis.
Although fish oil is currently the primary dietary source of DHA and
eicosapentanoic acid [EPA, 20:5(n-3)], its consumption is low.
Various chemical forms of DHA have been used in rats and humans for an
efficient distribution from blood cells to target tissues such as
brain, mainly triglycerides (TG) containing DHA, FA ethyl esters and FA
arginine salts (Brossard et al. 1996
, El Boustani et al. 1987
, Ikeda et al. 1993
, Nordoy et al. 1991
). Despite the biological properties of DHA, its
packaging in phospholipids (PL) has been poorly investigated, except
for the lysophosphatidylcholine (lyso-PC)-DHA (Thies et al. 1994
), although its accumulation in PL classes is evident.
In this study, we examined DHA-enriched PL from pig brains (BPL) or hen eggs (EPL), as sources of DHA. We examined their effects on lipid FA composition of the pineal glands and daytime and nighttime concentrations of 6-sulfatoxymelatonin (aMT6), the main MEL urinary metabolite, in adult male control and (n-3)–deficient rats fed BPL or EPL for 5 wk.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The protocol of this study was approved by the French
(87/848/Ministère de l'Agriculture et de la Forêt) and
European Economic Community (86/609/ECC) guidelines for care and use of
laboratory animals and was approved by a regional ethical committee for
animal use. Efforts were made to minimize animal suffering and to
reduce the number of animals used. Two generations of female rats
(originating from the Laboratoire de Nutrition et Sécurité
Alimentaire, Jouy en Josas, France) were given a diet containing 6
g/100 g total lipids in a form of African peanut oil specifically
deficient in -linolenic acid [18:3(n-3)] (Belzung et al. 1998
). This deficient diet provided ~1200 mg linoleic acid
[18:2(n-6)] but <6 mg 18:3(n-3)/100 g diet. Two weeks before mating,
female rats originating from the second generation of the
18:3(n-3)–deficient rats were divided into two groups. The first group
received the deficient diet (deficient group), and the second group
received a diet in which peanut oil was replaced by a mixture of
African peanut oil and rapeseed oil (60 and 40%, respectively). This
diet (control group) provided 1210 mg [18:2(n-6)] and 205 mg
[18:3(n-3)]/100 g diet [(n-6)/(n-3) = 6]. Diets were consumed
ad libitum by both groups. At weaning, the male progeny of these two
groups of female rats were fed the same diet as their respective dams.
A two-generation model was used so that the offspring could not
derive (n-3) PUFA from maternal stores during gestation and lactation.
The composition of the diets and their fatty acid composition are
reported in Tables 1
and
2.
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for 5 wk. Detailed information on the
composition of BPL and EPL is given in Table 3
. BPL and EPL were a gift of Institut de Recherche Biologique Yves
Ponroy. EPL and/or EPL supplementation provided ~200 mg DHA/100 g
diet in the control or (n-3)–deficient groups. These formulas, without
neutral lipids or cholesterol, contained almost exclusively DHA as
(n-3) PUFA and a similar proportion of (n-6) PUFA (Table 3)
. The BPL
experiment was conducted in September and the BPL experiment in
February. In the first experiment, the following four groups
(n = 12) of 8-wk-old rats were used: control,
control + BPL, deficient and deficient + BPL. In the second experiment,
the following four groups (n = 12) were used:
control, control + EPL, deficient and deficient + EPL. All rats were
kept in individual plastic cages under the following similar
conditions: constant temperature and humidity (21 ± 1°C and
60%, respectively); a 12-h light:dark cycle (lights on at 0700 h); and free access to diet and water for 1 wk. All rats were fed their
respective diets for 5 wk. Then, each rat was placed individually into
a metabolism cage for 2 d before collection of urine for 2
consecutive days to minimize stress due to isolation. Each rat received
20 g diet/d. To determine differences between day and night (12 h
light, 12 h dark) in urine aMT6 concentrations, urine was
collected into plastic tubes at the beginning of the light period (0700
h, nighttime excretion) or the dark period (1900 h, daytime excretion)
and stored at -20°C. At the end of each experiment, rats were killed
by decapitation. Pineal glands were collected within ~30–40 s
between 0900 and 1000 h, and immediately frozen and stored at
-80°C until assays were conducted.
