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Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602 and * Department of Foods and Nutrition, College of Family and Consumer Sciences, The University of Georgia, Athens, GA 30602.
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • water maze • spatial memory • zinc plus L-histidine • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In the brain, zinc plays an important
role in neurotransmission (Vallee and Falchuk 1993
) by
modulating the activity of glutamate and 
-aminobutyric acid
receptors. Zinc-containing neurons/nerve terminals have been
identified in several regions of the brain including the hippocampus,
cortex and the cerebellum (Donaldson 1973
). The
hippocampus contains the highest concentration of zinc of any brain
region. It is particularly enriched in nerve terminals of the
hippocampal mossy fiber system in which it functions in synaptic
transmission (Donaldson 1973
, Haug 1976
,
Slomianka 1992
, Xie and Smart 1991
). The
hippocampus participates in spatial learning and memory (Morris et al. 1982
), probably by assessing the relative familiarity of
object placement (Wan et al. 1999
). Collectively, these
facts implicate zinc in memory processing (Takeda et al. 1994
).
Zinc deficiency may result from several factors such as dietary
restriction, gastrointestinal dysfunction and elevated levels of
dietary phytate or calcium. Dietary zinc deficiency causes a number of
abnormalities, depending on the severity, duration and timing of the
deficiency. For instance, feeding a diet severely restricted in zinc to
pregnant rats causes a range of congenital anomalies in the offspring,
including facial deformities, hydroencephalus and anencephaly
(Dreosti et al. 1981
, Hurley and Shrader 1972
). Although gross morphological changes in the CNS are not
induced by zinc deficiency in adult animals, behavioral changes have
been recognized (Caldwell et al. 1970
, Halas et al. 1983
and 1986
). Zinc deficiency may alter brain function
and metabolism through several different mechanisms. For example, the
activity of zinc metalloenzymes (e.g., glutamic acid dehydrogenase) is
reduced in the brain of zinc-deficient rats (Dreosti et al. 1981
). In addition to altered enzymatic activity, zinc
deficiency is associated with changes in neurotransmitter content and
receptor affinity (Colom et al. 1997
, Palma et al. 1998
, Peters et al. 1987
, Westbrook and Mayer 1987
). In spite of the obvious importance of zinc to
CNS development and function, only limited study has been done to
determine how changes in dietary zinc intake affect zinc function in
the CNS.
Brain zinc content appears to be under strict homeostatic control. In
adult rats, brain zinc was highly conserved for several weeks after
severe dietary zinc restriction (O’Dell et al. 1989
)
even though these rats showed clinical signs of systemic zinc
deficiency (e.g., anorexia, weight loss or hair loss). Additional
studies indicate that the effects of dietary zinc perturbations on
brain zinc concentrations are equivocal. This likely reflects
differences in both the methodology involved in measuring zinc
concentrations and the bioavailability of different zinc formulations.
For instance, studies using dietary sources of zinc supplemented with
amino acids, such as methionine or histidine (Wedekind et al. 1992
) found the zinc in these amino acid–supplemented diets to
be more bioavailable to rat brain than the zinc salt formulations alone
(Ashmead 1991
). In particular, zinc from zinc histidine
has been shown to be taken up by the brain better than zinc from zinc
salt (Van Wouwe et al. 1989
). Further,
L-histidine, when added directly to the bathing medium,
stimulated greater 65Zn uptake into rat brain
compared with albumin (Buxani-Rice et al. 1994
). On the
other hand, other studies have reported that supplemental dietary zinc
above adequate levels has little effect on brain zinc content
(Franklin et al. 1992
, Kasarskis 1984
).
These later data must be interpreted with caution, however, because
only inorganic forms of zinc were used, and inorganic zinc does not
readily cross the blood-brain barrier (BBB) (Takeda et al. 1994
).
