Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

Abstract

The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147-154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009).

Full text

REVIEW PAPER
Manganese and its Role in Parkinson’s Disease: From Transport
to Neuropathology
Michael Aschner ÆKeith M. Erikson Æ
Elena Herrero Herna
´ndez ÆRonald Tjalkens
Received: 16 June 2009 / Accepted: 24 July 2009 / Published online: 6 August 2009
!Humana Press Inc. 2009
Abstract The purpose of this review is to highlight recent
advances in the neuropathology associated with Mn expo-
sures. We commence with a discussion on occupational
manganism and clinical aspects of the disorder. This is fol-
lowed by novel considerations on Mn transport (see also
chapter by Yokel, this volume), advancing new hypotheses
on the involvement of several transporters in Mn entry into
the brain. This is followed by a brief description ofthe effects
of Mn on neurotransmitter systems that are putative modula-
tors of dopamine (DA) biology (the primary target of Mn
neurotoxicity), as well as its effects on mitochondrial dys-
function and disruption of cellular energy metabolism. Next,
we discuss inflammatory activation of glia in neuronal injury
and how disruption of synaptic transmission and glial-neu-
ronal communication may serve as underlying mechanisms of
Mn-induced neurodegeneration commensurate with the
cross-talk between glia and neurons. We conclude with a
discussion on therapeutic aspects of Mn exposure. Emphasis
is directed at treatment modalities and the utility of chelators
in attenuating the neurodegenerative sequelae of exposure to
Mn. For additional reading on several topics inherent to this
review as well as others, the reader may wish to consult As-
chner and Dorman (Toxicological Review 25:147–154, 2007)
and Bowman et al. (Metals and neurodegeneration, 2009).
Keywords Manganese !Parkinson’s !Glia !
Neuroinflammation !GABA !Glutamate !MRI
Introduction
Mn is an essential metal, yet excessive exposure to it, whe-
ther from air or food, is associated with neurological
sequelae. Manganese (Mn) is an essential nutrient important
to protein and energy metabolism, bone mineralization,
metabolic regulation, and cellular protection from reactive
oxygen species. It is a cofactor for enzymes, such as mito-
chondrial superoxide dismutase (Hearn et al. 2003), arginase
(Shishova et al. 2009), pyruvate carboxylase (Zwingmann
et al. 2004), and glutamine synthetase (Takeda 2003).
Occupational exposure to Mn has been the principal
cause of human Mn intoxication in individuals working in
such industries as mining and the manufacturing of dry
batteries, steel, aluminum, welding metals, and organo-
chemical fungicides (Keen et al. 2000; Keen and Leach
1987). In addition, individuals receiving total parenteral
nutrition (Bertinet et al. 2000) and patients with chronic liver
failure are at higher risk of Mn intoxication (Hauser et al.
1994; Krieger et al. 1995). Mn exposure in the general
population can occur from consumption of well water con-
taining high levels of the metal (Kawamura et al. 1941;
Wasserman et al. 2006), from soy-based infant formulas
(Krachler and Rossipal 2000; Lonnerdal 1994), and possibly
M. Aschner (&)
Departments of Pediatrics and Pharmacology and the Kennedy
Center for Research on Human Development, Vanderbilt
University Medical Center, 2215-B Garland Avenue,
11425 MRB IV, Nashville, TN 37232-0414, USA
e-mail: michael.aschner@vanderbilt.edu
K. M. Erikson
Department of Nutrition, University of North Carolina
at Greensboro, Greensboro, NC, USA
E. H. Herna
´ndez
Center for Research on Occupational and Environmental
Toxicology, Oregon Health and Science University,
Portland, OR, USA
R. Tjalkens
Environmental and Radiological Health Sciences,
Colorado State University, Fort Collins, CO, USA
Neuromol Med (2009) 11:252–266
DOI 10.1007/s12017-009-8083-0

from Mn released into the atmosphere as a result of the
addition of methylcyclopentadienyl manganese tricarbonyl
(MMT) to gasoline as an anti-knock agent (Finkelstein and
Jerrett 2007; Walsh 2007). Both in rats (Fitsanakis et al.
2008) and humans (Kim et al. 2005) with chronic iron (Fe)
deficiency, Mn also accumulates at higher levels in the basal
ganglia.
Manganism, characterized by excessive brain Mn
deposition, shares multiple features with Parkinson’s dis-
ease (PD). In the early stages of the disease patients with
manganism display psychotic symptoms, which progress to
chronic symptoms associated with disturbances in extra-
pyramidal circuits, such as akinetic rigidity, dystonia, and
bradyskinesia (Olanow 2004; Pal et al. 1999). Neuronal
loss and gliosis in the globus pallidus, the substantia nigra
pars reticulata, and the striatum characterize manganism at
the morphological level (Olanow 2004). Manganism is
caused by neuronal injury in both cortical and subcortical
brain regions, particularly the basal ganglia. The basis for
the selective neurotoxicity of Mn remains incompletely
understood but an increasing number of studies are eluci-
dating underlying mechanisms through characterization of
the transport of Mn into the brain, the effects on synaptic
transmission and neuronal function, and the inflammatory
response of populations of glial cells in affected brain
regions. The pleiotropic effects of excess Mn on numerous
metabolic and trophic pathways in the CNS suggest a
complicated disease process that is dependent upon the
dose and duration of Mn received, the age at which
exposure occurs, and the nutritional status of the individ-
ual, particularly with respect to other metals, such as Fe. To
date, chelation therapy in exposed individuals remains the
primary treatment modality (Discalzi et al. 2000; Herrero
Herna
´ndez et al. 2006), but neurological symptoms may
worsen even years after the cessation of chronic exposure
(Rosenstock et al. 1971). Therefore, elucidation of the
cellular and molecular pathways underlying onset and
progression of the disorder is likely the best hope for
development of disease modifying therapeutic strategies.