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Following the method of Harthé et al. (1991), the daytime and nighttime urine aMT6 concentrations were measured by a direct 125I-RIA using an antiserum provided by Dr. B. Claustrat (Hopital Neurocardiologique, Lyon). The sensitivity limit of the assay was 25 pmol/L.
Analyses of tissue lipids.
Because the lipid composition of pineal glands of control and
(n-3)–deficient rats was described previously (Gazzah et al. 1993
), only six pineal glands, randomly taken in each
experiment, were used for lipid analysis in control and deficient
groups. Pineal glands (~2 mg) were homogenized with a Polytron
homogenizer for 20 s in a mixture of chloroform/methanol (2:1,
v/v) according to the method of Folch et al. (1957)
. The
homogenates were centrifuged for 10 min at 500 x g
at 4°C. The supernatants were evaporated completely under a stream of
nitrogen. The total lipid extracts were methylated with 0.6 mol/L
methanolic sulfuric acid. Separation of the FA methyl esters was done
by capillary gas chromatography on a Hewlett-Packard model N 5890
gas chromatograph (Hewlett-Packard, Palo Alto, CA) equipped with a
flame-ionization detector and a capillary column (length, 50 m; diameter, 0.25 mm; CP-Sil 88; Chrompack, Les Ulis, France). The
oven temperature was programmed to rise from 170 to 230°C at a rate
of 2°C/min. The injector temperature was 230°C and the detector
temperature 270°C. Peaks were integrated by a programmable
integrator-calculator (D 2500A chromato-integrator; Merck, Nogent
sur Marne, France). FA were identified by comparing the retention times
with those of appropriate standard FA methyl esters. The relative
concentration of each FA is expressed as the percentage of identified
FA equal to or >16 carbon atoms for tissue samples.
Analyses of diet PL classes.
Separation of the PL classes from respective BPL and EPL were performed
by TLC on precoated silica gel 60 plates (E. Merck, Darmstadt, Germany)
according to the method previously described (Gazzah et al. 1995
).
Data analysis.
The data are presented as means ± SD. For aMT6 data,
the statistical significance of differences between diet groups was
determined by a two-way ANOVA (StatView, Abacus Concepts, Berkeley,
CA) and comparisons between groups were found to be significant at
P 
0.05 by a Fisher post-hoc test.
Differences in aMT6 concentration between day and night were tested
using the Mann-Whitney U-test. Fatty acid levels were analyzed by
ANOVA for multigroup comparisons. When a significant difference was
noted between diet groups, means were compared using unpaired
Student's t test. There was no significant difference
in fatty acid composition in either control or (n-3)–deficient groups
between the two experiments; thus the results were pooled. Differences
were considered significant at P < 0.01 level.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pineal fatty acid composition
(n-3)–Deficient diet.
As expected, the differences in pineal FA composition between the
deficient group and the control group involved the PUFA. DHA was 572%
lower (P < 0.01) in the pineal glands of deficient
rats than in those of controls. This low level of DHA was compensated
for by higher amounts of 22:4(n-6) and 22:5(n-6) (120 and 800%,
respectively, P < 0.01) in the (n-3)–deficient group
than in the control group. Total (n-3) PUFA was lower (569%,
P < 0.01) in the deficient group than in the control
group, whereas total (n-6) PUFA level was substantially higher (16%,
P < 0.01) in the deficient group than in the control
group. The result was that the total PUFA levels [(n-3) + (n-6)] were
not different in the pineal glands of control and deficient rats,
whereas the ratio of (n-6) to (n-3) was dramatically greater in the
pineal glands of deficient rats (+700%, P < 0.01)
than in those of controls (Table 4
).
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.
EPL diet.
