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Department of Preventive Medicine and Community Health and
*
Center for Bioengineering and Department of Neuroscience, University of Texas Medical Branch, Galveston, TX 77555-1109;
NeuroBioTex, Incorporated, Galveston, TX 77550; and
**
U.S. Department of Agriculture, Agricultural Research Service Grand Forks Human Nutrition Research Center, Grand Forks, ND 58201
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONZinc in brain tissueBrain developmentBrain function in animalsFindings in humansREFERENCES |
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KEY WORDS: • zinc • brain • hippocampus • neurotransmission • cognition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONZinc in brain tissueBrain developmentBrain function in animalsFindings in humansREFERENCES |
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Zinc in brain tissue |
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TOPABSTRACTINTRODUCTIONZinc in brain tissueBrain developmentBrain function in animalsFindings in humansREFERENCES |
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first reported
65Zn uptake by brain in dogs and mice. Uptake was
slower and the amount retained was less than that in other tissues. A
decade later, Maske (1955)
serendipitously discovered
that diphenylthiocarbizone (dithizone) stains a pool of Zn that is
strikingly localized. Staining of hippocampal mossy fibers was intense.
Subsequently, Hu and Friede (1968)
measured Zn in 24
regions of human brain by atomic absorption spectroscopy.
Concentrations in hippocampus were highest, but gray matter of the
cortex was nearly as rich. White matter had the lowest concentrations.
Concentrations of Zn in newborn brain were lower than in adults.
Soon after Maske, McLardy (1960)
found Zn in
mossy-fiber "giant" boutons. Later, he reported several other
Zn-containing fiber systems (McLardy 1970
). After
McLardy (1960)
, von Euler (1962)
found
that bathing the surface of the hippocampus with
H2S-saturated saline removed Zn and changed the
evoked potential response after electrical stimulation. He noted that
the H2S caused a variety of changes and therefore
was cautious in concluding that removal of Zn caused the changes.
Nearly simultaneously with the above anatomical studies, Zeigler et al. (1964)
measured the effect of Zn deficiency on the
kinetics of Zn in chick brain. Zn deficiency increased the
65 Zn uptake but had no apparent effect on the
concentration of stable Zn. Cox et al. (1969)
used rats
to confirm that Zn deficiency had little effect on the concentration of
Zn in brain. He also showed that high intakes of Zn increased the
concentration of Zn in brain. About a decade later, Wallwork et al. (1983)
used weanling rats to confirm that Zn deficiency has
little effect on brain Zn, with the exception of a decreased
concentration of Zn in the olfactory bulb. In addition, he found that
brain copper was increased by Zn deficiency.
Studies by Haug (1967)
built on the work of
McLardy (1960)
. With the use of electron microscopy and
a modified silver-sulfide stain (Timm 1958
), Haug
showed electron-dense silver particles that were located within the
mossy-fiber giant boutons, evenly distributed, and not in
mitochondria. Later, Haug et al. (1971)
showed that
transection of mossy-fiber axons caused a rapid disappearance of Zn
from the vesicles in the presynaptic boutons (terminals).
Nearly two decades after von Euler, Hesse et al. (1979)
confirmed that Zn status can affect synaptic responses in the
hippocampus. Using Zn-deprived rats, he showed decreases in evoked
responses after repeated low frequency stimulation of the dentate
gyrus. In contrast, repeated stimulation of commissural axons did not
result in decreased evoked responses. Hesse suggested that his findings
were caused by a decrease in vesicle Zn. More recent findings suggest
that this is unlikely. Commissural axon terminals were shown to contain
as much vesicle Zn as mossy-fiber terminals (Frederickson et al. 1992
, Long et al. 1995
).