Occupational Manganism
Occupational exposure generally occurs by inhalation of Mn
dusts and fumes. The current threshold limit value time-
weighted average (TLV-TWA) indicated by the American
Conference of Governmental Industrial Hygienists for Mn is
0.2 mg/m
3
(ACGIH 2009). Manganism, an extrapyramidal
syndrome associated with exposures to excessive Mn levels,
was first detected in 1837 in Mn dioxide-exposed workers
(Couper 1837). The prevalence of occupational manganism
is unknown, with a 0.5–2% rate reported among exposed
workers in China (Gao et al. 2003; Wang et al. 2001; Wang
2003), where metal poisoning ranks among the 10 leading
occupational diseases (Liang and Xiang 2004). In the US
alone, about 750,000 welders (HSBC 2003) are or have been
exposed to metal fumes and the legal litigation costs relating
to occupational Mn-related disorders are estimated in bil-
lions of US$ (HSBC 2003).
Clinical Aspects
Manganism is not only an occupational disease, as, even in
the absence of relevant exogenous exposures, it can affect
patients with chronic liver failure (Hauser et al. 1994) (due
to impaired biliary excretion of Mn), chronic iron defi-
ciency (Boojar et al. 2002; Herrero Herna
´ndez et al. 2002)
mostly due to Fe/Mn competition for transporters (review
by Roth & Garrick 2003) (Roth and Garrick 2003), subjects
on parenteral nutrition (Fell et al. 1996), drug addicts using
high Mn injectable solutions (de Bie et al. 2007; Levin
2005; Meral et al. 2007; Sanotsky et al. 2007; Sikk et al.
2007), patients in chronic renal failure undergoing he-
modialysis (da Silva et al. 2007; Ohtake et al. 2005) (for
unclear reasons), and subjects with genetic defects affect-
ing Mn homeostasis (Tuschl et al. 2008). It should be
stressed that Fe deficiency affects about 2 billion subjects
(Garcia et al. 2007) and is a risk factor for Mn neurotox-
icity even in absence of relevant exogenous exposures. Mn
toxicity from various sources has been repeatedly reported
in children (Fell et al. 1996; Herrero Herna
´ndez et al. 2003;
Komaki et al. 1999; Woolf et al. 2002), including cognitive
effects (Wasserman et al. 2006).
In 1837, Couper of Glasgow described a neurologic dis-
order in five patients who worked in a Mn ore-crushing plant
that bore similarity to the ‘‘shaking palsy’’ syndrome
reported only 20 years earlier by James Parkinson (Couper
1837). This and later reports (Embden 1901; Rodier 1955;
Scholten 1953; von Jaksch 1907; Voss 1939) described a
chronic, progressive disorder of the basal ganglia, termed
manganism that is characterized by extrapyramidal symp-
toms resembling PD. The clinical manifestations of work-
place Mn neurotoxicity include behavioral changes,
parkinsonism, and dystonia with gait disturbances (Cerso-
simo and Koller 2006). While it is generally recognized that
manganism appears after several years of exposure, early
reports described cases occurring after one or more months
(Fairhall and Neal 1943; Rodier 1955), the latter occurring
under extremely elevated exposures. Non-specific symp-
toms (headaches, muscular cramps, and fatigue) may pre-
cede overt manganism. A psychosis (locura manganica)
marked by aggressivity was reported among workers
exposed via dust to very high Mn levels. Long-term changes
in neuromotor, cognitive, and mood domains have been
described in exposed occupational groups (Bouchard et al.
2007; Roels et al. 1985). Manganism can progress even after
Neuromol Med (2009) 11:252–266 253

cessation of exposure and has long been considered irre-
versible (Huang et al. 1993). Neurological signs seem to
reach a plateau after an initial 5–10 years of progression
(Huang et al. 2007), but this observation is based on the
follow up of four patients only. However, it has been doc-
umented, in a few cases and in uncontrolled studies (Discalzi
et al. 2000; Herrero Herna
´ndez et al. 2003; Herrero Her-
na
´ndez et al. 2006; Ky et al. 1992; Ono et al. 2002; Penalver
1957; Tuschl et al. 2008) that manganism can be reversed if
promptly diagnosed and treated with chelating drugs.
Manganism frequently appears in young, active workers.
The metal primarily targets the globus pallidus and the onset
is generally symmetric. The syndrome includes hypertonia
with cogwheel rigidity, limb action/postural tremor, brady-
kinesia, ‘‘cock walk’’, and falling when walking backwards.
New Considerations Regarding Mn Transport
Mn can enter the CNS through the cerebral spinal fluid or
by crossing cerebral capillary endothelial membranes.
Physiological concentrations of Mn range from 2 to 8 lM
in brain tissue (Pal et al. 1999), but can increase several-
fold upon overexposure in rodents (Liu et al. 2006; Zheng
et al. 1998) and humans (Crossgrove and Zheng 2004;
Kessler et al. 2003). How Mn crosses the blood–brain
barrier (BBB) has been the subject of much investigation
and it appears that several pathways are operative,
including facilitated diffusion and active transport by the
divalent metal transporter 1 (DMT-1), ZIP8, and the
transferrin receptor system [recently reviewed in (Aschner
et al. 2007)]. Mn accumulates in multiple brain regions
including the basal ganglia, frontal cortex, pre-optic area,
and hypothalamus, indicated by analytical determination in
autopsy samples (Yamada et al. 1986) and by T1-weighted
magnetic resonance imaging (MRI) (Shinotoh et al. 1997;
Kim et al. 1999; Herrero Herna
´ndez et al. 2002; Guilarte
et al. 2006; reviewed by Aschner and Dorman 2007).
Consistent with a large number of observations, Mn and
Fe share common cytoplasmic transporters, such as the
divalent metal transporter-1 (DMT-1) and the transferrin
(Tf)/transferrin receptor (TfR) system (Aschner et al.
2007). Mn may also be transported as a citrate complex,
and candidates for this transporter include the organic
anion transporter or a monocarboxylate transporter (MCT)
and/or members of the organic anion transporter polypep-
tide (OATP) or ATP-binding cassette (ABC) super-fami-
lies (Crossgrove et al. 2003). A role in Mn transport has
also been ascribed to the ZIP transporter proteins in Mn
transport, though not specifically in the brain. This family
of transporter proteins is members of the solute-carrier-39
(SLC39) metal-transporter family; the family contains 14
members, which are all highly conserved between mouse
and human (Eide 2004). It was recently suggested (He et al.
2006) ZIP8 possesses high affinity for Mn (K
m
close to
physiological concentrations of Mn in various tissues).
