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Distribution of iron in different brain regions and subcellular compartments in Parkinson's disease.

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Distribution of Iron in DdKerent Brain
Regions and Subcellular Compartments
in Parkinson's Disease
P. Riederer," A. Dirr," M. Goetz," E. Sofic," K. Jellinger,? and M. B. H. Youdimt:
Careful attention should be given to the role of iron
in brain physiology, because tissue iron deficiency and
iron overload represent prevalent metabolic disorders.
The essential participation of iron in brain development and maturation indicates that an abnormality
of early iron metabolism could have profound, even
long-term irreversible consequences [l-31. Iron deficiency as a cofactor of many heme and nonheme enzymes would alter many metabolic processes, including
synthesis of protein, DNA, and RNA 14, 51. Excessive
accumulation of tissue iron may lead to oxidative stress
via formation of oxygen free radicals, which can be
highly cytotoxic 16, 71. Such a phenomenon has now
been implicated in Parkinson's disease (PD) [S}.
The mechanism of neurotoxicity that leads to degeneration of nigrostriatal dopamine neurons of zona compacts, which in turn leads to a deficiency of dopamine
in PD, remains obscure. On numerous occasions, involvement of endogenously or exogenously produced
neurotoxins has been implicated in the progression of
PD. Evidence, however, is lacking, even though synthetic neurotoxins such as N-methyl-4-phenyl-l,2,3,6tetrahydropyridine (MPTP) and 6-hydroxydopamine
produce a parkinsonian syndrome in humans and animals [91. It is apparent that during normal aging of
human brain there is loss of melanized nigrostriatal
neurons. When approximately 80% of the neurons are
lost, symptoms (e.g., akinesia, tremor, rigidity) of PD
appear. PD is characterized by an accelerated degeneration of pigmented (melanized) dopamine neurons in
the pars compacta of the substantia nigra (SN). The
neurons project to the striatum, where they regulate
dopamine-dependent motor activity and synthesize,
store, release, and catabolize dopamine as their neurotransmitter. The characteristic pigmentation of the SN
is related to formation of neuromelanin as a result of
polymerization of autooxidative products of dopamine.
Dopamine can also be oxidatively metabolized by the
enzyme monoamine oxidase (MAO-A and MAO-B),
which is highly active in the basal ganglia.
The presence of lipid and highly localized large deposits of iron in neurotransmitter-rich brain regions
(such as the SN, the globus pallidus, and the caudate
nucleus) makes the brain an ideal organ for oxidative
stress resulting from metal-induced lipid peroxidation
in the presence of hydrogen peroxide (H202)[lo].
Both oxidative deamination and autooxidation of dopamine result in generation of H202.In addition, iron
activates tyrosine hydroxylase, which could increase
dopamine levels El 1, 121. An inability to detoxify
H202 (i.e., catalase, peroxidase, glutathione peroxidase) could result in its accumulation, and its interaction with Fe2+ may promote the Fenton reaction.
Iron-induced oxidative stress and lipid peroxidation
can proceed optimally with either Fe2+ or Fe3+,provided mechanisms exist to facilitate the interconversion
of iron between its oxidation-reduction (redox) states.
Fe3+ can be converted to Fe2+ in the presence of endogenous reducing agents, such as ascorbate and glutathione.
Under normal circumstances, iron is stored in its
inactivated form bound to ferritin. Dexter and colleagues [131 found decreased levels of ferritin, and Jellinger and associates El41 showed that ferritin is increased in the SN of patients with PD compared with
control subjects. But melanin also has the ability to
bind metals. It is the pigmented melanin-containing
dopamine neurons that degenerate in PD. The potentiation of melanin-iron-induced lipid peroxidation has
been attributed to the ability of melanin to reduce Fe3+
to Fez+ in the presence of H202 and to drive a
Fenton-like reaction that includes liberation of cytotoxic hydroxyl radicals 115, 161.
From the *Department of Psychiatry, Clinical Neurochemistry, Universiry of Wiinburg, Germany; tL. Boltzmann Institute of Clinical
Neurobiology, Lainz Hospital, Vienna, Austria; and the SDepartment of Pharmacology, Technion, Haifa, Israel.
Address correspondence to Dr Riederer, Department of Psychiatry, Clinical Neurochemistry, University of Wiirzburg, Wurzburg,
Germany.
Analytical Studies
Biochemisty
Biochemical studies (Table) of total iron, Fez+, and
Fe3+ using spectrophotometry in different brain regions of patients with PD with and without Alzheimer-type dementia (DAT) by Sofic and colleagues
SlOl
Content of Total Iron, Fd+,and Fd+ in the Substantia Nigra of Patients with
Parkinson’s Disease Found by Different Investigators and Using Different Methods
References
Fetoral
Fez+
Fe”
Sofic et al, 1988 [17]
Sofic et al, 1991 [18]
+++
+++
++++
+++
+++
+++
+-
++-
...
...
...
...
...
...
...
...
...
...
...
...
Dexter et al, 1989 [19]
Dexter et al, 1991 [20)
Jellinger et al, 1990 1211
+-
+-
...
+++
Hirsch et al, 1991 [223
Perl et al, 1992 [23)
+++
+++
+++
+-
Uitti ec al, 1989 1263
De Volder et al, 1989
+++
...
Jellinger et al, 1992 [14]
+++
f -
...
...
...
Brain
Regions
Patients
SN
SNC
SNR
SN
SN
SNC
SNR
SNC
SNR
SN
SN
SN
SN
Putamen
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD
Severe PD + AD
Mild PD
AD
Inhomogenous group
Severe PD
+
E251
+
+ + = Increased compared with control subjects; + - = unchanged compared with control subjects; SN = substantia nigra; PD
Parkinson’s disease; SNR = substantia nigra zona reticulata; SNC = substanria nigra zona compacta; AD = Alzheimer’s disease.
