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Basic Neurochemistry Part Five. Metabolism 33. Nutrition and Brain Function

Nutrition and Functional Neurochemistry


The availability of some nutrients can have immediate effects on behavior,
especially on the ability to respond to stimulation. Several studies suggest
that brain function, including cognitive processing, responds to changes in
nutrients.

Nutrition can influence neurotransmitter concentrations and associated behaviors


Important neurotransmitters are synthesized from compounds which are essential
dietary constituents. For instance, norepinephrine (NE) and serotonin are formed
from the essential amino acids tyrosine and tryptophan, respectively. However,
elevation of a precursor in the blood does not necessarily elevate its
concentration in the brain. For example, increasing the blood concentration of
large neutral amino acids such as phenylalanine, as occurs in phenylketonuria
(see Chap. 44), reduces tryptophan uptake into the brain because these two
compounds share a common carrier across the bloodbrain barrier (see Chap. 32).
Furthermore, the response to an increased concentration of precursor often
depends on the demand, such as firing frequency of the neurons. Enhanced
precursor availability may matter only when physiological demand is increased.

Choline for acetylcholine (ACh) synthesis can be obtained from either brain
choline, the phosphatidylcholine in the membranes or serum choline (Table 33-1).
It is taken up by a high-affinity choline-uptake system at the synapse (see
Chap. 11). Although choline can be made in the body, its synthesis can be
limited by the availability of "single-carbon" units in the diet. Ingestion of
choline together with phosphatidylcholine can increase brain choline and ACh
concentrations and enhance the ability of ACh synthesis to increase upon demand.
For example, increased dietary choline permits the brain to make excess ACh
following stimulation with atropine. Dietary phosphatidylcholine simultaneously
increases memory and the ACh content of the brains of "demented" mice, which
normally have reduced brain ACh concentrations [1]. Increasing choline
prenatally and postnatally improves the working and reference memory of young
rats.

Glucose normally provides the acetyl moiety of ACh. Extensive evidence indicates
that relatively modest increases in circulating glucose concentrations can also
increase ACh release and has been claimed to enhance learning and memory. The
relative safety of glucose administration has permitted tests of its effects on
cognitive functions in humans. Glucose enhances learning and memory in healthy
aged humans and improves several other cognitive functions in subjects with
severe cognitive pathologies, including individuals with Alzheimer's disease and
Down's syndrome. Thus, moderate increases in circulating glucose concentrations
may have robust and broad influences on brain functions that span many neural
and behavioral measures and cross readily from rodents to humans. Considerable
evidence suggests that these effects are mediated via ACh. Increasing glucose
availability can increase the amount of ACh released during conditions of
increased demand [2] (Fig. 33-1) (see also Chaps. 11 and 31).

Tryptophan, like tyrosine, crosses the bloodbrain barrier predominantly by the
carrier system for long-chain neutral amino acids. As a result, a protein-rich
meal can actually increase blood tryptophan but reduce the passage of tryptophan
into the brain by elevating at the same time the concentrations of other amino
acids, such as phenylalanine, that compete for that carrier. Serotonin
(5-hydroxytryptamine, 5-HT) synthesis depends on brain tryptophan, which in turn
depends on blood tryptophan concentrations, which can be manipulated by varying
the diet (Table 33-1). Elevating tryptophan in the brain produces
physiologically important changes in the serotonergic system (see Chap. 13).
Animals that are poor in brain tryptophan have a heightened sensitivity to
painful stimuli that can be reversed with tryptophan ingestion, which rapidly
elevates brain serotonin. Therapeutically, tryptophan has been reported to be
useful in treating subgroups of patients with depression, sleeplessness or
hyperactive behaviors.

Tyrosine is the precursor of NE and epinephrine (Table 33-1). Increasing
tyrosine reduces blood pressure in both normotensive and hypertensive animals.
The action of tyrosine on blood pressure occurs via CNS mechanisms since
co-administering other large neutral amino acids that reduce the uptake of
tyrosine into the brain blocks the effect. The antihypertensive action of
tyrosine appears to be mediated by an acceleration in NE or epinephrine release
within the CNS; injection of tyrosine produces a concurrent increase in brain
concentrations of 3-methoxy-4-hydroxyphenylethylglycol sulfate, a catecholamine
metabolite [3]. Tyrosine induces increased NE and alters NE and a and b receptor
densities in hippocampus, providing further evidence of its physiological role.
Furthermore, dietary restriction to 40% of normal food intake diminishes maze
performance, and this effect can be reversed by administration of tyrosine.