Despite the apparent tight regulation of brain zinc concentrations,
studies have shown that moderate dietary zinc restriction results in
behavioral changes, including memory deficits. This suggests that
behavior may serve as a more sensitive index of CNS zinc status than
measures of zinc concentration alone (Golub et al. 1995
). The central hypothesis of this research is that
zinc-dependent cognitive function in young adult rats is influenced
by the formulation of the dietary source of zinc. Thus, the objective
of this particular study was to test this hypothesis by comparing the
effect of dietary zinc given as zinc chloride or as zinc chloride
supplemented with L-histidine on short-term memory of
young adults rats. To achieve this, we evaluated CNS function in
postweaned young rats during periods of dietary zinc restriction and
repletion using a short-term memory task.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Sprague-Dawley rats (n = 49; Harlan
Sprague Dawley, Indianapolis, IN) between 36 and 40 d of age were
housed individually in 18 x 20 cm stainless steel wire-mesh
cages at a temperature of 22 ± 2°C, relative humidity between
40 and 60% and a 12-h light:dark cycle (lights on 0700 h) in a
facility approved by the American Association for the Accreditation of
Laboratory Animal Care. The experimental design was approved by the
University Animal Care and Use Committee. Food intake and body weight
were recorded daily each weekday. Rats were fed one of the following
egg white–based purified diets: zinc chloride–adequate (zinc at 20
mg/kg as zinc chloride), zinc-deficient (zinc at 1–2 mg/kg), or
zinc chloride supplemented with L-histidine (zinc 20 mg/kg
as zinc chloride plus added L-histidine at 40 mg/kg) from
Purina Mills Nutrition International Test Diet (Richmond, IN; exact
compositions in Table 1
). To minimize exposure to extraneous sources of zinc, rats had
unlimited access to deionized distilled water
(ddH2O) from glass bottles fitted with stainless
steel sipper tubes.
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In a second experiment, male Sprague-Dawley rats (n = 23; 36–40 d of age) were divided into control (n = 6), pair-fed (n = 6) and zinc-restricted (n = 11) groups, and given the same dietary treatments over the three phases as described above, with the exception that the depletion phase lasted for an additional week. At the end of the depletion phase, three rats from each group were killed, and serum and tissues samples collected for zinc determination. The remaining rats in each group were killed on repletion d 3, and serum and tissues were collected for zinc determination.
Morris water maze.
Before the beginning of each experiment, rats were trained on the
distal-cue version of the Morris water maze (MWM) until they
learned to search quickly for a hidden platform (Brandeis et al. 1989
, Morris et al. 1982
, Morris 1984
, Wenk 1998
). During each subsequent phase,
rats were evaluated in the MWM a minimum of twice weekly. The water
maze had a diameter of 1.25 m, a height of 0.46 m and a water
depth of ~0.24 m. A plexiglass platform (16.5 cm2) was
submerged 2 cm below the surface of water made opaque by the addition
of ColorArt white nontoxic powder Tempera paint (Dixon, Maitland, FL).
Rats were tested on two blocks of two trials per test day. During the
acquisition trial, the rat was placed in the water and was expected to
search each of the quadrants of the maze until locating the hidden
platform that was the only escape out of the maze. After 20 s, the
rat was then removed from the platform and placed in a cage for 90 s (intertrial interval). Following this, the rat was placed back in the
water (retrieval trial) and was expected to relocate the hidden
platform quickly by using visual cues found in the room. If rats failed
to remember where the platform was located within 120 s they were
tested using a visible platform to ensure that the failure was not due
to visual, motivational or sensorimotor deficits. Between each test day
and each block of trials, the platform was randomly placed in different
quadrants of the maze.
Sample collection and analyses.
Throughout all phases, blood was obtained weekly from each rat by tail bleed at approximately the same day and time. At the end of the depletion phase, control (n = 3), pair-fed (n = 3) and zinc-restricted (n = 6) rats were killed by decapitation; brain, liver and femur samples were collected and frozen (-80°C). At the end of the repletion phase, the remaining rats were killed and tissues samples collected as described.
Total zinc concentrations from blood and tissue samples were analyzed by atomic absorption spectrophotometry. Samples were weighed in borosilicate glass culture tubes. After drying overnight in a 95°C oven, samples were ashed for 32 h in a 450°C furnace. The resultant ash was digested with 1 mol/L HCl for 45–60 min and diluted with ddH2O. The solubilized samples were read on a Perkin-Elmer 5000 flame spectrophotometer (Perkin-Elmer, Norwalk, CT) and compared with zinc reference solution (Fisher Scientific, St. Louis, MO).
Data analyses.