Notably, while to date the role of the transporter in Mn has
been ascribed only in the testis (He et al. 2006), ZIP8 is
expressed in brain capillaries (Girijashanker et al. 2008).
Additional studies have also established that bolus injec-
tions of Mn directly into the blood may lead to Mn diffu-
sion across the BBB (Bock et al. 2008). As pointed by
these authors, Mn can be transported via the cerebrospinal
fluid and the ventricles and a significant difference in Mn
transport, and regional brain accumulation exists between
non-human primates and rodents.
Although Tf is the most likely carrier molecule for Mn
3?
transport across the BBB, the existence of other transport
mechanisms should also be considered. Clearly, binding of
Mn
2?
to alpha
2
-macroglobulin or albumin cannot be
invoked in the transport of Mn across the BBB, because
neither alpha
2
-macroglobulin nor albumin is transported
across this barrier. Unlike many other metals, Mn
2?
does not
posses high affinity for any particular endogenous ligand
[i.e., methylmercury (MeHg) and -sulfhydryl groups (–SH)].
There is almost no tendency for Mn
2?
to complex to –SH
groups and to amines. Metal ion hydrolysis interferes well
before Mn
2?
might complex to uni-dentate amines. Not
surprisingly, Mn
2?
does not have much variation in its sta-
bility constants for endogenous complexing ligands
(log
10
k=3, 4, 3, and 3, for glycine, cysteine, riboflavin, and
guanosine, respectively, where kis the affinity constant). The
strongest stability constants occur with multi-dentate amino
carboxylate ligands such as EDTA [log
10
k=13.5; (Martel
et al. 1998)], the only effective chelator of extracellular Mn.
EDTA supplies two nitrogen and four oxygen ligands to Mn,
and a water molecule is also coordinated to Mn (Reardan
et al. 1985). While noting the strong affinity of Mn to multi-
dentate amino carboxylate ligands, it must be considered that
in plasma, lipid soluble conjugates of Mn may exist. These
may provide a mechanism, not only for the transport of Mn
through the blood stream, but also for egression of the metal
from the blood stream into cells. The greater acute, oral
toxicity of the chloride–Mn salt compared to the oxide salt in
the young rat (Holbrook 1976) may be primarily associated
with the greater relative solubility of the chloride salt, and
thereby enhanced uptake of Mn. It is likely that minute
amounts of Mn
2?
in plasma exist, according to the Mass Law
Principle, as a chloride complex. While the amount of this
complex in plasma at any one time must be minute, the Mass
Law Principle states that a definite infinitesimal amount is
always present. It also holds that if any Mn
2?
should leave
the system by dissolving in a lipid membrane that the pro-
tein–Mn
2?
complex should dissociate to maintain equilib-
rium. The process of Mn dissolving in a membrane in not
clear. Although the Mass Law Principle maintains some
254 Neuromol Med (2009) 11:252–266

concentration of Mn in blood, it is not directly involved in the
process of transport across membranes; it simply provides
the Mn available for transport. The plausibility that this
mechanism is involved in the transport of Mn across mem-
branes remains open for experimentation.
Other transport mechanisms for Mn should be considered
as well. Snyder et al. (1986) proposed a novel transport
mechanism—the ‘‘sulfhydryl shuttle’’—for the membrane
transport of Auranofin 9, an antiarthritic agent, into mac-
rophage cells. They suggest that the compound shuttles
from albumin or cysteine to membrane –SH groups, and
thence is internalized. Interestingly, Haest et al. (1977)
found that approximately 80% of –SH groups in the
erythrocyte membrane are close enough to each other to
allow chemical interactions. Snyder et al. (1986) used
mainly indirect evidence to support this model. The key
data was the observation that N-ethylmaleimide (NEM)
blocked uptake of Auranofin 9, whereas metabolic inhibi-
tors, such as 2,4-dinitrophenol (DNP) and sodium fluoride
(NaF), did not exert an inhibitory effect. These results
suggest that binding of membrane –SH by NEM blocked the
‘‘sulfhydryl shuttle’’, and that active transport processes of
phagocytosis or endocytosis were not a part of the process.
This feature led Snyder et al. (1986) to suggest that a
‘‘sulfhydryl shuttle’’ may comprise a generic phenomenon
for transport, whereby, closely apposed fixed membrane
–SH groups are ‘‘shuttling’’ solutes across the BBB. Gerson
and Shaikh (1984) have published evidence in support of
Cd
2?
entry into hepatocytes by an –SH carrier.
The mechanisms considered so far are ‘‘shuttle’’ pro-
cesses involving water soluble complexes of Mn that are
transported on membrane carriers or a nonspecific exchange
of Mn between closely apposed membrane –SH groups.
Foulkes and McMullen (1987) proposed an intriguing
mechanism for transport of metals across membranes. For
example, the transport of Cd
2?
across the intestinal mem-
brane was postulated to consist of two distinct phases. The
first is the binding of the metal to negatively charged groups
on the surface of the membrane. This process is not specific
to Cd
2?
since several polyvalent cations can inhibit this
step. The second transport phase involves the ‘‘internali-
zation’’ of the membrane bound metal. Thus, less metal can
be removed from the intestinal surface with non-penetrating
complexing agents, such as EDTA, as a function of time and
temperature. Once inside the cell, Cd
2?
binds to metallo-
thionein making it even less susceptible to mobilization by
complexing agents. A similar scheme of events may be
operative in the brain capillaries, as well as astrocytes and
neurons (and other eukaryotic cells). Future studies could be
profitably directed at testing the possibility for a two step
entry process for Mn across biological membranes. It is
noteworthy that when MPTP is given to mice, the expres-
sion of an isoform of DMT1 increases in the ventral
mesencephalon of treated animals concomitant with iron
accumulation, oxidative stress, and dopaminergic cell loss
(Salazar et al. 2008). Thus, DMT1 mutation impairs iron
transport and protects against MPTP and 6-hydroxydop-
amine. Whether specific SNP variants in other Mn trans-
porters represent a risk factor for developing manganism
(at reduced Mn exposures) or PD has yet to be studied.