Nutrition can influence brain energy reserve


Brain energy is more resistant to changes in fasting or overfeeding than that in
liver or muscle. For example, severe fasting decreases liver ATP concentrations
and ATP: phosphocreatine ratios, while brain energy metabolism is preserved.
However, brain energy metabolism can be manipulated by diet. A high-fat (90% of
caloric value), carbohydrate-free ketogenic diet low in protein (10%) does not
significantly alter regional brain glucose utilization or cerebral
concentrations of glucose, glycogen, lactate or citrate. However, a
high-carbohydrate diet (78%) low in fat (12%) and low in protein (10%) markedly
decreases brain glucose utilization and increases cerebral concentrations of
glucose 6-phosphate. These findings indicate that long-term, moderate ketonemia
does not significantly alter brain glucose phosphorylation. However, even
marginal protein dietary deficiency when coupled with a carbohydrate-rich diet
depresses cerebral glucose utilization to a degree often seen in metabolic
encephalopathies (see Chap. 38) [4].

Carnitine participates in mitochondrial reactions. Like choline, it can be
synthesized by mammals if dietary sources of one-carbon groups are adequate. It
participates in the transfer of acyl groups across mitochondrial membranes
(Chap. 42). These include acetyl groups for ACh synthesis. Both carnitine and
acetylcarnitine cross the bloodbrain barrier (BBB), but the more lipid-soluble
acetyl-l-carnitine has been described as having a variety of effects on the
nervous system in experimental animals not seen with carnitine.

Hereditary deficits in the ability to transport carnitine or to synthesize its
acyl derivatives have been associated with diseases of skeletal and cardiac
muscle and, to a variable extent, with metabolic encephalopathy (see Chap. 34).
Secondary deficiency of carnitine has been described in a number of disorders of
mitochondrial oxidation, due in part to the detoxification and urinary excretion
of potentially damaging short-chain acids as the carnitine derivatives [5]. The
anticonvulsant valproic acid can increase carnitine requirements in susceptible
individuals [6]. Treatment with acetylcarnitine has been reported to slow the
progression of Alzheimer's disease [7].

Vitamins can regulate normal neuronal activity


Many vitamins function as cofactors in fundamental pathways, such as glycolysis,
the Krebs cycle, the respiratory chain and amino acid metabolism. Although all
tissues have these vitamin-dependent pathways, they take on increased importance
in the brain because of its high metabolic rate and dependence on continuous
metabolism. In fact, the discovery of vitamins was closely linked to the
sensitivity of the brain to deficiency, specifically that of thiamine [8].
Furthermore, in the brain these pathways are linked to neurotransmitter
synthesis.

Vitamin B1 (thiamine) is critical to normal brain function. Thiamine
pyrophosphate (TPP) functions as a cofactor of key enzymes of the Krebs cycle:
the pyruvate and a-ketoglutarate dehydrogenase complexes (PDHC and KGDHC,
respectively), the branched-chain dehydrogenase complex (BCDHC) and the pentose
shunt enzyme transketolase (TK) (Table 33-2). These dehydrogenase complexes
share a common enzyme component, lipoamide dehydrogenase. TK rearranges sugars
(see Chap. 31). A kinase can convert a membrane-bound form of TPP to thiamine
triphosphate (TTP), and a specific phosphatase hydrolyzes TTP to the
diphosphate. TTP appears to play a role in nerve membrane function, notably in
Na+ gating. The cDNAs for a number of TPP-requiring enzymes have been obtained,
and a TPP-binding motif has been proposed that is partially conserved in yeast,
rat and human.

Thiamine deficiency is a classical and well-studied example of the interaction
of nutrition with brain function. Research on thiamine deficiency continues to
attract considerable interest. In developed countries, clinically significant
thiamine deficiency is rare except as a complication of severe alcoholism or
other conditions that impair nutrition [9]. It is more common in developing
countries in which polished rice is the staple grain. It can be detected by
measuring the "TPP effect," the percentage increase in red cell TK activity upon
addition of exogenous TPP in vitro, and has been widely used in laboratory as
well as in epidemiological studies of thiamine deficiency.

