Chapter 20

Astrocytes Role in Parkinson: A Double-Edged Sword

Ricardo Cabezas, Marco Fidel Avila, Daniel Torrente,

Ramon Santos El-Bachá, Ludis Morales,
Janneth Gonzalez and George E. Barreto

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54305

1. Introduction

Parkinson Disease (PD) is the second most chronic neurodegenerative disorder in the world,
after Alzheimer´s Disease (AD), and is estimated to affect about 1% of the population over
60 years of age. PD is caused by the disruption of dopaminergic neurotransmission in the
basal ganglia, which causes a reduction in the numbers of dopaminergic neurons in the sub‐
stantia nigra and formation of cytoplasmic inclusions called Lewy bodies [1].
Both in normal and pathological circumstances, astrocytes are critical supporters of neuro‐
nal function in processes such as antioxidant protection, glutamate clearance, the develop‐
ment and/or maintenance of blood brain barrier characteristics, the release of
gliotransmitters and cytokines [2-4]. In recent years, much research on PD has focused on
the astrocytic-neuronal crosstalk, suggesting that this interaction is important for future
therapies against neurodegenerative processes. During brain damage events, astrocytes be‐
come transiently or permanently impaired, and the subsequent impact on neuronal cells
may lead to pathological conditions such as PD [5-7].
In the present chapter, we provide a brief overview of the astrocytic functions and the path‐
ophysiological events elicited during PD. Additionally, we explore the beneficial and dam‐
aging consequences of reactive astrogliosis in dopaminergic neurons during PD, particularly
on oxidative damage, which is a main component of numerous neuropathological condi‐
tions, and that may have a damaging effect in astrocytic functions. We also highlight some
of the cellular and animal models currently used in Parkinson research, such rotenone, 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and paraquat as inducers, which have
many similar features with this disease. Finally, a brief overview of the future perspectives
in astrocytic protection during Parkinson development is discussed.

© 2013 Cabezas et al.; licensee InTech. This is an open access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
492 Neurodegenerative Diseases

2. Parkinson´s disease

PD is a progressive neurodegenerative disorder caused by the neuronal death in the sub‐

stantia nigra (SN), degeneration of dopaminergic neurotransmission, and the presence of α-
synuclein and protein inclusions in neuronal cell bodies (Lewy bodies) [4-5,7]. Main
symptoms of Parkinson are asymmetrical bradikinesia, rigidity, resting tremor and postural
instability. Other non-motor symptoms that generate serious disability problems have also
been noted, including fatigue, pain, Lewy Body dementia, psychosis, depression, and apa‐
thy [1]. Although there is not a cure for the disease, the most used and cheaper treatment for
PD continues to be Levodopa [1,8]. However, about 40% of patients developed motor fluctu‐
ations and dyskinesias after 4 to 6 years of treatment [1], demonstrating that further phar‐
macological research is needed in order to counterbalance side effects. In this aspect,
treatments using long-acting dopaminergic agents or a continuous dopaminergic effect in
the striatum have been associated with less severe motor complications, given alone or in
combination with L-dopa [9]. Some pharmacological agents that have shown promising ap‐
plications, include dopamine agonist like apomorphine and ropinirole, and catechol-O-
methyltransferase (COMT; EC 2.1.1.6) inhibitors [9].
Numerous reviews and articles agree that the exact cause of PD remains unknown [1,9-10].
Mutations in various proteins such as leucine-rich repeat kinase 2 (LRRK2; EC 2.7.11.1), Par‐
kinson protein 2 (PARK2), probable cation-transporting ATPase type 13A2 (ATP13A2; EC
3.6.3-), phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1; EC
2.7.11.1), and Parkinson disease (autosomal recessive, early onset) 7 protein (DJ-1) have been
observed in familiar cases of Parkinson, which only accounts for 10-15% of diagnosed cases
[6,11-12]. Interestingly, LRRK2, PINK1, and DJ-1, which are present in mitochondrial mem‐
branes, have been suggested to play a role in reactive oxygen species (ROS) production by a
defective maintenance of the mitochondrial membrane potential [12-13].
A number of environmental factors have been found to induce PD-like symptoms, and are
currently used in animal and cellular models of the disease. Environmental factors include
vascular insults to the brain, oxidative stress, neuroleptic drugs and repeated head trauma.
[6,14]. Additionally, the exposure to pesticides like rotenone or 1-methyl-4-phenylpyridini‐
um (MPP+) and heavy metals (manganese) increases the risk of PD development [6, 10,
14-15]. In this aspect, numerous epidemiologic and toxicologic studies have examined pesti‐
cides as a risk factor for PD and parkinsonism and the possible mechanisms by which pesti‐
cides may act [14-17].
Initiation and progression of PD is dependent upon cellular events, including failures in the
protein degradation machinery, oxidative stress, mitochondrial dysfunction, defects in mito‐
chondrial autophagy (mitophagy) and the continuous accumulation of α-synuclein, driven
through cell to cell interactions between glial cells and neurons that ultimately lead to apop‐
tosis [7,10,18]. Previous studies pointed that astrocytic α-synuclein deposition initiates the
recruitment of phagocyte microglia that attacks and kills neurons in restricted brain regions
[7,19], correlating this α-synuclein accumulation with nigral neuronal cell death [20], and
suggest the importance of astrocytes in the initiation of the disease. Conversely, astrocytes
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also have beneficial roles during PD progression [21-22]. For example, astrocytes express
different antioxidant molecules such as glutathione peroxidase (EC 1.11.1.9), which have
been inversely correlated with the severity of dopaminergic cell loss in the respective cell
groups in patients with PD [4].