Data were expressed as the mean value of each phase or each time point
± SEM for each treatment group. The experimental
design and statistical analyses were conducted in consultation with the
University of Georgia Department of Statistics using statistical
analysis software (SAS version 6.12, SAS Institute, Cary, NC). Food
intake, body weight and escape latencies (acquisition and retrieval
trials), as well as blood, brain, liver and femur zinc concentrations
were analyzed using a split-plot repeated-measures ANOVA to
determine the effects of treatment (diet) over time (within phases) and
within groups (Montgomery 1997
). P-values
< 0.05 were considered significant. When analyzing the escape
latencies within each phase, acquisition and retrieval trials were used
as the response.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A 50% reduction in escape latency for the retrieval trial compared with the acquisition trial was used to establish that the rats were adequately trained. The training period lasted ~1 wk, and all rats successfully learned the task. Once all of the rats had demonstrated this ability, the adaptation phase of the study was initiated.
Adaptation phase.
No significant differences in either food intake or body weight were
found during this phase of the study. There were no significant
differences in escape latencies between rats in either the acquisition
or the retrieval trials. Further, no significant differences were found
in whole-blood zinc between rats. Zinc concentrations obtained from
whole-blood samples ranged from 50.5 to 119.3 µmol/L
and were consistent with normal values reported in the literature for
rat whole-blood zinc (Walker and Kelleher 1978
).
Zinc depletion phase,
During the depletion phase, a cyclic anorexia developed in the
zinc-restricted group around the middle of wk 2 of depletion and
resulted in significantly decreased food intake (Fig. 1A
). The mean daily intake of the zinc-restricted group throughout the
phase was 23.2% lower than that of the control group. By design, the
pair-fed group received only what the zinc-restricted rats ate;
therefore, their mean daily intake was also significantly lower than
that of the control group. As expected, the mean daily body weights of
the zinc-restricted and pair-fed groups were significantly
different from the control group (Fig. 1B
). The control
group continued to gain weight in a linear manner, whereas the weight
gain of the zinc-restricted group approached a plateau around the
end of wk 1 of depletion, and the pair-fed group around the middle
of wk 2. The zinc-restricted group gained an average of 52.3% less
than the control group during this 3-wk period. Further, the
zinc-restricted group gained an average of 41.1% less than the
pair-fed group, whereas the pair-fed group gained an average of
19.1% less than the control group during this period.
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, test d 5). When the retrieval latencies were averaged across the
entire 3-wk phase, the mean retrieval latency of the
zinc-restricted group was 86.0 and 61.0% longer than the control
and pair-fed groups, respectively. The mean retrieval latency of
the pair-fed group was not significantly different from that of the
control group.
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). However, the zinc-restricted group had significantly
lower liver (25.5 and 25.2% less) and femur (32.5 and 31.7% less)
zinc concentrations than the control and pair-fed groups,
respectively (Table 2
). In addition, although total brain zinc concentrations were not
significantly different among the control, pair-fed and
zinc-restricted groups, hippocampal zinc concentrations in the
zinc-restricted group were reduced significantly by 3.2 and 3.6%
compared with the control and pair-fed groups, respectively.
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During the 2-wk repletion phase, no significant differences in the average daily food intake or body weight were found between the control or pair-fed subgroups fed the zinc chloride or the zinc chloride supplemented with L-histidine diets. Further, no significant differences were found in retrieval latencies between these control (P = 0.97) or pair-fed (P = 0.85) diet subgroups. Thus, the data from the two control and pair-fed subgroups were pooled into one group of control and one group of pair-fed. When considering the repletion phase as a whole, food intakes were not significantly different between the control and zinc-restricted groups (data not shown); however, the pair-fed group consumed significantly less than the control and both zinc-repleted groups. The mean daily intake of the pair-fed group was 10.8% less (P = 0.007) than the control group, and 7.6% (P = 0.010) and 16.6% less (P = 0.002) than the zinc chloride supplemented with L-histidine and zinc chloride–repleted groups, respectively. However, by the end of the repletion phase, the mean daily intake of the pair-fed group had returned to control levels. The mean body weights of pair-fed and both zinc repletion groups were still significantly different from the control group when measured across the whole phase. The zinc chloride supplemented with L-histidine and the zinc chloride–repleted groups gained an average of 34.9% less (P = 0.0001) and 24.8% less (P = 0.0020) than the control group, respectively, over the 2-wk period; the pair-fed group gained 26.4% less (P = 0.0016) than controls.