Shortly after Hesse (1979)
, Frederickson et al. (1982
and 1983)
, with the use of stable-isotope dilution
mass spectrometry, found that ~8% of Zn in the hippocampus is in
vesicles. Soon after, three groups showed that Zn is released from axon
terminals during electrophysiologic activity. Howell et al. (1984)
showed that electrical stimulation in vitro caused
uptake of 65 Zn tracer by presynaptic terminals of
mossy-fiber axons, and that previously incorporated 65
Zn was released. Assaf and Chung (1984)
reported similar
findings on the basis of the chemical analysis of poststimulation
superfusate, and Sloviter (1985)
showed by electron
microscopy and modified silver stain (Timm 1958
) that
electrical stimulation decreased vesicle Zn in mossy-fiber axon
terminals. About the same time Perez-Clausell and Danscher (1985)
showed by electron microscopy and modified silver stain
(Timm 1958
) that Zn is present in ~10% of the clear
round vesicles of Gray’s Type I (excitatory) synaptic boutons. These
authors subsequently showed (Perez-Clausell and Danscher 1986
) by in vivo sulfide binding that Zn released from vesicles
can move from the synaptic cleft to the extracellular space.
Peters et al. (1987)
and Westbrook et al. (1987)
showed that vesicle Zn that is released into the
synaptic cleft during neurotransmission modulates
N-methyl-D-aspartate
(NMDA)4
-specific postsynaptic receptors for glutamate in a rapid,
dose-dependent and reversible manner. Consistent with Zn having a
modulator role, Fukahori et al. (1988)
found lower Zn
concentrations in the dentate area of the hippocampus of a strain of
mice with a high propensity for seizures. Zn deficiency decreased
hippocampal Zn and increased seizures, whereas high intakes of Zn
increased hippocampal Zn and decreased seizures (Fukahori and Itoh 1990
). Mitchell et al. (1990)
confirmed
that Zn status can affect seizure susceptibility. In vivo chelation of
Zn with dithizone increased the sensitivity of rats to kainic
acid–induced seizures. Morton et al. (1990)
also found
that Zn status affected seizure threshold. Subcutaneous administration
of Zn decreased noise-induced seizures in DBA/2J mice, but had no
effect on seizures caused by kainic acid.
Findings of Frederickson et al. (1990)
were consistent
with vesicle Zn affecting cognition. Reversible chelation of Zn in vivo
"produced a time-locked and selective disruption of
hippocampal-dependent spatial-working memory." Subsequently,
Browning et al. (1994 and 1995) found in Guinea pigs that
Zn deficiency decreased the concentration of postsynaptic
NMDA-specific glutamate-mediated calcium channels in cortical
synaptosomes.
Palmiter (1996a
and 1996b)
and Palmiter and Findley (1995)
reported specific Zn-transporter (Zn-T)
membrane proteins. ZnT-1 facilitates Zn efflux from cells; ZnT-2
facilitates Zn uptake by endosomal vesicles; and ZnT-3 in facilitates
Zn uptake by the Zn-containing vesicles of axon terminals of
glutaminergic neurons.
In vitro studies showed that oxidation of metallothionein (MT) by
glutathione disulfide (GSSG) released Zn to specific ligands
(Maret 1994
and 1995
). This suggests that one function
of MT is to serve as a store for Zn. Induction of liver MT by Zn was
described nearly three decades ago (Bremner and Davies 1975
, Richards and Cousins 1975
, 1976a
and 1976b
, Winge et al. 1975
). Soon after,
Cherian (1977)
showed that Zn bound to liver MT can be
released to other ligands. Subsequently, Sas and Pethes (1981)
showed that Zn deficiency decreases incorporation of
65Zn into brain MT, and Brady (1983)
found
that the MT concentration in brain of suckling rats is similar to that
in kidney and greater than that in heart, lung, spleen and thymus.
Ebadi and Swanson (1987)
characterized brain MT in rats
and Gulati et al. (1987)
showed that MT in monkey brain
is not inducible by Cd. Later, Hao et al. (1994)
reported high concentrations of metallothionein-I (MT-I) mRNA in
cerebellum, hippocampus and the ventricles. The same year,
Gasull et al. (1994)
confirmed that Zn status influences
MT concentrations and that there are substantial differences in
MT-I and MT-II concentrations among different regions of brain.
In addition, Masters et al. (1994)
showed that the mRNA
for isoform MT-III, a metallothionein unique to brain, is present
in glutaminergic neurons that have Zn-containing vesicles. They
also showed that MT-III in cultured cells stimulates Zn uptake.