After 5 to 6 days of a diet deficient in thiamine, healthy young men developed a
nonspecific syndrome of lassitude, irritability, muscle cramps and
electrocardiographic changes, which were reversed by dietary thiamine.

Prolonged thiamine deficiency frequently leads to damage to peripheral nerves
(see Chap. 36). This neuropathy tends to be worse distally than proximally,
involves myelin more than axons and is often painful. The neuropathy may be
linked to deficiencies in multiple water-soluble vitamins known for historical
reasons as the vitamin B complex.

Wernicke-Korsakoff syndrome consists of an acute (Wernicke) phase and a chronic
(Korsakoff) phase [9]. The acute syndrome consists of staggering gait, paralysis
of eye movements and confusion, associated with small hemorrhages along the
third and fourth ventricles and with reduced cerebral metabolic rate as measured
by cerebral blood flow. Injections of thiamine can be lifesaving, with clinical
improvement often evident within minutes. It is believed that prompt treatment
with thiamine can prevent the onset of the chronic Korsakoff phase. In
Korsakoff's syndrome, a striking loss of working memory accompanies relatively
little loss of reference memory (see Chap. 50). Affected patients
characteristically make up stories, or confabulate, in response to leading
questions. In this phase, patients do not respond to thiamine treatment. The
neuropathological lesions responsible for Korsakoff's syndrome have been
debated; severe damage to the cholinergic neurons of the nucleus basalis complex
has been reported.

Thiamine requirements can be altered genetically or environmentally. Among
genetic disorders, thiamine-dependent maple syrup urine disease is due to a
reduced affinity of BCDHC for TPP (see Chap. 44). A rare form of lactate
acidosis is due to reduced affinity of PDHC for TPP. Both disorders respond to
treatment with large doses of thiamine. Wernicke-Korsakoff syndrome is
associated with a variant form of TK having a decreased affinity for TPP [9].
This variation, which may be more common in chronic alcoholics, puts patients at
risk when on a diet marginal or deficient in thiamine. Subacute necrotizing
encephalomyelopathy (SNE) of Leigh is an uncommon, autosomal recessive disorder
in which the neuropathology resembles Wernicke-Korsakoff syndrome. Patients with
SNE in whom a defect in PDHC has been documented at the cDNA level have been
described. The role of thiamine in this disorder is controversial.

Environmentally, a number of dietary constituents are known to impair the
absorption of thiamine, including ethanol. Severe illness or injury also has
been reported to increase thiamine requirements. Rarely, patients have been
found who are intolerant to very large doses of thiamine. Thiamine-dependent
enzymes are reduced in the brains of patients with a variety of
neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's
diseases.

Thiamine-deficient animals model many aspects of human thiamine deficiency [10].
Experimentally, thiamine deficiency is frequently induced by the combination of
a thiamine-deficient diet and a thiamine antagonist, either pyrithiamine or
oxythiamine. However, pyrithiamine can directly inhibit action potentials and
oxythiamine does not enter the brain efficiently. In the pyrithiamine model in
mice, abnormal neuropsychological responses develop within 5 to 7 days, gross
neurological abnormalities in 8 to 9 days and death usually by 10 to 11 days.
Strain significantly modifies the response to experimental thiamine deficiency
in mice (Fig. 33-2). In rats, abnormalities of motor performance occur by day 3,
additional neurological symptoms by day 12 and death within 2 weeks. Thiamine
deficiency leads to a selective cell death that is accompanied by accumulation
of amyloid precursor protein in surrounding neurons. It causes severe memory
disruption and loss of cholinergic function. The activities of
thiamine-dependent enzymes decline in early stages of thiamine deficiency, but
surprisingly, selective cell death is not related to the cellular or regional
distribution of thiamine-dependent enzymes or to their response to thiamine
deficiency. Instead, the general reduction in thiamine-dependent enzymes
predisposes particular brain regions to other insults. The earliest known change
that reflects selective vulnerability is an alteration in the BBB that is
accompanied by oxidative stress, which causes increased ferritin and iron
deposition, and induction of nitric oxide synthase. The results suggest that
cerebrovascular endothelial cells of these brain regions may be particularly
vulnerable to thiamine deficiency [10].