During the initial period of repletion, the rats were tested daily on
the MWM until an improvement in retrieval latencies was evident;
thereafter, they were tested every 2nd d until the end of the phase. In
general, the previously zinc-restricted group improved their
retrieval escape latencies during the 2-wk repletion phase, although
the phase mean remained significantly prolonged compared with the
control and pair-fed groups (Fig. 3A
). However, when the two repletion groups were compared separately, only
the mean retrieval escape latencies of the zinc chloride–repleted
group were significantly prolonged (Fig. 3B
). When comparing
the retrieval latencies averaged across the whole phase, the zinc
chloride supplemented with L-histidine–repleted group was
no longer significantly different from the control or pair-fed
groups. The mean retrieval latencies of the zinc chloride–repleted
group, however, remained 75.0% above control values. As is evident in
Figure 4
, the retrieval latencies of the zinc chloride supplemented with
L-histidine–repleted group began to return to control
values after repletion d 2 (test d 2), whereas the latencies of the
zinc chloride–repleted group remained significantly elevated until the
beginning of wk 2 of repletion (test d 5).
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In a second experiment, serum zinc concentrations obtained by cardiac puncture from a sample of the zinc-restricted group (n = 3) at the end of the 4-wk depletion phase were significantly lower by 56.4 and 55.5% compared with the control (n = 3; P < 0.0001) and pair-fed (n = 3; P < 0.0001) groups, respectively. Further, the hippocampal zinc concentrations of the zinc-restricted group at the end of depletion were significantly lower by 15.2 and 10.8% compared with the control (P = 0.007) and pair-fed (P = 0.036) groups, respectively, and this was associated with impaired performance on the MWM. However, no significant differences in either serum or hippocampal zinc concentrations were found between the control and pair-fed groups. During repletion, the remaining rats were killed and tissues collected for zinc determination on repletion d 3, which was the 1st d on which the zinc chloride supplemented with L-histidine group in the first experiment showed significant improvement in the MWM. At this time, hippocampal zinc concentrations of the zinc supplemented with L-histidine group (n = 4) were within 2.7% of the control zinc concentrations, and were no longer significantly different from the control (n = 3; P = 0.713) or pair-fed (n = 3; P = 0.9) groups. However, hippocampal zinc concentrations in the zinc chloride–repleted group (n = 4) were still lower than the control, pair-fed and L-histidine–supplemented groups by 7.2% (P = 0.356), 10.6% (P = 0.171) and 9.8% (P = 0.177) respectively. No differences in serum zinc concentrations were found among any of the four treatment groups by d 3 of repletion.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we chose the Morris water maze task to assess cognitive
function in previously zinc-replete young adult rats undergoing
short-term dietary zinc restriction. Impaired cognitive performance
has been reported in a number of studies of the offspring of rat dams
fed a zinc-deficient diet during gestation and/or lactation
(Halas et al. 1983
and 1986
). The current study was
designed in particular to assess working or short-term memory in
young rats initially exposed to a zinc-deficient diet after weaning
between 50 and 54 d of age. All of the rats used in this study
were first trained on the MWM to ensure that they could perform the
task adequately. The young rats learned the task quickly, demonstrating
adequate learning capabilities and confirming that their short-term
memory function was intact before consuming the zinc-deficient diet
(Brandeis et al. 1989
, Morris 1984
). Rats
adapted to their new diet and the task within 1 wk.
Zinc depletion.
The earliest relevant finding of the zinc depletion phase was the onset
of anorexia in the zinc-restricted group at ~d 10 of dietary
restriction. This anorexia was characterized by a cyclic pattern, a
phenomenon often associated with rats that are zinc depleted
(Golub et al. 1995
, Halas et al. 1983
).
Coincident with this pattern of anorexia, the zinc-restricted rats,
as well as the pair-fed rats, demonstrated reduced weight gain
compared with controls. The fact that the zinc-restricted group
demonstrated a greater reduction in body weight gain than did the
pair-fed group is evidence of the importance of zinc in growth. In
particular, decreased protein synthesis associated with decreased zinc
has been reported by other investigators (Vallee and Falchuk 1993
).