Later, Erickson et al. (1997)
) showed that mice lacking
the MT-III gene had low Zn concentrations in hippocampus, whereas,
at the same time, their histochemically reactive Zn in presynaptic
vesicles appeared similar to that of controls. The MT-III–deficient
mice were highly susceptible to kainic acid–induced seizures and
postsynaptic neuron injury (like other zinc-deficient rodents). In
contrast, mice with the extra MT-III gene were resistant to
seizures and postsynaptic neuron injury. These findings suggest that
MT-III might influence the release of vesicle Zn into the synaptic
cleft.
Extension of the in vitro studies, cited above, of the oxidation of MT
by GSSG (Maret 1994
) revealed that certain selenium
compounds also release Zn from MT (Jacob et al. 1999
).
In addition glutathione (GSH) (Jiang et al. 1998b
) and
ATP (Jiang et al. 1998a
) facilitate Zn release by GSSG.
In addition, oxidation of certain Zn-binding ligands by GSH
releases Zn to thionein (Maret et al. 1999
).
Churchich et al. (1989)
reported that Zn-ATP is
required by pyridoxal (PL) kinase for the formation of
pyridoxal-5-phosphate (PLP). Subsequently, Yamada et al. (1990)
and Nakano and McCormick (1991)
found
that Zn-ATP is also required by flavokinase for synthesis of flavin
mononucleotide (FMN), the precursor of FAD. PLP and FAD are coenzymes
for biogenic-amine synthesis (Dakshinamurti et al. 1990
) and monoamine oxidase (MAO) metabolism, respectively
(Hsu et al. 1988
). The susceptibility of these processes
to Zn deficiency is unknown.
High concentrations of extracellular Zn can kill neurons.
Yokoyama et al. (1986)
found that 30
µmol/L or more of Zn in tissue culture killed neurons.
Soon after, Frederickson et al. (1988
and 1989)
reported
the toxicity of Zn for neurons in vivo. With the use of a quinoline
fluorescence technique, they found that kainic acid–induced seizures
caused loss of Zn from the presynaptic axon terminals of hippocampal
mossy fibers and that, coincidentally, the postsynaptic neurons showed
intense fluorescence for Zn and signs of degeneration. Soon after,
Tonder et al. (1990)
found similar abnormalities in rats
that had been subjected to cerebral ischemia. Recently, Choi (1996)
, Sensi et al. (1997)
, Yin and
Weiss (1995) and Yin et al. (1998)
suggested mechanisms
whereby Zn enters postsynaptic neurons. They include passage through
voltage-gated calcium channels, transporter-mediated exchange
with intracellular sodium, passage through NMDA receptor–gated
channels and penetration through calcium-permeable
-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)- or kainate
receptor–gated channels.
Other in vitro evidence of the toxicity of Zn was provided by
Bush et al. (1993
, 1994a
, 1994b
and 1994c
). At
physiologic concentrations and pH, Zn complexed with "amyloid protein
precursor," and "A-ß-1–40," a component of cerebral amyloid
that is present in spinal fluid. A-ß-1–40 solubility was decreased
and resistance of the resulting amyloid to tryptic digestion was
increased. Bush suggested that a similar in vivo phenomenon might
contribute to dementia.
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Brain development |
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first reported that
severe Zn deprivation of rats during organogenesis causes brain
malformations. They also found decreased DNA synthesis in embryonic
brain tissue (Swenerton et al. 1969
). Later,
McKenzie et al. (1975)
showed that maternal Zn
deprivation during the last third of gestation decreased brain DNA.