3. Astrocytes in PD

3.1. Astrocytic functions

Astrocytes are the most common cell type in the mammalian brain, conforming the glia with
oligodendrocytes and microglia [23]. They are characterized by the expression of the inter‐
mediate filaments glial fibrillary acidic protein (GFAP) and vimentin (Vim). Astrocytes are
essential for the metabolism of the brain, transporting multiple nutrients and metabolic pre‐
cursors to the neurons by the malate-asparte shuttle and other transporters [24]. There are
two main types of astrocytes in the SNC: Protoplasmic astrocytes, which envelope neuronal
bodies and synapses and fibrous astrocytes which interact with the nodes of Ranvier and
oligodendroglia [7]. Current research has shown that only protoplasmic astrocytes have an
increase in the accumulation of α-synuclein, whereas fibrous astrocytes do not [7,19].

Current knowledge indicates that astrocytes are critical for some cellular processes, such as
the development and/or maintenance of blood–brain barrier characteristics, the promotion
of neurovascular coupling, the attraction of cells through the release of chemokines, K+ buf‐
fering, release of gliotransmitters, release of glutamate by calcium signaling, maintenance of
general metabolism, control of the brain pH, metabolization of dopamine and other sub‐
strates by monoamine oxidases (MAOs; EC 1.4.3.4), uptake of glutamate and γ-aminobuty‐
ric acid (GABA) by specific transporters and production of antioxidants [2-3,25-27] (Figure
1). Recent evidence has shown that astrocytes are arranged in non-overlapping domains
forming a syncytial network that may contact approximately 160.000 synapses, thus inte‐
grating neural activity with the vascular network [4,28]. In this aspect, astrocytic terminal
processes, known as endfeet, contact the brain vasculature and enwrap the neuronal synap‐
ses, enabling the modulation of both neuronal activity and cerebral blood flow, following an
elevation in intracellular Ca2+ levels in the endfeets [24,29].

During brain damage (including diseases, brain injury and oxidative stress), these astrocytic
functions become transiently or permanently impaired, and the subsequent impact on neu‐
ronal cells may lead to pathological conditions and neurodegenerative diseases [3,26]. Neu‐
rons are more susceptible to injury than astrocytes, as they have limited antioxidant
capacity, and rely heavily on their metabolic coupling with astrocytes to combat oxidative
stress [3]. However, severe brain damage also results in astrocyte dysfunction, leading to in‐
creased neuronal death [30].