Vitamin B3 (niacin) deficiency in humans leads to pellagra, which is
characterized by dementia, dermatitis, diarrhea and eventually death. The
deficiency was recognized in the eighteenth century, shortly after the
introduction of American corn (maize) into Europe [8].

Niacin and niacinamide refer to nicotinic acid and its amide, respectively.
Although these pyrimidine derivatives can be synthesized from tryptophan in
mammals, perhaps at least in part by intestinal bacteria, 60 mg of dietary
tryptophan are required to synthesize 1 mg of the vitamin. Niacin is considered
to be a vitamin because most human diets do not contain enough tryptophan to
fulfill the normal human requirement for the vitamin of 10 to 30 mg/day.

Hartnup's syndrome is a hereditary disorder in which tryptophan transport is
impaired and requirements for dietary niacin increase. Phenylketonuria and
hyperphenylalaninemia can increase niacin requirements by increasing the
concentrations of amino acids that compete with tryptophan for transport systems
(see also Chap. 44). A high-corn diet predisposes to niacin deficiency since the
major storage protein of American corn (zein) has relatively little tryptophan
relative to other amino acids that compete for the same carrier. Addition of
purified niacin to the diet has largely abolished pellagra, which was once a
common disease in areas where corn was a dietary staple.

Niacin is incorporated into the coenzymes NAD+ and NADP+ and their reduced
forms. These cofactors are involved in numerous oxidation/reduction reactions,
including the coupling of the Krebs cycle to the respiratory chain.
Antimetabolites, particularly 6-aminonicotinamide and 3-acetylpyridine, have
been particularly useful in determining the role of niacin deficiency in the
brain in experimental animals. Newborn mice that received a single
intraperitoneal injection of 6-aminonicotinamide consistently developed lesions
in the CNS, the skin and the intestinal tract. Anterior horn cells in the spinal
cord as well as motor neurons in the brain exhibit the ultrastructural features
of neuronal chromatolysis, while glial and ependymal cells show edematous
changes. 3-Acetylpyridine administration leads to selective neuropathological
lesions in the brainstem. Although the pathological features of
antimetabolite-treated mice are not identical to those of human pellagra,
possible contributory mechanisms in the development of pellagra lesions,
including dementia and selective cell loss, may be elucidated with this
experimental model [11].

Vitamin B6 (pyridoxine) is necessary for the biosynthesis of several
neurotransmitters. It is a pyridine derivative that can exist as an alcohol,
amine or aldehyde. The concentration in brain is normally about 100-fold higher
than that in the blood. The active coenzyme is the phosphorylated derivative
pyridoxal phosphate, which readily forms Schiff bases. This coenzyme
participates in decarboxylation reactions, including those that form GABA from
glutamate, 5-HT from 5-hydroxytryptophan and probably DOPA from
dihydroxyphenylalanine. It is also involved in transaminations, including that
converting a-ketoglutarate to glutamate. The conversion of tryptophan to
nicotinamide requires pyridoxyl phosphate as a cofactor, and the excretion of
xanthurenic acid after a tryptophan load is widely used to test the adequacy of
pyridoxine nutriture. In vitamin B6 deficiency in rats, biochemical and
morphological abnormalities, including decreased dendritic arborization and
reduced numbers of myelinated axons and synapses, are associated with behavioral
changes, such as epileptiform seizures and movement disorders. Reduced seizure
threshold and delayed neuronal recovery are related to the significantly reduced
brain regional GABA and elevated glutamate concentrations in
pyridoxine-deficient rats [12]. In addition, vitamin B6 deficiency during
gestation and lactation alters the function of N-methyl-d-aspartate (NMDA)
receptors.

Pyridoxine deficiency has occurred in human infants fed a formula from which
vitamin B6 had been inadvertantly omitted. The prominent finding was intractable
seizures which responded promptly to injections of the vitamin. Deficiency of
pyridoxine can contribute to the polyneuropathy of B-complex deficiency.
However, very large doses of pure pyridoxine can lead to a persistant sensory
neuropathy [13] (Chap. 36).

