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), hydrogen peroxide (H
2
O
2
),
peroxynitrite (ONOO
), hydroxyl
radical (OH
/K
/K
/K
) (de
Murcia & de Murcia, 1994). Activation of PARP/PARS
signicantly depletes NAD
to H
2
O
2
and O
2
, and it repre-
sents the rst line of defense against oxidative toxicity
(Olanow, 1993). There are two zinc atoms and two
copper atoms in the enzyme, and all four ions are
necessary for optimal SOD activity (Willson, 1989).
Zinc is believed to have a structural function, while
copper is involved in the catalytic sites of dismutation
(Willson, 1989). SOD is structurally very stable and
remains active even at high (8 M) urea concentrations
(Willson, 1989). SOD has a relatively low affinity for
zinc (K
D
10
5
M) (Fabris & Mocchegiani, 1995).
Nonetheless, the metal chelators 1,10-phenanthroline
(K
D
Zn
10
17
M, pH 5.5) and EDTA (K
D
Zn
10
16
M,
pH 7.4), chelate only 13 and 10% of Zn
2
in SOD,
respectively (Willson, 1989), which indicates that most
of the structural zinc is inaccessible to zinc chelators.
Very recently, the effect of the mutation on the binding
of the metal constituents of the enzyme was reported
(Lyons et al., 1996). It was found that SOD1 mutation
affects the native zinc-binding sites of the enzyme,
which may possibly result in an unstable protein
structure.
MMP-2 and MMP-9 activities were recently reported
to be signicantly different in brain and spinal cord of
ALS patients compared with controls (Lim et al., 1996).
MMP-9 activity was markedly elevated in the frontal
and occipital cortices, particularly in the motor cortex,
and in the thoracic and lumbar regions of the spinal
cord of ALS sufferers (Lim et al., 1996). On the other
hand, MMP-2 activity in the motor cortex was signi-
cantly reduced. As zinc may inhibit both MMP-2 and
MMP-9 activities in vitro (Backstrom et al., 1992),
evidence for an abnormal zinc metabolism in ALS
would not explain these observed changes.
PKC activity in ALS spinal cord is signicantly
increased, possibly attributable to abnormal Ca
2
buff-
ering (for a recent review, see Krieger et al., 1996) or
aberrant zinc levels which could inuence its activity
(Csermely et al., 1988; Murakami et al., 1987; Zalewski
et al., 1990, 1991). Note that MT expression is signi-
cantly increased in the spinal cord gray matter of
protoplasmic astrocytes (Sillevis-Smitt et al., 1992a), as
well as in liver and kidney (Sillevis-Smitt et al., 1992b)
of ALS patients. These reports could mean that either
metal ion levels are elevated or an increased oxidative
stress is present (reviewed in Sillevis-Smitt et al., 1994).
The observations presented here suggest some associa-
tion of metal cations and oxidative injury in the
pathogenesis of ALS. Hence, investigations need to be
done to determine whether abnormal zinc or copper
function in mutant SOD has any relevance to disease
progression.
GuamALS-Parkinsonism Dementia
Guamanian ALS-PD is a subtype of ALS. The pres-
ence of cycad (genus Cycas) in food or medicine has
been implicated in the pathogenesis of ALS-PD of
Guam (Duncan et al., 1992). It was found that cycad
our samples produce a signicant but dose-depen-
dent cytotoxicity to mesencephalic and cerebellar gran-
ule cell cultures (Duncan et al., 1992). Zinc was found
to be the neurotoxic constituent which contaminates
cycad our, and similar zinc levels (100 M) calculated
to be present in the our samples also produced a
156 Cuajungco and Lees
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1997 by Academic Press
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concentration-dependent toxicity on cultured mesence-
phalic and cerebellar granule cells. Addition of EDTA
(200 M) in the culture medium conferred protection
against zinc neurotoxicity. Meanwhile, zinc levels in
the gray matter of the frontal cortex of Guam ALS-PD
brains were reported to be markedly reduced com-
pared with normal controls (Yasui et al., 1993). Further
investigations are necessary in order to understand the
relationship between alterations in zinc metabolism
and exacerbation of the disease.
Parkinsons Disease
As with ALS, oxidative stress may be an etiologic
factor in Parkinsons disease (PD) (Jenner et al., 1992).