Sandstead et al. (1972)
found low
3H-thymidine incorporation into DNA and
35S into protein in Zn-deficient neonatal
rats on postnatal d 11. Later, Fosmire et al. (1975)
found a decrease in brain polysomes and protein per cell in
Zn-deprived pups on postnatal d 5. Consistent with these findings,
Duerre et al. (1977)
discovered that Zn deficiency
impaired the incorporation of 3H-leucine into
brain histone- and nonhistone-proteins on postnatal d 10, and
Buell et al. (1977)
showed that Zn deficiency decreased
brain growth, DNA, RNA and protein concentrations in pups, aged 21 d. In addition, division and migration of external granular cells of
the cerebellum were retarded. Dvergsten (Dvergsten 1984
,
Dvergsten et al. 1983
, 1984a
and 1984b
) described the
histologic effects of severe Zn deficiency on cerebellum of rat pups,
aged 21 d. Granule cell number relative to Purkinje cells was
decreased ~60%. Dendrite growth of Purkinje, basket and stellate
cells was decreased and the height of the Purkinje cells dendrite arbor
and its branching were severely decreased. Consistent with immaturity,
ribosomes were clustered in the basal cytoplasm of Purkinje cells. In
addition, asymmetric synapses between parallel fibers (axons of granule
cells) and dendrites of the Purkinje, basket and stellate cells were
decreased ~40%. |
Brain function in animals |
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TOPABSTRACTINTRODUCTIONZinc in brain tissueBrain developmentBrain function in animalsFindings in humansREFERENCES |
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and Chesters and Quarterman (1970)
reported cyclic feeding in Zn-deficient
rats. Wallwork et al. (1981)
and Wallwork and Sandstead (1983)
showed that plasma Zn concentrations were
inversely related to the cycle and that concentrations of glucose and
amino acids in plasma, and amino acids in brain, did not appear related
to the cycle. Subsequently, Reeves and O’Dell (1984)
found that dietary restriction of tyrosine decreased the concentrations
of tyrosine and catecholamines in the hypothalamus and increased the
appetite of Zn-deficient rats. More recently, Selvais et al. (1997)
found that Zn-deficient Wistar rats had galanin mRNA
and increased neuropeptide Y (NPY) mRNA in hypothalamus. NPY in the
suprachiasmatic nuclei of the geniculohypothalamic tract was inversely
related to the appetite cycle. Zn repletion decreased NPY mRNA toward
normal. In contrast, in Zucker rats, which have high basal NPY, Zn
deficiency had no effect on NPY.
Macapinlac et al. (1967)
first noted that
Zn-deficient squirrel monkeys were apathetic. Subsequently,
Caldwell et al. (1970)
found that Zn-deficient rats
were more hesitant and made more errors in a simple water maze than the
pair-fed control rats. Hesse et al. (1979)
confirmed
their findings. Subsequently, Gordon et al. (1982)
showed that severe Zn deficiency caused less activity and grooming in
aged rats (300 d old); Massaro (1982)
reported that
moderate Zn deprivation impaired complex behaviors; and Valdes et al. (1982)
found an association between lateralization of Zn
in the brain and spatial preference in rats.
Golub et al. (1994
and 1996)
measured effects of
"moderate" Zn deprivation on behavior of prepubertal and adolescent
nonhuman primates. Fifteen weeks of Zn deprivation in prepubertal
animals decreased plasma Zn but had no apparent effect on growth.
"Spontaneous motor activity was lower and performance of a
visual-attention task and short-term-memory task were impaired."
In adolescent females, "moderate" Zn deficiency retarded the
adolescent growth spurt, and decreased daytime activity and attention.
Halas (Halas et al. 1977a
, 1976
and 1980
, Halas and Eberhardt 1975
, 1977b
, 1979
, 1983
, 1986
and 1987
, Halas and Sandstead 1975
and 1980
, Lokken et al. 1973
) first measured the effects of developmental Zn
deprivation in rats. The first experiment found that Zn deprivation of
dams throughout lactation (birth to postnatal d 21) caused errors of
choice during running of a "Tolman Honzig" maze without affecting
the running time of offspring, aged 60–80 d (Lokken et al. 1973
). The second experiment found that Zn deprivation on d
15–20 of gestation impaired avoidance of shock by young adult male
offspring but had no similar effect on female offspring (Halas et al. 1976
, Halas and Sandstead 1975
). The
third experiment found that intrauterine Zn deprivation increased
shock-induced aggression in nutritionally rehabilitated 75-d-old
female offspring but not in males (Halas et al. 1975
and 1977b
). The last experiment differed from all others in that
Halas measured the effects of mild maternal Zn deficiency (10
µg/g diet) throughout gestation and lactation on
subsequent performance of adult offspring (Halas et al. 1986
). Pups and dams showed no overt signs of Zn deficiency
other than mild growth deficit in pups. After weaning, the pups were
fed a complete diet that was adequate in Zn. When tested at age
100 d, the previously Zn-deprived rats made many more errors
in an open 17-arm radial maze than did controls. Penland and Sawler (1987)
measured the electroencephalogram (EEG) of rats
from Halas’ last experiment. In addition to changes in EEG activity in
the Zn-deprived group, brain zinc/copper ratios were positively
correlated with left-minus-right hemisphere asymmetries in the EEG.