Like those of other nutrients, requirements for pyridoxine can be altered by
genetic or environmental factors and are increased in a number of disorders of
the nervous system [8,14,15]. Treatment of "pyridoxine-deficient" infants may
require doses of pyridoxine several hundredfold the normal daily requirement.
Maintenance with doses at least tenfold the normal requirement typically permits
normal development if irreversible brain damage has not yet occurred. It has
been suggested that mild forms of pyridoxine dependence may be a relatively
common cause of intractable seizures and mental retardation, but neurochemical
studies of these patients are limited. In homocystinuria and cystothioninuria,
two disorders of amino acid metabolism, some patients respond to large doses of
pyridoxine. In these patients, the mutations appear to reduce the affinity of
the relevant enzymes for pyridoxal phosphate (see Chap. 44).

Environmentally, hydrazides and oximes can increase pyridoxine requirements.
Large doses of pyridoxine are routinely given with the antituberculous
medication isonicotinic hydrazide, to prevent drug-induced neuropathy.

Vitamin B12 (cobalamin) deficiency is commonly associated with neurological
syndromes. The cobalamins are a series of porphyrin-like compounds [16]. The
active forms contain a cobalt ion linked to one of the methylene groups. The
cobalamins are synthesized by many microorganisms but not by higher plants or
animals. A rich dietary source is meat, particularly liver. Effective absorption
requires a series of transport proteins, including a glycoprotein intrinsic
factor secreted by gastric parietal cells. Conversion to the active coenzymes
adenosylcobalamin and methylcobalamin requires at least two reductase reactions
and an adenosyltransferase step. The reductases are flavoproteins that require
NAD+ as a cofactor. Thus, B12 metabolism involves at least three vitamins: B12
itself, niacin and riboflavin. Body stores of cobalamins are normally large
enough to maintain health for over 2 years without a dietary source of the
vitamin.

Cobalamins have two well-established biochemical functions. Adenosylcobalamin is
the cofactor for the mutase that converts methylmalonyl CoA to succinyl CoA.
This reaction is part of the pathway of metabolism of propionic acid, which
itself derives from the metabolism of odd-chain fatty acids and from certain
amino acids. Methylcobalamin is the cofactor for the methyltransferase that
converts homocysteine to the amino acid methionine. This reaction is important
in folate metabolism as well. Its impairment appears to foster folate deficiency
by an accumulation of N5-methyltetrahydrofolate in a "folate trap." Deficiency
of cobalamins or of folate or of both can restrict the supply of metabolically
available one-carbon groups for metabolic pathways, including those of nucleic
acid synthesis.

Cobalamin deficiencies are relatively common clinically [16]. Pure dietary
deficiency responding promptly to treatment with oral cobalamins has been
described in a few children of strict vegan mothers. A more common syndrome is
caused by failure of absorption due to an inadequate supply of the glycoprotein
intrinsic factor, usually on an autoimmune basis. The most characteristic
abnormality is pernicious anemia, characterized by enlarged erythrocytes, called
megaloblasts, and abnormal leukocytes. Neurological symptoms occur in many of
these patients and can precede the hematological changes [17].

Combined system disease is the most common B12-mediated neurological syndrome.
Affected patients develop unpleasant tingling sensations (paresthesias),
followed by loss of vibratory sensation, particularly in the legs, and spastic
weakness. The characteristic neuropathology is a spongy demyelination in the
long tracts of the spinal cord, particularly prominent in the posterior columns
as well as corticospinal tracts. Combined system disease responds poorly to
treatment with cobalamins.

Cobalamin deficiency is characteristically associated with malaise that does
respond dramatically to treatment, even before the hematological response is
evident. Relatively low serum concentrations of B12 have been reported in
subgroups of psychiatric patients, including patients with Alzheimer's disease,
but responses to treatment with the vitamin have, in general, not been dramatic.
Recent studies indicate that elevated concentrations of serum or cerebrospinal
fluid methylmalonate can identify patients whose neuropsychiatric manifestations
benefit from B12 treatment, even though the amounts of vitamin in serum are not
in the deficient range [17].