Cognitive impairment.
Approximately 14–16 d into the depletion phase, the
zinc-restricted group began to demonstrate a deficit in cognitive
performance. This was demonstrated by significantly prolonged retrieval
escape latencies in the MWM on test d 5 and 6. The prolonged retrieval
escape latencies indicated that the zinc-restricted rats had
difficulty remembering where they had found the platform in the
acquisition trial given only 90 s earlier. Thus, the data from
this study demonstrate for the first time that short-term zinc
restriction in previously zinc-replete young adult rats impairs
short-term memory. Interestingly, acquisition escape latencies were
unaffected by zinc restriction; in fact, these responses continued to
improve over the course of the study in all of the rats, including the
zinc-restricted group. This suggests that although their
short-term memory was impaired, the rats still knew how to perform
the task. Therefore, long-term memory associated with the initial
learning of the task remained intact in the young rats. Further, the
lack of significant differences between the control and pair-fed
groups during this phase indicates that reduced energy intake had no
effect on short-term memory, confirming similar work done by
Halas and Sandstead (1980)
. Naive rats were not tested
on the water maze during zinc restriction; therefore, the effects of
dietary zinc restriction on strategy learning of a novel task were not
evaluated.
Zinc status.
To confirm that the behavioral deficits noted during dietary zinc
restriction did indeed result from zinc depletion, it was necessary to
correlate changes in behavior with changes in zinc status. Despite a
number of studies of zinc nutriture, a reliable and sensitive
biochemical indicator of zinc status has not been identified
(Cousins 1996
, King 1990
). Previous
studies have utilized plasma or serum zinc concentrations with
equivocal results, particularly in rats (Bremner 1993
,
Sato et al. 1984
). In the first experiment of this
study, the small amount of blood obtained by weekly tail bleed
precluded our ability to obtain adequate quantities of serum or plasma
for zinc measurement; thus it was necessary to measure the zinc content
of whole blood. No significant differences were noted in
whole-blood zinc among the three treatment groups during depletion.
It is probable that this lack of significant difference was due to the
large variation in individual zinc concentrations noted even in the
control group. The reasons for this variation are unknown but may be
due to stress effects, possibly related to tail bleeding, or to
individual differences in the length of time between animal feeding and
blood sampling (Sato et al. 1984
). Blood samples were
collected at the same time of day; however, the rats were not deprived
of food the evening before the samples were taken. Although we could
not confirm that the zinc-restricted rats were depleted of zinc by
measuring whole-blood zinc, zinc depletion was suggested by the
significantly lower liver and femur zinc concentrations found in the
zinc-restricted group compared with the control and pair-fed
groups. These findings, combined with the clinical signs of anorexia
and decreased weight gain, confirm that these rats were indeed zinc
depleted. This is further supported by the significantly lowered serum
zinc concentrations found in the zinc-restricted group of the
second experiment, when measured at the end of the depletion phase.
More importantly, significant reductions in hippocampal zinc
concentrations were found in the zinc-restricted groups of both
experiments compared with the nonrestricted groups. The relatively
small but significant decrease in hippocampal zinc in the first
experiment resulted in a rather large functional impairment in
short-term memory, confirming the important role of zinc in
short-term memory processes. Further, it can be concluded from
these data that behavioral assessment is a more sensitive indicator of
brain zinc status than is whole-blood zinc.
The pair-fed group of the first experiment had significantly elevated whole-blood zinc compared with the control group during the depletion phase. The reasons for this are unknown; however, one potential explanation is that forced energy restriction may have activated a compensatory mechanism in the gut to increase the uptake of dietary zinc. Although this compensatory mechanism may also have been activated in the zinc-restricted rats, its effect was likely blunted by the low level of zinc in the deficient diet.
Zinc repletion.