Neuropathological Characteristics of Mn Exposure
Mn is generally described as a neurotoxicant selectively
affecting the basal ganglia structures of the lower forebrain
and midbrain, including the globus pallidus, striatum,
subthalamic nucleus, and substantia nigra pars reticulata;
nevertheless, involvement of other regions, such as the
cortex and hypothalamus has also been reported (Yamada
et al. 1986). The most prominent neuropathologic findings
in human manganism are neuronal loss and reactive gliosis
in the globus pallidus and substantia nigra pars reticulata
(SNpr) (Yamada et al. 1986). Damage involving the stri-
atum (caudate nucleus and putamen) and subthalamic
nucleus has also been reported and, less frequently, the
substantia nigra pars compacta (Calne et al. 1994; Perl and
Olanow 2007). This stands in contrast to idiopathic PD,
where neuronal loss in the substantia nigra pars compacta
with the appearance of Lewy bodies is a neuropathological
hallmark of the disease (Pal et al. 1999). Notably, dopa-
minergic soma in the pars compacta are typically spared in
manganism (Olanow 2004; Olanow et al. 1996). A key
feature of the reactive gliosis observed in human and
experimental manganism is the presence of Alzheimer type
II astrocytosis (Bikashvili et al. 2001; Pentschew et al.
1963). Ultrastructural studies report that reactive astrocytes
and microglia surround degenerating neurons and contain
increased numbers of large secondary lysosomes, indica-
tive of an active phagocytic process (Bikashvili et al.
2001). Additionally, it has been reported that Mn induces
astrogliosis in the pre-frontal cortex of exposed Cynomol-
gus macaques and that activated astrocytes in this model
were noted proximal to degenerating neurons that expres-
sed amyloid-bprecursor-like protein 1 (Guilarte et al.
2008b). Collectively, reports from human cases and animal
models of manganism suggest a broad spectrum of
neuropathological changes in both neurons and glia not
only within the basal ganglia, but also within cortical
regions as well, which may help to explain some of the
non-motor symptoms of the disorder.
Effects of Mn on Norepinephrine
Due to the similarities of manganism and PD, most
research in the area of Mn neurotoxicity has focused on
Neuromol Med (2009) 11:252–266 255

dopamine (DA) biology; however, alterations in the biol-
ogy of other neurotransmitters, such as norepinephrine
(NE) (Autissier et al. 1982; Chandra et al. 1984; Seth and
Chandra 1984) have been reported. It should be noted that
depletion of NE in the substantia nigra by greater than 80%
is a hallmark of idiopathic PD (Marien et al. 2004) and it is
hypothesized that degeneration of the locus coeruleus may
precede and potentially surpass dopaminergic degeneration
in the substantia nigra (Rommelfanger and Weinshenker
2007), due to shared anatomical and biochemical similar-
ities (Zecca et al. 2004). In this section, we aim to highlight
some recent findings coupled with some older studies that
suggest that disturbances in NE biology due to Mn expo-
sure may be a part of the etiology of manganism.
Mn exposure has been found to affect brain tissue
(Autissier et al. 1982) and extracellular concentrations
(Anderson et al. 2009) of NE, as well as the uptake of NE
(Anderson et al. 2009; Chandra et al. 1984; Lai et al. 1982)
and expression of the NE transport and a
2
-adrenergic
receptor protein and mRNA levels (Anderson et al. 2009).
The effects of Mn on NE biology may potentially result from
perturbations in the locus coeruleus, the main noradrenergic
region of the brain (Troadec et al. 2001), and the neuro-
modulatory effect the region exerts on the nigrostriatal
dopaminergic pathway (Meyer and Quenzer 2005). Studies
using a
2
-adrenergic receptor antagonist treatment in rodents
showed that attenuating NE neurotransmission significantly
depleted DA release in the striatum, mimicking the neuro-
chemistry observed due to PD (Lategan et al. 1990).
Recently, it was reported that Mn exposure was associated
with a two-fold reduction of both protein and mRNA levels
of the a
2
-adrenergic receptor in the locus coeruleus and
substantia nigra (Anderson et al. 2009). Thus, it is plausible
that the altered a
2
-adrenergic receptor levels and attenuated
NE uptake caused by Mn accumulation in the locus coeru-
leus (Anderson et al. 2009), likely cause some of the
behaviors associated with manganism (e.g., anxiety-like
behaviors).
Effects of Mn on c-aminobutyric Acid
Much more research has been performed on examining the
role of c-aminobutyric acid (GABA) in mediating the
effects of Mn neurotoxicity compared to NE. Mn exposure
has been shown to affect tissue concentrations in a differ-
ential manner depending upon species and type of exposure.
A significant increase in striatal GABA due to Mn exposure
was found in rats (Garcia et al. 2006,2007; Gwiazda et al.
2002); while a marginally significant (P\0.1) decrease in
pallidal GABA concentrations in monkeys exposed to air-
borne MnSO
4
has been reported (Struve et al. 2007); and no
statistical difference was found in brain regional GABA
concentrations in primates injected with Mn intravenously
(Burton et al. 2009). While tissue GABA concentrations can
capture the overall status of GABA biology in an organism,
it does not fully reflect the extracellular concentrations
which are critical for neurotransmission. Recently, it was
found that Mn exposure via the drinking water led to
increased extracellular concentrations of GABA (Anderson
et al. 2008), attenuation of striatal GABA uptake (Anderson
et al. 2007), and alterations of GABA receptor and trans-
porter expression (Anderson et al. 2008) (see Fig. 1for
summary). Currently, in vivo extracellular GABA data are
lacking for Mn exposed primates.
Alterations in extracellular GABA could potentially
mediate the locomotor effects seen in Mn neurotoxicity,
such as hyperkinesia, ataxia, and dystonia. Normandin et al.
(2004) observed decreases in locomotor activity in Mn-
exposed young adult rats, while motor deficits were also
observed in a study utilizing a pre-Parkinsonian rat model
and cumulative low-dose Mn exposure (Gwiazda et al.
2002). In both of these studies, DA was not altered, sug-
gesting that changes in GABA may precede and facilitate
changes in DA during manganism. GABAergic neurons in
the striatum receive dopaminergic terminals from the sub-
stantia nigra (Smith and Bolam 1990), in turn modulating the
dopaminergic functioning in the striatum (Galindo et al.