Whether the damage to the nervous system relates to decreased activity of the
methylmalonyl mutase or of the methyltransferase or of both remains unsettled.
Increased excretion of methylmalonate has been reported to be a marker for
patients whose neuropsychiatric manifestations will improve with B12 treatment,
but clinically normal children with a mutase deficiency are known. Children with
homocystinuria and related disorders do not develop the clinical or pathological
stigmata of combined system disease (see Chap. 44). An infant with an apparent
reduction in methyltransferase activity was clinically normal when reported at
age 1 year. Patients with severe inherited deficiencies in the activities of
both enzymes secondary to a defect in the metabolism of the cobalamins do
develop profound disease of the nervous system, with some characteristics of
combined system disease.

As with other nutrients, requirements for cobalamin can be modified by genetic
and environmental influences. Genetic factors apparently predispose to intrinsic
factor deficiencies with resultant cobalamin deficiency. Furthermore, at least
six different inherited methylmalonic acidurias have been described [16]:
absence of the mutase, decreased affinity of the mutase for adenosylcobalamin,
deficiency of mitochondrial cobalamin reductase, deficiency of a mitochondrial
cobalamin adenyltransferase and two distinguishable defects associated with
abnormal cytosolic metabolism of cobalamin (see Chap. 44). Other conditions
leading to increased cobalamin requirements include surgical removal of the
stomach, excessive destruction of cobalamins in the gut by bacteria in a blind
loop or destruction by certain kinds of intestinal tapeworm.

Folic acid contains a pterin moiety linked to para-aminobenzoic acid, which is
linked to one or more glutamate residues [18]. It plays a key role in the
transfer of one-carbon (active methylene) groups, including the conversion of
serine to glycine and the cobalamin-dependent transfer from homocysteine to
methionine. Dietary deficiency of folate with normal cobalamin leads to anemia
without significant neurological signs. However, both genetic and environmental
disorders of folate metabolism have been associated with disease of the nervous
system. Genetic defects in the relevant enzyme reactions are discussed further
in Chapter 44.

Genetic disorders of folate absorption, intraconversion and utilization are rare
[18]. They have occasionally been associated with phenocopies of well-known
psychiatric syndromes. A boy with apparent deficiency of hepatic dihydrofolate
reductase was treated with folate and developed a sociopathic personality in his
teens. A folate-responsive form of mental retardation with catatonia has been
described in an adolescent girl with N5,10-methylenetetrahydrofolic acid
reductase deficiency. Her younger sister was mentally impaired with "psychosis";
an unrelated boy with a defect of the same enzyme had seizures and proximal
muscle weakness without notable psychiatric problems. Most patients with
glutamate formiminotransferase deficiency have had a syndrome of psychomotor
retardation in infancy, but a few have been entirely normal clinically.

Environmentally, a number of common medications, including phenytoin and certain
antitumor agents, increase requirements for dietary folate. Treatment with
folate can mask the hematological signs of cobalamin deficiency without
affecting the progressive damage to the nervous system.

Pantothenic acid is a substituted hydroxybutyric acid that is a constituent of
CoA [19]. Experimental induction of pantothenic acid deficiency leads to signs
of peripheral nerve damage, for example, demyelination in laboratory animals and
paresthesias in humans. Late signs of CNS damage in animals may relate as well
to the adrenal failure that is a prominent part of the syndrome.

The brain depends on select vitamins and closely related compounds as
antioxidants to control potentially damaging free radicals


The main antioxidants in brain are vitamin E (tocopherol), vitamin C (ascorbic
acid) and glutathione (Table 33-2). The first two can be easily manipulated by
diet, whereas the latter is more difficult to control. Dietary a-lipoate appears
to be a useful compound to regenerate the antioxidant capacity of these other
compounds (see below). Dietary manipulation of antioxidants has practical
implications for brain function. Aging has been associated with free radical
damage in the brain (see Chap. 34). In aged patients tested over a 22-year
period, free recall, recognition and vocabulary correlated positively with
ascorbic acid and b-carotene in blood, even after controlling for possible
confounding variables, such as age, education and gender. These results indicate
the important role played by antioxidants in brain aging and may have
implications for prevention of progressive cognitive impairments [20].