Developmental Zn deprivation was also studied in nonhuman primates.
Early studies (Sandstead et al. 1978
, Strobel and Sandstead 1984
) in a small number of animals found that
maternal Zn deprivation in the last third of pregnancy changed
maternal-infant interactions and impaired later ability to solve
complex problems at about age 2 y; by age 3 y,
problem-solving ability was similar to that of controls. More
recently, Golub et al. (1995)
found that "marginal"
Zn deprivation of dams throughout gestation caused a syndrome of
lethargy, apathy and hypoactivity in offspring.
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Findings in humans |
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.
Subsequently, the condition was identified among poor Egyptian farm
boys who displayed dwarfism, hypogonadism, iron deficiency, hookworm
and schistosomiasis (Prasad et al. 1963a
and 1963b
,
Sandstead et al. 1967
). These patients were similar in
appearance to those with severe hookworm that were described in the
first decade of this century by Dock and Bass (1910)
.
Abnormal behaviors occurred in some. In the second decade of this
century, the International Health Board of the Rockefeller Foundation (1919)
reported an association between hookworm
infection and low cognitive performance in U.S. Army recruits and in
children from South-Eastern mill towns. The same year Waite and Nelson (1919)
found a direct association between the
severity of hookworm infection and impaired mental development in
children from North Queensland, Australia. One suspects that Zn
deficiency contributed to the cognitive abnormalities described.
Twenty-five years ago Henkin et al. (1975)
discovered
that severe Zn deficiency impaired neuromotor and cognitive performance
of adults. He induced Zn deficiency by administration of large doses of
histidine, which caused high urinary excretion of Zn. All subjects
developed abnormal taste and smell acuity. Some were ataxic, some were
depressed, some hallucinated and some developed paranoia. Soon after
Henkin’s report Moynahan (1976)
described abnormal
behavior in a patient with acrodermatitis enteropathica, and Kay et al. (1976)
found abnormal behaviors in patients with Zn
deficiency as a result of inadequate parenteral feeding.
Hambidge et al. (1975)
reviewed the effects of
inadequately treated maternal acrodermatitis enteropathica on
offspring. Some infants had brain malformations. Related to these
observations, reports from Turkey suggested that low maternal Zn
nutriture increased the occurrence of fetal anencephaly
(Çavdar et al. 1983
and 1988
).
Relevant to human fetal development and postnatal risk of behavioral
deficits, nearly three decades ago, Jameson (1976)
found
significantly higher maternal serum Zn concentrations among women who
normally delivered mature infants than he found among women who had
abnormal deliveries and/or abnormally developed infants. In the latter
group, eight infants had congenital malformations. In addition, women
with dysmature infants had significantly lower serum Zn concentrations
than women who had uncomplicated deliveries of mature infants.
Subsequently, Meadows et al. (1983
and 1981)
found that
low Zn concentrations in maternal and newborn leukocytes were
associated with fetal growth stunting. A subsequent double-blind
randomized placebo-controlled Zn repletion trial by Cherry et al. (1989)
found significant decreases in premature delivery
and a highly significant decrease in the need for respiratory
assistance among newborn infants of normal-weight low income black
teen-age girls. More recently, Goldenberg et al. (1995)
found higher birth weight and larger head size among
infants of Zn-repleted low income mothers. Kirksey et al. (1991
and 1994)
first reported relationships between the
maternal diet during pregnancy and postnatal behavior of infants.