1999), with increased extracellular levels of GABA
Cortex
STN
Striatum
GP
SN
Glutamate
Glutamate
Glutamate
GABA
GABA
GABA
Dopamine
[GABA]EC
1
2
3
4
5
Fig. 1 GABA biology during Mn overload. This simple schematic of
the basal ganglia represents the potential consequences of the
increased extracellular GABA concentrations in the striatum due to
Mn exposure. (1) Increased extracellular GABA concentrations in the
striatum would reduce the activity of the GABA striatopallidal
projection neurons (Anderson et al. 2008) (2) (dotted line). This
reduction in activity would (3) increase the GABAergic inhibitory
firing from the globus pallidus (GP) to the subthalamic nucleus (STN)
(heavy black line), in turn (4) decreasing the excitatory glutamatergic
firing from this region to the substantia nigra (SN) (dotted line). (5)
Decreased glutamatergic excitation in the substantia nigra, along with
decreased GABAergic inhibition from the striatonigral projection
neurons (dotted line) and decreased protein expression of GAT-1 and
GABA
B
(Anderson et al. 2008) would lead to a dysregulation of
dopaminergic firing to the striatum (alternating line)
256 Neuromol Med (2009) 11:252–266

affecting GABA projection neurons to the substantia nigra
(Koos and Tepper 1999), leading to dysregulation of the
nigrostriatal pathway, a hallmark of Mn neurotoxicity (see
Fig. 1).
Mitochondrial Dysfunction and Disruption of Cellular
Energy Metabolism
Mitochondria are one of the most important sites of Mn-
induced cellular dysfunction and early studies into the
cellular actions of Mn reported that mitochondria are the
principal intracellular repository for the metal (Cotzias and
Greenough 1958). More recent data indicate that mito-
chondria actively sequester Mn, resulting in rapid inhibition
of oxidative phosphorylation (Gavin et al. 1992), likely by
the 2
?
valence species (Gunter et al. 2006). Mn is rapidly
transported into the mitochondrial matrix via the calcium
(Ca
2?
) uniporter, but is cleared slowly, which can result in
accumulation and subsequent inhibition of Na
?
-dependent
and -independent Ca
2?
efflux and a sustained increase in
matrix Ca
2?
levels (Gavin et al. 1990). Elevated matrix
calcium increases formation of reactive oxygen species
(ROS) by the electron transport chain (Kowaltowski et al.
1995) and results in inhibition of aerobic respiration (Kru-
man and Mattson 1999). Various studies report that Mn
directly inhibits complex II (Singh et al. 1974) and com-
plexes I–IV (Zhang et al. 2003) in brain mitochondria.
Astrocyte mitochondria may also be a direct target of Mn,
demonstrated by studies examining mitochondrial calcium
responses in primary cortical astrocytes stimulated with
ATP (Tjalkens et al. 2006). Pretreatment of astrocytes with
concentrations of Mn as low as 1 lM resulted in large
increases in mitochondrial calcium that were accompanied
by osmotic swelling of mitochondria, loss of interconnected
mitochondrial networks, and depletion of thapsigargin-
releasable endoplasmic reticulum (ER) Ca
2?
stores. Mn
also decreases mitochondrial membrane potential and ele-
vates intracellular reactive oxygen species (ROS) in cul-
tured astroglial cells (Barhoumi et al. 2004).
The effects of Mn on mitochondria in both astrocytes
and neurons suggest that disruption of cellular metabolism
is a critical feature of Mn neurotoxicity. Studies using
high-resolution multinuclear NMR-spectroscopy to exam-
ine cell-specific pathways of
1,13C
glucose metabolism by
primary cultured astrocytes and neurons reported that Mn
hindered the ability of neurons to compensate for mito-
chondrial dysfunction by oxidative glucose metabolism
and predisposed neurons to energy failure (Zwingmann
et al. 2003). These studies also reported that Mn inhibited
glutamine synthesis and release in astrocytes that corre-
lated with a failure of astrocytes to provide neurons with
substrates for energy and neurotransmitter metabolism,
leading to decreased neuronal glutathione levels and
energy metabolism. Mn has been shown to decrease glu-
tamate uptake and downregulate expression of the high-
affinity glutamate transporter, GLAST, in cultured astro-
cytes (Erikson and Aschner 2002). Studies in rhesus
monkeys exposed to Mn by inhalation also reported down
regulation of GLAST in the globus pallidus in parallel to
decreased levels of glutathione (Erikson et al. 2008), sug-
gesting that oxidative stress and disruption of the gluta-
mate–glutamine metabolic coupling cycle between
astrocytes and neurons is an important etiological factor in
the progression of Mn neurotoxicity. Because neurons rely
on metabolic intermediates, such as pyruvate, lactate, and
glutamine, provided by astrocytes to sustain energy
metabolism (Deitmer et al. 2003; Sonnewald et al. 1991;
Tekkok et al. 2005), disruption of astrocyte-neuron meta-
bolic coupling by Mn may be an important mechanism
underlying mitochondrial dysfunction and failure of neu-
ronal metabolism in neurons following exposure to Mn.
Inflammatory Activation of Glia
Pathologic activation of both microglia and astrocytes is
associated with the progression of neurotoxic injury fol-
lowing exposure to excessive Mn. Astrocytes were first
implicated in Mn neurotoxicity following demonstration
that glutamine synthetase, for which Mn is a required
cofactor, is located solely in this cell type in the central
nervous system (Martinez-Hernandez et al. 1977). It was
subsequently shown that astrocytes selectively accumulate
Mn at more than 50-fold greater concentration than neu-
rons (Wedler et al. 1989) and possess a high affinity uptake
system for the divalent metal (Aschner et al. 1992). Hen-
riksson and Tjalve (2000) postulated that astrocytes were
the initial target of Mn based upon their observation that
Mn exposure in rats resulted in decreased immunoreac-
tivity for glial fibrillary acidic protein (GFAP) and S100b
in the absence of any apparent neuronal injury. This
assertion is supported by more recent studies that noted an
early upregulation of the ‘peripheral-type’ (mitochondrial)
benzodiazepine receptor in adult rats exposed subacutely to
Mn that was associated with Alzheimer type-II astrocytosis
in the globus pallidus (Hazell et al. 2003). Spranger et al.