Vitamin E (a-tocopherol) deficiency produces a characteristic neurological
syndrome. It presumably results from increased oxidative stress arising from a
reduction in antioxidant capacity. Vitamin E deficiency in neural tissues
increases endogenous lipid peroxidation, as evidenced in brain tissues by the
appearance of thiobarbituric acid-reactive substances such as malondialdehyde.
The brain is more susceptible to the deficiency than muscle. Within the brain,
the cortex, striatum and cerebellum are the most sensitive regions. Isolated
fractions from myelinated nerve tracts show that the axoplasmic membranes and
organelles are particularly vulnerable to oxidative stress [21]. Vitamin E
deficiency reduces tyrosine hydroxylase-immunopositive neurons in the substantia
nigra but not in the adjacent ventral tegmental area. The enhanced sensitivity
of the nigrostriatal pathway to oxidative stress could have important
implications for the pathogenesis of Parkinson's disease (see Chap. 45). A diet
deficient in vitamin E increases glutamate and GABA and decreases tryptophan
concentrations in the substantia nigra. The increase of nigral glutamate
suggests possible links to degenerative processes through glutamatergic
excitotoxicity. These results suggest that vitamin E may play a significant role
in the degeneration of the substantia nigra and that this tissue may be
particularly sensitive to oxidative stress. Furthermore, these findings support
the widely held view that oxidative stress in the substantia nigra is important
in the pathophysiology of Parkinson's disease.

Vitamin C (ascorbate) deficiency leads to extensive oxidative damage of proteins
and protein loss in the microsomes, as evidenced by accumulation of carbonyl
groups on proteins as well as tryptophan loss. This oxidative damage is reversed
by ascorbate therapy. Ascorbate deficiency also leads to lipid peroxidation in
microsomes, as evidenced by accumulation of conjugated dienes, malondialdehyde
and fluorescent pigment. Lipid peroxides disappear after ascorbate therapy but
not after treatment with vitamin E. These results indicate that vitamin C may
exert a powerful protection against degenerative changes in the brain associated
with oxidative damage [22].

Oxidation of vitamin E and C is maintained by glutathione, the predominant thiol
antioxidant in the brain. Glutathione cannot be directly manipulated by diet,
whereas the metabolic antioxidant a-lipoate can be absorbed from the diet and
cross the BBB to reduce oxidized glutathione and vitamins A and C (Fig. 33-3).
a-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which
is also exported to the extracellular space; hence, protection is afforded to
both intracellular and extracellular environments. Both a-lipoate and
dihydrolipoate are potent antioxidants that regenerate other antioxidants, like
vitamins C and E, and raise intracellular glutathione concentrations. Protective
effects by antioxidants have been reported in cerebral ischemiareperfusion,
excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and
diabetic neuropathy, inborn errors of metabolism and other causes of acute or
chronic damage to the brain or neural tissue. Thus, a-lipoate administration may
prove to be an effective treatment in numerous neurodegenerative disorders [20].

Trace nutrients in the diet have a vital role in maintaining normal brain
function


Zinc (Zn2+) influences numerous cellular functions, including immune mechanisms,
actions of several hormones and enzyme activities. More than 200 enzymes are
known to be Zn2+-dependent, including mRNA-editing enzymes, superoxide
dismutase, metalloproteins and a "Zn2+-finger" family of sequence-specific
DNA-binding proteins that regulate transcription. Metallothionein binds excess
Zn2+, thus maintaining its steady-state concentration and preventing inhibition
of an extensive number of sulfhydryl-containing enzymes and receptor sites;
hence, it protects against metal-related neurotoxicity. Metallothionein donates
Zn2+ to an extensive number of Zn2+-activated, pyridoxal phosphate-mediated
biochemical reactions. The complex nature of the interactions of Zn2+ with
multiple enzymes is exemplified by the observation that epileptic seizures that
are blocked by GABA can be blocked by either deficiency or excess of either Zn2+
or pyridoxal phosphate. A proposed explanation of these observations is that at
physiological concentrations Zn2+ stimulates the activity of hippocampal
pyridoxal kinase, enhancing the formation of pyridoxal phosphate and of GABA via
glutamate decarboxylase formation, whereas at higher doses Zn2+ inhibits the
activity of glutamate decarboxylase by preventing the binding of pyridoxal
phosphate [23]. Severe Zn2+ deficiency during the period of rapid brain growth
has effects similar to that seen with protein-calorie malnourishment, including
altered regulation of emotions; food motivation; lethargy (reduced activity and
responsiveness), and deficits in learning, attention and memory. In addition to
the many deficits produced by Zn2+ deficiency in the brain, the severe effect of
Zn2+ deficiency on other tissues leads to additional peripheral mechanisms that
alter brain function [24]. Although Zn2+ is essential at low concentrations,
higher concentrations are toxic. For example, high Zn2+ concentrations enhance
and prolong the firing rate of neurons, significantly depress paired-pulse
potentiation, block the action of NMDA on cortical neurons, enhance quisqualate
receptor-mediated injury and inhibit the Ca2+-dependent release of transmitter
by inhibiting the entry of Ca2+ into nerve terminals.