117, 181 showed an increase of total iron in the SN of
patients with PD versus patients with DAT and control
subjects. Fe3+in the SN of patients with PD was nearly
twice as high as in patients with DAT and control subjects; in both the substantia nigra zona compacta (SNC)
and the substantia nigra zona reticulata (SNR), it was
increased by approximately one third, whereas Fe2+
levels showed no differences. The ratio of Fe2+to Fe3+
in the SNC changes from almost 2 : 1 in control subjects to 1.25 : 1 in patients with PD. In the cortex hippocampus, the putamen, and the globus pallidus, there
was no significant difference in the levels of Fe3+ or
total iron. The findings of increased total iron in the
SN of patients with PD were confirmed by Dexter and
colleagues [19, 201 with inductively coupled plasma
spectroscopy.
Histochemisty
Similar results (see Table) were obtained by Jellinger
and associates 12 11 via histological examination of paraffin sections from PD patients with and without DAT
and control subjects using Perl’s stain for Fe3+,Turnbull’s blue stain for Fez’, and Quincke’s reaction for
both Fe2+ and Fe3+, with four randomly selected degrees of severity. Turnbull’s stain for Fe2+ was consistently negative; in the cerebral cortex and the hippocampus, only a few perivascular Fe3+ deposits were
present. In the globus pallidus, putamen, SNC, and
SNR, Fe3+was commonly observed in microglia, astrocytes, macrophages, around small vessels, and occasionally in nonpigmented neurons. No Fe3+ was detected in melanin-containing SNC neurons or in Lewy
bodies. The Fe3+ content in the globus pallidus, the
putamen, and the SNR was not different in patients
=
with PD and control subjects, but was significantly increased in the SNC of patients with PD compared to
patients with DAT and control subjects. The finding
of increased iron in the SN of patients with PD was
confirmed by the findings of Hirsch and associates [22}
using radiographic microanalysis.
Energy Dispersive Radiographic Microanalysis
Subcellular regions in S N neurons of patients with PD
and control subjects were investigated for iron by Jellinger and co-workers [141 using transmission electron
microscopy and energy dispersive radiographic microanalysis. Only the analysis of neuromelanin in SN neurons of patients with PD showed iron levels that were
significantly greater than baseline control levels. N o
significant demonstration of iron accumulation was observed in the central core or the periphery of Lewy
bodies, in the cytoplasm of SN neurons in patients
with PD, or in cytoplasm and neuromelanin in SN
neurons of control subjects. These results agree with
previous histochemical findings indicating that Lewy
bodies are consistently negative for Fe3+ [21). They
are at variance with the radiographic microanalysis data
reported by Hirsch and colleagues [22), who found
higher iron concentrations in Lewy bodies in SN neurons of patients with PD than in control subjects.
LAMMA Method
Using laser microprobe mass analysis (LAMMA), Perl
and associates E231 studied the subcellular distribution
of iron and aluminum in neuromelanin-containing SN
neurons of patients with P D and age-matched control
subjects. When LAMMA was directed to the intraneuronal neuromelanin granules of S N neurons of patients
S102 Annals of Neurology Supplement to Volume 32, 1992
with PD, prominent peaks related to the presence of
iron and aluminum were identified. Probe sites directed to nonmelanized portions of cytoplasm of these
cells or to the adjacent neuropil revealed considerably
lower concentrations of iron or aluminum. Neuromelanin granules in SN neurons of patients with PD
showed markedly increased concentrations of aluminum and a moderately increased iron signal when compared with control subjects.
Magnetic Resonance Imagipg Analysis
Brooks and colleagues 1241 could not measure differences in iron levels by T2 (bulk water proton spin-spin
relaxation time) magnetic resonance imaging (MRI) of
postmortem samples from the caudate nucleus, the
frontal COKeX, and the white matter of control subjects
and patients with PD. It was not possible to provide
strong evidence, however, that iron deposition per se
was responsible for the attenuated signal obtained from
the basal ganglia using T2-MRI. T2-MRI was also used
by De Volder and associates 1251 for diagnosis and
pathophysiological studies of patients with PD and
other diseases with striatonigral degeneration. This investigation disclosed the presence of abnormal iron deposits in the putamen in all patients, but indicated no
cortical anomalies.
Atomic Absorption and Emission
Analyses of iron and aluminum in four brain regions
(frontal cortex, caudate nucleus, substantia nigra, cerebellum) in patients with PD and control subjects by
Uitti and co-workers 1261 using atomic absorption and
atomic emission are in contrast to many mentioned
results. These authors did not find significant differences in iron or aluminum concentrations in all brain
regions of patients with PD compared with control
subjects. The groups analyzed were heterogenous,
however, so direct comparison to the studies mentioned is not possible.
Therapeutic Aspect
It is now generally accepted that a selective increase in
iron content occurs in the SN of patients with PD. The
persistent presence in PD of a selective increase in iron
in the SN pars compacta has given rise to the hypothesis of a possible reaction of this metal with H,O, (Fenton reaction) to induce oxidative damage (stress) resulting from formation of highly reactive oxygen free
species such as the hydroxyl radical. On the basis of
this hypothesis, new therapeutic strategies in the treatment of PD would include administration of an iron
chelator (deferoxamine mesylate) 127 ) to decrease iron
concentrations or administration of a MAO-B inhibitor
(deprenyl) 1281 to decrease H202production, especially that generated after L-dopa treatment.
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Supplement to Volume 32, 1992
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