(1998) speculated that activated astrocytes contribute to
Mn neurotoxicity through excessive production of NO
based upon their data demonstrating that Mn-induced
neuronal injury required the presence of astrocytes and was
associated with increased expression of the inducible iso-
form of nitric oxide synthase (NOS
2
). Collectively, these
studies suggested that debilitation of astrocytic mitochon-
drial function and increased production of NO could be
salient mechanisms in Mn neurotoxicity.
Mn enhances the release of inflammatory cytokines
interleukin-6 and TNF-afrom microglial cells (Chang and
Neuromol Med (2009) 11:252–266 257

Liu 1999; Filipov et al. 2005) that can promote the acti-
vation of astrocytes and subsequent release of inflammatory
mediators such as prostaglandin E
2
and nitric oxide (NO)
(Chen et al. 2006; Hirsch et al. 1998; Spranger et al. 1998).
Mn also strongly potentiates NO production in cytokine-
stimulated astrocytes, leading to apoptosis in co-cultured
neurons (Liu et al. 2006; Spranger et al. 1998; Tjalkens et al.
2008). This observation is supported by studies demon-
strating increased expression of NOS
2
in activated astrocytes
surrounding degenerating neurons in the striatum and globus
pallidus of Mn-treated mice (Liu et al. 2006). Mn also
enhances the capacity of bacterial lipopolysaccharide to
promote NO production in both astroglial (Barhoumi et al.
2004) and microglial (Filipov et al. 2005) cells. Low con-
centrations of Mn can increase the capacity of TNF-a,
interferon-c, and IL-1bto induce expression of NOS
2
and
production of NO in astrocytes by promoting activation of
the transcription factor NF-jB (Liu et al. 2005; Spranger
et al. 1998). The mechanism underlying the pronounced
effect of low-level Mn on expression of NOS
2
in astrocytes
appears to reside in the capacity of the divalent metal to
potently stimulate soluble guanylate cyclase, leading to
elevated intracellular levels of cGMP and MAP kinase-
dependent activation of NF-jB (Moreno et al. 2008).
Disruption of Synaptic Transmission
and Glial-Neuronal Communication
There is evidence that Mn affects both pre- and post-syn-
aptic neurons within the nigro-striatal dopaminergic system.
Neuropathological examination of the few cases of human
manganism that have come to autopsy report the absence
(Yamada et al. 1986) and presence (Ashizawa 1927;
Scholten 1953) of lesions within the substantia nigra pars
compacta. Loss of pigmented dopaminergic neurons within
the substantia nigra pars compacta has also been reported in
Mn-exposed monkeys (Gupta et al. 1980). Functional
imaging studies using positron emission tomography (PET)
and single-photon emission computed tomography
(SPECT) report similarly contrasting evidence. PET studies
examining [
18
F]-6-fluoro-L-DOPA uptake in patients suf-
fering from manganism (Shinotoh et al. 1997) and in
Mn-intoxicated monkeys (Shinotoh et al. 1995) reported
intact dopamine transporter function on pre-synaptic ter-
minals in the striatum. In contrast, Kim et al. (2002)
observed a decrease in binding of [
123
I]-1r-2b-carboxy-
methoxy-3b-(4-iodophenyl)tropane to pre-synaptic dopa-
mine transporters using SPECT in two patients with chronic
manganism, indicating either a direct effect on pre-synaptic
nigrostriatal dopaminergic neurons or perhaps Mn intoxi-
cation with symptoms manifesting from underlying idio-
pathic Parkinson’s disease. However, post-synaptic injury is
most frequently observed in human Mn intoxication, noted
studies by Kessler et al. (2003), who demonstrated mark-
edly reduced striatal post-synaptic D2-receptor density by
[
18
F]-methylspiperone PET imaging in an advanced case of
chronic manganism. These data suggest a direct involve-
ment of striatal-pallidal structures in the characteristic
neurological dysfunction observed in manganism. In addi-
tion, studies in Cynomolgus macaques revealed that
amphetamine-induced dopamine release was inhibited in
Mn-exposed animals (Guilarte et al. 2008a), suggesting a
direct involvement of pre-synaptic dopaminergic pathways.
There appears to be an excitotoxic component to man-
ganism that may ensue from disruption of both astroglial
and neuronal energy metabolism. Mn downregulates the
glutamate transporter GLAST in astrocytes (Erikson and
Aschner 2002) and decreases levels of glutamine synthetase
in exposed primates (Erikson et al. 2008). Striatal lesions
caused by direct injection of Mn in rats are prevented by the
non-competitive glutamate receptor antagonist MK-801
(Brouillet et al. 1993). Interestingly, decreased ATP and
lactate in this model seem to precede excitotoxic injury,
suggesting a direct effect on astrocytes that subsequently
impairs neuronal function. More recent studies report con-
trasting evidence in this regard. Neonatal rats exposed
subcutaneously to lower levels of Mn for 4 weeks had
increased levels of glutamate in the striatum and evident
neurotoxicity that was prevented by MK-801 (Xu et al.
2009), whereas studies in which monkeys were exposed
intravenously to Mn reported no change in glutamate levels
or glutamate receptor density (PUBMED ID 19520674).
Additional studies using the neonatal rat model indicated
that both pinacidil, a potassium channel agonist, and
nimodipine, a Ca channel antagonist, reversed Mn neuro-
toxicity and loss of glutamine synthetase activity, further
implicating excitotoxicity in the mechanism of Mn-induced
basal ganglia injury (Deng et al. 2009). A role for early
dysfunction of astrocytes is also supported by data in Mn-
exposed animals demonstrating changes in markers of
astrocyte activation, such as Sb100 and the peripheral
benzodiazepine receptor, prior to any evident neuronal
lesion (Hazell et al. 2003; Henriksson and Tjalve 2000). Mn
also inhibits ATP-dependent intercellular calcium waves in
primary cultured astrocytes (Tjalkens et al. 2006), which are
critical to heterosynaptic suppression of excitatory gluta-
matergic synapses (Haydon and Carmignoto 2006). Thus,
excessive Mn may lead to excitotoxic neuronal injury both
by decreased astrocytic uptake up glutamate and by loss of
ATP-mediated inhibition of glutamatergic synapses.