Mother-baby pairs were studied in an Egyptian village. Maternal
consumption of foods derived from animals that were rich in Zn was
positively associated with higher neonatal attention scores on the
Brazelton Neonatal Development Assessment Scale. At 6 mo of age, motor
performance scores on the Bayley Scales of Infant Development were
inversely associated with maternal intakes of Zn from plants, dietary
phytate and fiber during pregnancy.
Effects of postnatal Zn nutriture on infant development were reported
by Friel et al. (1993)
. Linear growth and motor
development were higher in newborns <1500 g that were given 11 mg Zn/L
of formula from birth to 6 mo compared with infants given 6.7 mg Zn/L.
Later, Sazawal et al. (1996)
reported that repletion
with 10 mg Zn/d simultaneously with potentially limiting vitamins
increased activity and energy expenditure of low income urban Indian
children, aged 12–23 mo. Similarly, Bentley et al. (1997)
found that Guatemalan infants given 10 mg Zn/d for 7 mo
sat up and played more than infants given placebo. Ashworth et al. (1998)
also found that Zn repletion improved behavioral
ratings. His subjects were low-birth-weight Brazilian infants, aged 12
mo, who were given 5 mg Zn/d 6 d/wk during the first 8 postnatal weeks.
Controls given 1 mg Zn/d lagged behind.
In children Thatcher et al. (1984)
found a direct
association between an index of Zn status (hair Zn concentration) and
reading performance on a standardized test. In addition, coherence of
the frontal lobe EEG was related directly to the concentration of Zn in
hair. Consistent with Thatcher, Wachs et al. (1995)
found that certain preadolescent behaviors of Egyptian children were
associated with the consumption of foods that were derived from animals
and are rich in Zn.
Sandstead et al. (1998)
and Penland (Penland 1999
, Penland et al. 1997
, 1999a
and 1999b
)
found in three groups of children that repletion of Zn nutriture, in
the context of repletion of other potentially limiting micronutrients
(Ronaghy et al. 1974
), improved neuropsychological
function. The subjects were low income urban (n = 740)
and rural (n = 540) Chinese, aged 6–9 y, and low
income urban U.S. Mexican-Americans, aged 6–9 y (n
= 240). They participated in 10-wk double-blind, randomized,
controlled treatment trials. Neuropsychological function was assessed
by a computerized task set that was configured by Penland (1994)
for testing of many facets of neuropsychological
function. All studies found that repletion with 20 mg Zn simultaneously
with other potentially limiting micronutrients caused the greatest
improvement in performance of a complex reasoning task, compared with
controls. The Chinese subjects also showed improvement in other
dimensions of neuropsychological function. Before these studies
Gibson et al. (1989)
and Cavan et al. (1993)
found no improvement in cognition of low income
children, aged 6–7 y, who were repleted with 10 mg Zn/d. The
assessment tool measured global indices of cognition. We suspect the
tool was insensitive.
In adults, Henrotte et al. (1977)
found that low
concentrations of Zn in RBC were associated with lower frequency of the
EEG during hyperventilation. Later he reported an association between
Type A personality, high resting RBC Zn concentration and low urinary
Zn concentration, as contrasted with Type B personality
(Henrotte et al. 1985
). When Type A subjects were
exposed to stress, they excreted more Zn in their urine than did type B
subjects. Goldstein and Pfeiffer (1978)
reported that
treatment of schizophrenic patients with Zn was followed by a decrease
in EEG amplitude (toward normal), in contrast to the effect of placebo.
The change was consistent with a decrease in cortical excitability.
Subsequently, Tang (1991)
reported lower concentrations
of Zn in hair from female epileptic patients than from controls. In
addition, the occurrence of seizures was associated with low plasma Zn
concentrations during the past year.