According to Dexter et al. (1989a), postmortem studies
revealed that polyunsaturated fatty acid levels in the
substantia nigra (SN) of patients with PD were re-
duced in comparison with other brain regions and that
of control (normal) tissue. Moreover, malondialdehyde
levels were elevated in the SN, suggesting occurrence
of lipid peroxidation (Dexter et al., 1989a). Zinc and
both cytoplasmic and mitochondrial SOD activities in
SN of patients with PD were also markedly increased
(Dexter et al., 1989b, 1991, 1992; Jenner et al., 1992),
while GSH levels were reduced in both early- and
late-stage PD (Jenner et al., 1992; Soc et al., 1992). In
contrast, there were no signicant alterations in the
activity of H
2
O
2
-degrading enzymes (catalase and
GPO) or in the concentrations of free radical scaven-
gers (ascorbic acid and -tocopherol) (Jenner et al.,
1992), as well as GSSG (Soc et al., 1992). The SN
contains a collection of neurons that utilize dopamine
as their major transmitter and which are selectively
lost in PD. These dopaminergic neurons also contain
melanin, an autoxidation by-product of dopamine
metabolism. Nonmelanized neurons are believed to be
less susceptible to oxidative stress than melanized
cells, since they are not likely to experience iron
melanin interactions that could produce excessive free
radicals (Ben-Shachar et al., 1991; Hirsch, 1992). Metabo-
lism of catecholamines such as DA autoxidation pro-
duces ROS and free radicals, thus making nigral cells
more susceptible to oxidative stress (Ben-Shachar et al.,
1991; Hirsch, 1992). Intracerebral injection of 6-hy-
droxydopamine in rats, a drug known to produce free
radicals, resulted in a reduction of zinc and MT
concentrations in the striatum, but not in any other
brain areas tested (Shiraga et al., 1993). Shiraga et al.
(1993) postulated that MT may reduce the effects of
generating ROS and free radicals by releasing zinc to
neuronal membrane and/or receptors, suggesting an
antioxidant role for both zinc and MT (Bray & Bettger,
1990; Sato & Bremner, 1993). Further, zinc may prevent
excessive NO
levels
among cortical neurons in vitro (Dawson et al., 1993).
HIV-1 gp120 induces apoptosis in hippocampal neu-
rons and interneurons in vitro (Aggoun-Zouaoui et al.,
1996) and in cortical neurons in vivo (Bagetta et al.,
1996; Charriaut-Marlangue et al., 1996). NO
-mediated
toxicity may be one of the underlying mechanisms of
death in both HIV neuropathy and ADC neuropathol-
ogy, since inhibition of NOS abolished the cytotoxic
effects of gp120 (Dawson et al., 1993). Likewise, inhibi-
tion of NOS by L-NAME reduces the extracellular
glutamate concentration in the rat hippocampus
(Rigaud-Monnet et al., 1995). Thus, zinc depletion
could be detrimental as it is a potent inhibitor of nNOS
activity (Persechini et al., 1995).
Provided that the chelation of zinc is not too toxic for
human cells (e.g., due to inhibition of nNOS activity),
the above results indicate that chelation of zinc from
HIVproteins could be effective in reducing the infectiv-
ity of the virus.
CONCLUDING REMARKS
Zinc is critical for the growth and survival of cells.
However, an abnormal metabolism of zinc in cells can
have deleterious effects. The evidence presented here
indicates that while the importance of changes in zinc
metabolism in causing neurological dysfunctions can
be debated, zinc does seem to play a role in ischemic-
related neuropathology. Although there is a high asso-
ciation with zinc and epilepsy, some contentious issues
need to be resolved. Studies have shown that zinc can
induce cytotoxicity in nervous and nonnervous tissue.
Zinc was also shown to play a role in apoptotic death
of nonneuronal cells. Whether zinc also serves any
function in neuronal apoptosis needs to be elucidated.
The involvement of zinc in Alzheimers and other
neurodegenerative diseases is far from being demon-
strated, but is currently the subject of thorough investi-
gation. Whether zinc is directly responsible in the
etiologic processes of these disorders or is a secondary
consequence of the disease process remains to be
proven. Therefore, further investigations are needed in
158 Cuajungco and Lees
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1997 by Academic Press
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order to determine if there is any role for zinc in
dysfunctions of the central nervous system. The knowl-
edge gained from investigations of the mechanism of
zinc-induced cell death may enable researchers to
develop therapeutic interventions that would reduce
or perhaps prevent further destructive processes occur-
ring in the brain.
ACKNOWLEDGMENTS
We thank the NZ Lotteries Grant Office, the University of
Auckland Staff Research Fund, and the Health Research Council of
NZ for providing nancial support to G.J.L. M.P.C. is a recipient of
the Miller scholarship fromthe NZ Neurological Foundation. We are
grateful to Professor Richard Palmiter and Professor GormDanscher
for providing results prior to publication, and we thank the Ameri-
can Association for the Advancement of Science for allowing us to
reproduce published materials.
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