The pineal glands of control + EPL and deficient + EPL groups had lower
levels of 16:0 (13 and 20% respectively, P < 0.01)
and higher levels of 18:0 (11 and 7% respectively, P
< 0.01) than those of control and deficient groups, without
difference in the total saturated FA level. Total MUFA levels were
slightly lower in the pineal glands of the control + EPL (16%,
P < 0.01) and deficient + EPL groups (14%,
P < 0.01) than in pineal glands of control or
deficient rats, respectively. These low levels of MUFA were associated
with low levels of 16:1(n-7), 18:1(n-7) and 18:1(n-9) in the pineal
glands of the control + EPL rats but a low level only of 18:1(n-9) in
the deficient + EPL rats (15%, P < 0.01). Total (n-6)
PUFA level was unaffected in the pineal glands of the control + EPL
rats but significantly lower in those of deficient + EPL rats (10%)
than in deficient rats. Levels of (n-6) PUFA were lower in the pineal
glands of the deficient + EPL rats than in deficient rats, due to low
20:4(n-6), 22:4(n-6) and 22:5(n-6) levels (13, 64 and 88%,
respectively, P < 0.01). DHA level was higher in the
pineal glands of control + EPL rats than in those of controls (54%,
P < 0.01) and dramatically higher in the pineal glands
of deficient + EPL rats (809%, P < 0.01) than in
deficient rats. Thus, a higher level of total (n-3) PUFA (846%,
P < 0.01) was observed in the pineal glands of the
deficient + EPL rats than in the deficient rats. The (n-6)/(n-3) and
20:4(n-6)/DHA ratios were not different in the pineal glands in control
and deficient rats fed either the BPL or EPL diet (Table 4)
.
Physiologic response of pineal glands.
In all groups, there were significant day vs. night differences in aMT6
concentrations, with higher values at night (P < 0.01)
(Fig. 1A
,
B). Daytime aMT6 concentrations were not significantly different among
groups in either experiment (Fig. 1
A, B).
Nighttime aMT6 concentrations in the deficient rats were significantly
lower than in control rats (32%, P < 0.01, in
Experiment 1; 44%, P < 0.03, in Experiment 2).
Nighttime aMT6 concentrations were significantly higher (75.8%,
P < 0.05 and 110%, P < 0.05,
respectively) in the deficient + BPL or EPL rats than in the deficient
rats, but not significantly different from the concentrations in
control and control + BPL or EPL rats.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), led to a specific DHA
enrichment. In fact, in the total lipid fraction of pineal glands in
control or (n-3)–deficient rats, the DHA level reached a plateau
between 10 and 11 mg/100 mg total FA because (n-6) PUFA levels did not
change.
Chronic dietary -linolenic acid deficiency modifies the fatty acid
composition of the pineal cells (Gazzah et al. 1993
).
Moreover, recent studies showed that this type of deficiency alters
functional properties of membrane pinealocyte receptors because a
decrease in response of adenosine pinealocytes occurred in rats fed an
(n-3) fatty acid–deficient diet (Gazzah et al. 1993
).
In this work, in a rat model deficient in -linolenic acid over
three generations, we confirm a reduced DHA level and
compensatory higher levels in the (n-6) fatty acids, specifically
22:4(n-6) and 22:5(n-6) in the pineal gland. These findings are in
agreement with those of Zhang et al. (1998)
, which
indicate the persistence of a low level of DHA accompanied by high
levels of (n-6) PUFA in PL classes in pineal glands of (n-3)–deficient
rats at 12 mo of age.
It has been reported that in vitro DHA incubation with pinealocytes for
48 h led to a dose-dependent DHA enrichment into PL and TG
pools, whereas under the same experimental conditions, 20:5(n-3)
incubation is accompanied by high 20:5(n-3), 22:5(n-3) and DHA levels
compensated by low levels of 18:2(n-6) and 20:4(n-6) in these lipid
classes (Delton-Vandenbroucke et al. 1996
). Similar
changes, particularly low 18:2(n-6) and 20:4(n-6) levels partially
compensated for by high (n-3) PUFA levels, have been observed in the
pineal gland of rats fed fish oil (Sarda et al. 1991
).
All of these results indicate the limits of such experiments to obtain
specific DHA-enriched membranes of pineal cells. It is interesting
to note that BPL or EPL constitute a new dietary approach to this
problem.
We found that BPL contains similar proportions of phosphatidylcholine (39.6%) and phosphatidylethanolamine (32.4%) with only 22.6% of phosphatidylserine, whereas EPL contains a high proportion of phosphatidylcholine (77.8%) and a low percentage of phosphatidylethanolamine (17.8%) (data not shown). Because BPL and EPL diets produce similar effects on the FA composition of pineal glands, we conclude that DHA delivery to pineal tissues is independent of the kind of PL classes present in each diet.