It was of primary interest to determine how subsequent dietary zinc repletion affected the depletion-induced cognitive impairment in these young adult rats. In addition, we were also interested in comparing the response of repletion with zinc chloride salt vs. repletion with zinc chloride supplemented with L-histidine. The cognitive impairment was reversed by dietary zinc repletion as indicated by the finding that the previously zinc-restricted group improved their retrieval escape latencies during repletion. Further, the results indicate that the addition of L-histidine to the zinc repletion diet improved the cognitive performance of previously impaired rats more efficiently than did zinc chloride alone, without affecting the performance of the nonrestricted groups. These findings are further supported by the results of the second experiment, which determined that the hippocampal zinc concentrations in the histidine-supplemented repletion group had returned to control levels by repletion test d 3, whereas those of the nonsupplemented repletion group, although not significantly different, were still lower than those of the control, pair-fed and histidine-supplemented groups. To the best of our knowledge, this is the first evidence that dietary repletion of young adult rats with zinc chloride supplemented with L-histidine is more effective at reversing cognitive impairment due to zinc depletion, than repletion with a zinc salt alone.
The lack of significant differences in tissue zinc concentrations at
the end of the 2-wk repletion phase confirmed that the rats were indeed
repleted. Further, these results indicate that the
L-histidine-supplemented diet did not increase brain or
hippocampal zinc concentrations above control values, suggesting that
brain zinc homeostasis was maintained in the presence of supplemental
L-histidine. Interestingly, when averaged across the
repletion phase, both zinc repletion groups had significantly higher
whole-blood zinc than the control or pair-fed groups. This
finding further supports the observation that a compensatory mechanism
in the gut was activated by reduced zinc intake (Menard and Cousins 1983
). Although the functioning of this mechanism may
have been blunted previously by the low levels of zinc in the
restricted diet, once the rats were given a zinc-replete diet, the
effect was measurable. Further, although the blood zinc concentration
of both repletion groups was elevated, they were not significantly
different from each another, suggesting that the enhanced cognitive
performance of the histidine-supplemented repletion group could not
be explained solely by an enhanced intestinal bioavailability of zinc
from the L-histidine–supplemented diet over the zinc salt.
Collectively, these data suggest that zinc provided as zinc chloride
supplemented with L-histidine is more bioavailable to the
CNS than zinc chloride alone.
We are confident that the differential effects of diet on memory
retrieval during repletion were due to zinc alone, and not a direct
effect of histidine itself on memory. Although histidine loading
(500–800 mg/kg body weight, intraperitoneal injection) has been shown
to ameliorate scopolamine-induced memory deficits in 45-d-old rats,
histidine alone when given intraperitoneally to control rats had no
effect on memory or learning (Miyazaki et al. 1995
). A
similar lack of effect of histidine alone has been reported in a
separate study, at doses <100 mg/kg body weight (Kamei et al. 1997
). Further, when the metabolism of histidine to histamine
is blocked by 
-fluoromethylhistidine, these effects were abolished
(Miyazaki et al. 1995
, Sakai et al. 1998
). Thus, this effect of histidine loading was shown to be
mediated by the metabolism of histidine to histamine; histamine has
been shown to modulate learning and memory. The amount of additional
histidine present in our L-histidine–supplemented diet was
40 mg/kg of diet. Given that the rats ingested a daily average of
20–22 g of diet during repletion, this means that the dietary intake
of additional histidine during this time was ~8.8 mg/d. This is well
below the minimum dose of histidine used in these loading studies.
Thus, these data, coupled with the fact that the
histidine-supplemented diet had no effect on the cognitive
performance of the control or pair-fed groups, suggest that the
faster improvement in memory in the
L-histidine–supplemented diet was due to the positive
effect of histidine on zinc bioavailability to the CNS of the
zinc-depleted rats. Although the exact mechanism of the enhanced
bioavailability of zinc chloride supplemented with
L-histidine is unknown, it is possible that it may be due
to an enhanced transport of zinc across the BBB (Buxani-Rice et al. 1994
). Using short vascular perfusion, Buxani-Rice and
her colleagues found that 65Zn transport across
the brain endothelium was enhanced when histidine was added to the
perfusate.
The findings of this study are important in that they highlight the need to consider diet formulation, age and the use of functional assessments in the determination of zinc nutriture.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations: BBB, blood brain barrier; CNS, central nervous system; ddH2O, deionized distilled water; MWM, Morris water maze.
Manuscript received July 14, 1999. Initial review completed September 29, 1999. Revision accepted February 28, 2000.
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