Three pilot studies suggested that mild Zn deficiency might decrease
cognition of adults. Tucker and Sandstead (1984)
found
decreased memory for digits and decreases in several perceptual tasks
in men who were fed diets that provided ~3.5 mg Zn/d while they were
living in a highly controlled environment. Darnell and Sandstead (1991)
found in 11 ambulatory women with serum ferritin
concentrations < 20 µg/L, that 8 wk of repletion
with 30 mg Zn/d simultaneously with other potentially limiting
micronutrients improved short-term visual memory (Wechsler 1981
). In contrast, six similar women who were given only
micronutrients showed no change in short-term visual memory.
Penland (1991)
found decreased neuropsychological
function in 11 men, aged 21–38 y, who were experimentally deprived of
Zn. In random and double-blind trials, they were fed diets that
provided 1, 2, 3 or 4 mg Zn/2000 kcal, each for intervals of 35 d
(Johnson et al. 1993
). The subjects were repleted with
10 mg Zn/d for 35 d at the end of the study. The low Zn diets
decreased function similarly. Two psychomotor tasks (tracking and
connect-the-dots), two attention tasks (orienting and misdirection),
one perceptual task (search-count), three memory tasks (letter, shape
and cube recognition) and one spatial task (maze) were impaired.
Relevant to Zn nutriture of the elderly, Burnet (1981)
suggested that low Zn nutriture increases the risk of dementia. He
based his thesis on the requirement of Zn for DNA synthesis and repair
(Lieberman and Ove 1962
, Lieberman et al. 1963
). The more recent findings of Tully et al. (1995)
appear to support Burnet’s idea. They found a negative
association between the serum Zn concentration 1 y before death
and the frequency of "senile" and "diffuse" plaques in the
brains of 12 elderly women who were examined postmortem.
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FOOTNOTES |
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4 Abbreviations used: AMPA,
-amino-3-hydroxy-5-methyl-4-isoxazole-propionate; EEG,
electroencephalogram; FMN, flavin mononucleotide; GSH, glutathione;
GSSG, glutathione disulfide; MAO, monoamine oxidase; MT,
metallothionein; NMDA, N-methyl-D-aspartate;
NPY, neuropeptide Y; PL, pyridoxal; PLP, pyridoxal-5-phosphate; ZnT,
zinc transporter.
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REFERENCES |
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|
TOPABSTRACTINTRODUCTIONZinc in brain tissueBrain developmentBrain function in animalsFindings in humansREFERENCES |
|---|
1. Ashworth A., Morris S. S., Lira P. I., Grantham-McGregor S. M. Zinc supplementation, mental development and behavior in low birth weight term infants in northeast Brazil. Eur. J. Clin. Nutr. 1998;52:223-227[Medline]
2. Assaf S. Y., Chung S. H. Release of endogenous Zn2+ from brain tissue during activity. Nature (Lond.) 1984;308:734-736[Medline]
3.
Bentley M. E., Caulfield L. E., Ram M., Santizo M. C., Hurtado E., Rivera J. A., Ruel M. T., Brown K. H. Zinc supplementation affects the activity patterns of rural Guatemalan infants. J. Nutr. 1997;127:1333-1338
4. Brady F. O. Metabolism of zinc and copper in the neonate: zinc thionein in developing rat brain, heart, lung, spleen, and thymus. Life Sci 1983;32:2981-2987[Medline]
5. Bremner I., Davies N. T. The induction of metallothionein in rat liver by zinc injection and restriction of food intake. Biochem. J. 1975;149:733-738[Medline]
6. Browning J. D., O’Dell B. L. Low zinc status in guinea pigs impairs calcium uptake by brain synaptosomes. J. Nutr. 1994;124:436-443
7. Browning J., O’Dell B. Zinc deficiency decreases the concentration of N-methyl-D-aspartate receptors in guinea pig cortical synaptic membranes. J. Nutr. 1995;125:2083-2089
8. Buell S. J., Fosmire G. J., Ollerich D. A., Sandstead H. H. Effects of postnatal zinc deficiency on cerebellar and hippocampal development in the rat. Exp. Neurol. 1977;55:199-210[Medline]
9. Burnet F. M. A possible role of zinc in the pathology of dementia. Lancet 1981;1:186-188[Medline]
10.
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