Copper is an integral component of multiple cellular enzymes, including the
cytochromes and superoxide dismutase. Copper deficiency produces clinical signs
analogous to those of Par-kinson's disease and results in low dopamine
concentration in the corpus striatum. Neuropathology in experimental animals
occurs in only part of the copper-deficient population and is dam- and
litter-related, suggesting the presence of a genetic component that alters the
response to copper deficiency. Insight into the role of copper in brain function
is provided by two genetic diseases.

Wilson's disease is an inherited disorder that leads to copper accumulation,
causing damage primarily to the liver and the brain (see Box 45-1). Psychiatric
and behavioral abnormalities occur in 30 to 100% of Wilson's disease patients
and are often the initial symptoms. The most common of the psychiatric and
behavioral manifestations include personality changes, such as irritability and
low anger threshold; depression, sometimes leading to suicidal ideation and
attempts; and deteriorating academic and work performance, which is present in
almost all neurologically affected patients [25].

Menke's disease is caused by a genetic deficiency of serum copper and of
copper-dependent enzymes and is characterized by neurological degeneration and
mental retardation, connective tissue and vascular defects, brittle and
depigmented hair and death in early childhood (see Box 45-1). Despite excessive
accumulation of the metal in various tissues, a functional copper deficiency is
evident, caused by a defective intracellular copper-transport protein. A large
amount of copper accumulates in the organelle-free cytoplasm, whereas
mitochondria are in a state of copper deficiency, indicating that the Menke's
mutation probably affects copper transport from the cytosol to the intracellular
organelles [26]. Brindled is a murine mutation that produces similar
copper-transport deficits, and studies of this animal model show that the copper
deficit in organelles causes reductions in critical copper-dependent enzymes,
such as cytochrome oxidase. It has been hypothesized that the Wilson's disease
gene is a copper-transporting ATPase with homology to the Menke's disease gene.
Dietary copper deficiency can affect brain development [27] (see below).

Selenium is vital in maintaining the antioxidant capacity of the brain.
Glutathione peroxidase is a selenium-dependent enzyme that is important for
maintaining the antioxidant capacity of brain glutathione (Fig. 33-2) and is
reduced in selenium-deficient animals. Selenium supplementation significantly
elevates Na,K-ATPase activity and significantly decreases lipid peroxide
formation. Since Na,K-ATPase activity is known to be inhibited by oxygen free
radicals, selenium supplementation appears to exert its beneficial effect on the
Na,K-ATPase activity by preventing free radical-induced damage. Selenium
significantly reduces the production of thiobarbituric acid-reactive substances,
a measure of lipid peroxidation, in response to an oxidative challenge in blood
and different regions of the brain [28]. Selenium deficiency increases dopamine
turnover in the substantia nigra but not in the striatum. These results suggest
that dietary selenium protects the brain, particularly the substantia nigra,
against oxidative damage.

Trace compounds are also important in brain function. Chromium-deficient
patients develop severe diabetic symptoms, including glucose intolerance, weight
loss, impaired energy utilization and nerve and brain disorders. Low dietary
boron is reported to cause significantly poorer performance on various cognitive
and psychomotor tasks. Additional research is likely to reveal additional trace
components of the diet that may be critical to normal brain function.



(c) 1999 by American Society for Neurochemistry
Published by Lippincott Williams and Wilkins.