Gene Expression Studies
The few studies available have addressed gene expression
changes in Mn-treated cells of human (Sengupta et al. 2007)
or rodent origin (Baek et al. 2004; HaMai et al. 2006). In a
258 Neuromol Med (2009) 11:252–266

genome-wide study on cultured human astrocytes (Sengupta
et al. 2007), Mn-induced expression changes were noted in
genes involved in inflammation (upregulated), DNA repli-
cation, and repair (downregulated). Gene expression on Mn-
treated mice brains (Baek et al. 2004) mainly showed an
upregulation of the S100bgene, and the increase of the
protein was confirmed by immunohistochemistry. Instead,
neurofilament subunit genes were downregulated in the
striatum and in the substantia nigra. Recent work on non-
human primates (Guilarte et al. 2008b) detected Mn-induced
brain gene expression changes mainly affecting apoptosis,
protein folding and degradation, inflammation and axonal/
vesicular transport. The most up-regulated gene was APLP1,
and diffuse amyloid-bplaques were documented in the
frontal cortex of the Mn-treated macaques (Guilarte et al.
2008b). These interesting results could support a link
between advanced manganism and dementia, as occasion-
ally reported (Bant and Markesbery 1977). However, few
animals and a partial gene set were studied. Age, Mn expo-
sure, dosage, and treatment duration showed some vari-
ability. Also, these animals were repeatedly anesthetized to
undergo i.v. injections and neuroradiological studies (Guil-
arte et al. 2006), and general anesthesia could have affected
gene expression. Further studies are needed and will proba-
bly clarify mechanisms of toxicity triggered by this metal
and relate polymorphisms in Mn transporters and affected
pathways with the human sensitivity to this metal.
Diagnosis
Clinical examination alone can fail in diagnosing man-
ganism (Racette et al. 2001), and additional assessments
(occupational history, detection of nonoccupational risk
factors, brain magnetic resonance imaging, Mn analyses in
biological fluids) are needed. Blood Mn concentration
(Mn–B) seems to reflect current exposure (when exposure
fluctuates as in occupational settings) and Mn body burden
(in steady exposures) (Alessio et al. 2007). While less than
an ideal biomarker, Mn–B can help diagnosis and follow
up. Mn–B and urinary Mn concentration (Mn–U) have both
been used to discriminate occupationally exposed from
non-exposed subjects. However, Mn–U is not a reliable
biomarker because the metal is mainly eliminated through
the biliary system, Mn–U is highly variable, subject to
contamination and does not correlate with airborne Mn in
exposed populations (Apostoli et al. 2000; Smith et al.
2007). Plasma Mn is only 6% of whole-blood Mn content
and is considered to have very limited utility as a bio-
marker of Mn load (Smith et al. 2007).
Mn is paramagnetic and detectable by MRI because the
metal’s atom has unpaired electrons in level 3d. MRI is the
most sensitive non-invasive method of detecting Mn in
the brain. Figure 2serves to illustrate typical accumulation
of Mn in brain-specific regions upon excessive occupational
exposure. A semiquantitative estimate of Mn content, known
as the Pallidal Index (Krieger et al. 1995) (PI, a ratio between
the intensity of the T1 signal in the pallidum and that of the
frontal white matter) can be calculated on brain MRIs. The
metal shortens the T1 relaxation time, causing hyperintensity
of T1-weighted sequences, mainly in the basal ganglia. This
abnormal signal, absent in Parkinson’s disease (PD), assists
differential diagnosis. The signal is observable in Mn-poi-
soned non-human primates, symptomatic and asymptomatic
Mn-exposed subjects, patients with hepatic cirrhosis, and in
subjects on parenteral nutrition (Fitsanakis et al. 2006; Kim
2006) for recent reviews), hemodialysis (Ohtake et al. 2005),
or with chronic iron deficiency (Herr Herna
´ndez et al. 2002).
T2 scans are normal. Brain Mn analysis in non-human pri-
mates (Park et al. 2007; Shinotoh et al. 1995) and in patients
Fig. 2 A welder before chelation therapy. Brain MRI, sagittal (a) and
axial (b) T1-weighted sequences showing a definite hyper signal of
globi pallidi (from Herrero Herna
´ndez et al. 2006)
Neuromol Med (2009) 11:252–266 259

with chronic liver failure (Klos et al. 2006; Krieger et al.
1995) has proven that Mn is the cause of the abnormal signal,
but the relationship between that signal and onset of symp-
toms is still unclear. The MRI signal tends to disappear
5 months-1 year after cessation of exposure (Newland et al.
1989; Ejima et al. 1992; Kim et al. 1999; Nelson et al. 1993),
but symptoms can persist and progress (Huang et al. 1993;
Nelson et al. 1993) in the absence of treatment to remove Mn.
Differences between manganism and PD can be detected
by clinical, neuroradiological, toxicological, and histopa-
thological means (Olanow 2004). Degeneration of the
globus pallidus, and less severely of the putamen, caudate,
and substantia nigra (but not the pars compacta, a hallmark
of PD) is reported in human and animal manganism
(Pentschew et al. 1963; Perl and Olanow 2007; Seth and
Chandra 1988); the pons, cortex, thalamus, subthalamic
nuclei, hippocampus, red nucleus, cerebellum, and anterior
horn of the spinal cord may also be involved. Lewy bodies,
another hallmark of PD, seem to be absent in manganism
(Perl and Olanow 2007). Excess Mn causes gliosis and
neuronal degeneration. PET with radiolabeled fluorodopa
shows reduced striatal uptake of the tracer in PD patients,
while normal uptake is generally seen in manganism (Kim
2006). Manganism is also distinguishable from PD by (a) a
less frequent resting tremor, (b) more frequent dystonia, (c)
a particular propensity to fall backwards, (d) a general
failure to achieve a sustained therapeutic response to
levodopa (though controversial), as well as (e) failure to
detect a reduction in fluorodopa uptake by positron emis-
sion tomography PET (Pal et al. 1999). Given these dif-
ferences, some have suggested that Mn intoxication is
associated with preservation of the nigrostriatal dopami-
nergic pathway, and that chronic Mn intoxication causes
parkinsonism-like effects by damaging output pathways
downstream of the nigrostriatal dopaminergic pathway, in
areas such as the globus pallidus (Pal et al. 1999), an area
with propensity to accumulate high amounts of Mn. Others
(Guilarte et al. 2008a) indicate a decrease of dopamine
release in absence of dopaminergic neuronal degeneration.