In the two experiments, the daytime and nighttime urinary aMT6
concentrations were in the range of those previously described in urine
of adult male rats (Yie et al. 1992
). We did not observe
any differences in daytime aMT6 excretion among groups, whereas
Zhang et al. (1998)
found greater daytime MEL
concentrations in pineal glands of (n-3)–deficient rats at 12 mo of
age. These discrepancies may be explained by (n-6)/(n-3) ratios and
20:4(n-6)/DHA ratios, which differ greatly with age, i.e., 2- and
1.3-fold higher in control and (n-3)–deficient-groups, respectively,
at 2 mo compared with 12 mo of age (Zhang et al. 1998
).
In addition, we measured the plasma MEL concentrations during the 12-h
light:dark cycle in rats of both groups. The individual profiles of
plasma MEL concentrations reflected changes in urinary aMT6 patterns
(data not shown). Because MEL is rapidly released from the pineal gland
once it is produced, the blood MEL concentration reflects the amount
being produced in the pineal gland at virtually the same time. From our
data, we hypothesize that the FA status modulates the synthesis rather
than the release of MEL from the pineal gland (or other sources) and
does not interfere with MEL catabolism.
The influence of MEL on human circadian rhythms, together with its
acute effects on sleep, body temperature and performance, has been
investigated extensively and results have been controversial
(Arendt 1998
, Nowak and Zawilska 1998
). A
number of recent studies conducted on rodents and humans demonstrated
that the nocturnal peak of serum MEL drops progressively, mainly during
senescence and, subsequently, the amplitude of MEL concentration with
or without a shift of its circadian phase (Arendt et al. 1997
, Reiter 1997
, Waldhauser et al. 1998
). Because aMT6 is an excellent indicator, both
quantitatively and qualitatively, of MEL production (Bojkowski et al. 1987
), these results suggest an effect of FA status on
neuroendocrine regulatory mechanisms and extend data on the
relationships that exist between DHA and hormones released from the
thyroid and/or adrenal corticotrope axis (Clandinin et al. 1998
, Romo et al. 1997
). Nonetheless, it is not
known whether similar changes may occur in humans and, consequently,
which biological rhythms would be affected in mammals when MEL
secretion and FA status decline to a critical or limiting level.
The observations of this study, although not conclusive in terms of demonstrating a clear effect of BPL and EPL (as source of DHA) on physiologic functions and circadian rhythms, suggest an effect on MEL regulatory mechanisms.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by funds provided by l'Institut de Recherche Biologique Yves Ponroy and l'Institut
National de la Santé et de la Recherche Médicale (Contrat INSERM/DGRST).
4 Abbreviations used: aMT6,
acetyl-6-sulfatoxymelatonin; BPL, brain phospholipids; DHA, docosahexaenoic acid: 22:6(n-3); EPA, eicosapentaenoic acid: 20:5(n-3);
EPL, egg phospholipids; FA, fatty acid; lyso-PC, lysophosphatidylcholine; MEL, melatonin; PL, phospholipids; MUFA,
monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid. TG, triacylglyceride.
Manuscript received January 22, 1999. Initial review completed March 3, 1999. Revision accepted July 20, 1999.
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  M. Lavialle, G. Champeil-Potokar, J. M. Alessandri, L. Balasse, P. Guesnet, C. Papillon, P. Pevet, S. Vancassel, B. Vivien-Roels, and I. Denis An (n-3) Polyunsaturated Fatty Acid-Deficient Diet Disturbs Daily Locomotor Activity, Melatonin Rhythm, and Striatal Dopamine in Syrian Hamsters J. Nutr., September 1, 2008; 138(9): 1719 - 1724. [Abstract] [Full Text] [PDF]
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A. Ikemoto, A. Fukuma, Y. Fujii, and H. Okuyama Lysosomal Enzyme Activities Are Decreased in the Retina and Their Circadian Rhythms Are Different from Those in the Pineal Gland of Rats Fed an {{alpha}}-Linolenic Acid-Restricted Diet J. Nutr., December 1, 2000; 130(12): 3059 - 3062. [Abstract] [Full Text] [PDF]
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