Treatment
PD cases respond to levodopa, while the drug is currently
considered ineffective in manganism (Herrero Herna
´ndez
et al. 2006; Koller et al. 2004; Lu et al. 1994), presumably
because the nigrostriatal pathway remains relatively intact
in the latter. Moreover, levodopa is contraindicated in
manganism, as Mn catalyzes dopamine autooxidation to
toxic quinones and semiquinones (Graham 1984; Lloyd
1995; Parenti et al. 1988). According to some studies
(Discalzi et al. 2000; Herrero Herna
´ndez et al. 2003;
Herrero Herna
´ndez et al. 2006; Ky et al. 1992; Ono et al.
2002; Penalver 1957) chelating treatment can reverse
manganese poisoning with persistent clinical benefit for
many years (Herrero Herna
´ndez et al. 2003; Herrero Her-
na
´ndez et al. 2006; Jiang et al. 2006). However, large
controlled clinical trials are lacking.
Chelation therapy is the indicated treatment for metal
poisoning. Chelators bind metal ions in a stable form and
the compound chelator ?metal is then excreted by the
urinary and/or biliary routes. This therapy aims to lower the
body’s burden of the metal and consequently its toxicity
(Sa
´nchez et al. 1995). Ethylene diamine tetraacetic acid
(EDTA) is a polyaminocarboxylic acid that chelates many
divalent and trivalent metals, properties that find commer-
cial application as a metal sequestrant in food additives.
However, EDTA and its sodium salt can induce severe
hypocalcemia, and these compounds have frequently been
misused for non-scientific indications, sometimes with fatal
consequences (CDC-MMWR 2006). Only the calcium
disodium salt (CaNa
2
EDTA), which does not induce
hypocalcemia, should be used for treatment. Recent data
have shown CaNa
2
EDTA protects renal function and tissue
integrity by increasing nitric oxide levels (Foglieni et al.
2006). However, it must be administered only by trained
physicians to hospitalized patients, with temporal moni-
toring of renal function and essential trace elements.
Polyaminocarboxylic acids mobilize Mn from internal
organs, enhance its excretion, and prevent mortality
induced by MnCl
2
in poisoned animals (Rodier et al. 1954;
Tandon and Khandelwal 1982). CaNa
2
EDTA decreases
liver and brain Mn levels in Mn-intoxicated rats (Kosai and
Boyle 1956); it also decreases Mn-induced dopamine
autoxidation in vitro (Nachtman et al. 1987) and inhibits
serum dopamine-b-hydroxylase in humans (De Paris and
Caroldi 1994), potentially preserving dopamine levels.
EDTA and CaNa
2
EDTA increase urinary Mn excretion in
humans (Cook et al. 1974; Discalzi et al. 2000; Herrero
Herna
´ndez et al. 2006; Sata et al. 1998) and have been used
with dubious justification to ‘‘prevent’’ occupational man-
ganism (Ritter and Marti-Feced 1960; Wynter 1962).
Some studies, mostly involving extremely high occupa-
tional exposures as those found in the past or those still
occurring in rapidly developing countries, reported a lack of
clinical amelioration with these chelators (Crossgrove and
Zheng 2004; Huang et al. 1989; Yamada et al. 1986). In some
cases (Cook et al. 1974), amelioration was observed, but not
maintained. Established irreversible neuronal damage,
inadequate treatment duration and/or follow-up period could
explain these unsatisfactory results. Several studies (Discalzi
et al. 2000; Herrero Herna
´ndez et al. 2003; Herrero
Hernandez et al. 2006; Ky et al. 1992; Ono et al. 2002;
Penalver 1957) have showed that CaNa
2
EDTA is clinically
effective in the treatment of overt manganism in humans.
These observations are consistent with recent therapeutic
success in a severe case of genetic hypermanganesemia with
260 Neuromol Med (2009) 11:252–266

extrapyramidal syndrome, polycythemia, and hepatic cir-
rhosis (Tuschl et al. 2008) and possibly in ephedrone-man-
ganic syndrome cases (Selikhova et al. 2008). Early studies
lacked detailed information on treatment and biomarkers,
and other drugs were co-administered, thus potentially
confounding the results. Recent work (Hazell et al. 2006) has
also shown that the Mn chelator 1,2-cyclohexylenedini-
trilotetraacetic acid (CDTA) blocked the development of
pathological changes in glial cells of rats treated with
MnCl
2
PAS-Na, an antitubercular and antiinflammatory
drug, has also been suggested to be useful in occupational
manganism (Jiang et al. 2006; Ky et al. 1992), but the patient
with the longest follow-up was also previously treated with
CaNa
2
EDTA (Jiang et al. 2006). PAS-Na has been reported
to actually increase brain Mn concentrations in MnCl
2
poi-
soned rodents (Sa
´nchez et al. 1995). Large controlled clinical
trials are still lacking and would be needed to establish the
most efficient and less toxic treatment strategies.
Conclusions
Understanding of the pathogenesis of Mn neurotoxicity and
its role in PD will have to incorporate a number of con-
siderations/mechanisms. Future consideration should fur-
ther be directed at (1) factors controlling Mn
2?
uptake and
distribution into the brain with emphasis on the relationship
between Mn uptake and efflux in other divalent metals, in
addition to Fe; (2) the apparent selectivity of dopaminergic
neurons; nevertheless, it should also be considered that
other neurotransmitter systems are targeted by Mn. Fur-
thermore, on a temporal scale these systems (norepineph-
rine, GABA, etc.) may be more vulnerable than the
dopaminergic system itself; (3) the mechanistic effects of
Mn at the molecular level, improving the understanding on
altered signal transduction pathways and cross talk
between various neural cells; (4) the interaction between
Mn exposure and genetics, vis-a
`-vis transport as well as the
interaction between Mn and wild-type or mutant alleles of
PD-associated proteins; and, finally, (5) the development of
more effective diagnosis and treatments for Mn poisoning.
Acknowledgments The authors gratefully acknowledge partial
support by grants from NIEHS 10563 and DoD W81XWH-05-1-0239
(MA), NINDS 061309-01 (KME) and NIEHS 012941 (RT).
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