As previously stated, astrocytes exert both neuroprotective and neurodegenerative roles, de‐
pending on the molecules released by them, and the pathological or normal circumstances
of their microenvironment [6]. For example, astrocytes release antioxidant molecules like
494 Neurodegenerative Diseases

glutathione (GSH) and superoxide dismutases (SODs; EC 1.15.1.1), and supply neurons with
neurotrophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor
(bFG), that constitute an important attempt to protect neurons during brain damaging proc‐
esses, including PD [6, 31-32]. On the other hand, during the process of reactive astrogliosis,
astrocytes release inflammatory cytokines that may affect the surrounding neurons, both by
the induced production of ROS and lipid peroxidation, and by the activation of apoptotic
mechanisms that induce neuronal dopaminergic death [6,10]. These unusual, and sometimes
contradictory, features of astrocytes in PD will be further explored in this chapter.

Figure 1. Astrocytes support neuronal function by multiple ways, including the development and maintenance of
blood–brain barrier and promoting the neurovascular coupling. Astrocytes regulate the levels of ions, neurotransmit‐
ters and fueling molecules such as K+, glutamate, GABA, dopamine, lactate and piruvate. Furthermore, astrocytes pro‐
mote the attraction of cells through the release of chemokines, and produce beneficial antioxidants, including
glutathione, superoxide dismutases (SODs 1, 2 and 3), and ascorbate.

3.2. Astrogliosis and parkinson

Reactive astrogliosis is the main reaction of astrocytes following brain insults such as infec‐
tion, trauma [33-34], α-synuclein accumulation [35], ischemia [36-37] and neurodegenerative
diseases [3]. This process involves both molecular and morphological changes in the astro‐
cytes, including increased expression of GFAP, vimentin and nestin, uptake of excitotoxic
glutamate, protection from oxidative stress by the production of GSH, neuroprotection by
release of adenosine, degradation of amyloid-beta peptides, facilitation of blood-brain barri‐
er, increased formation of gap junctions between astrocytes, formation of scars and, in some
cases release of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), and
production of ROS [3,35,38-40].
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Astrogliosis and microgliosis in the SN of Parkinson patients are key features of the
disease, which is a nonspecific consequence of neuronal degeneration [10]. Cellular and
animal models using environmental and biological toxins, especially lipopolysacchar‐
ides (LPS), herbicides and pesticides like rotenone or MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine), can induce both astrogliosis and microgliosis, which is
accompanied by neuronal death, mitochondrial dysfunction and nuclear fragmentation
[41-45]. Additionally, it was previously shown that the injection of LPS in rat brains
was followed by an increase in the inducible nitric oxide synthase (iNOS; EC
1.14.13.39), suggesting that chronic glial activation can cause oxidative stress in the
brain, similarly to that seen in neurodegenerative processes like AD and Parkinson [10,
39, 45]. A previous report showed that activated glial cells can participate in the death
of dopaminergic neurons, probably by the activation of apoptosis by cytokines like
TNF-α, IL-1B, IL-6 and interferon-γ and the subsequent production of nitric oxide
(NO) by the iNOS that may diffuse toward the neurons and induce lipid peroxidation,
DNA strands breaks and inhibition of mitochondrial metabolism [6,10]. Furthermore,
cytokines released by astrocytes may bind to their specific receptors in the dopaminer‐
gic neurons, such as TNFR1 and 2, and activate proapoptotic mechanisms through the
activation of caspase 3, caspase 8, and cytochrome c [10]. Interestingly, the excessive
uptake of neuronal α-synuclein by astrocytes can lead to accumulation of aggregates
of this protein in astrocytes, and cause an upregulation of IL-1 α, IL-1β and IL-6, fol‐
lowed by the release of TNF-α and IL-6 [6]. These results suggest that the inhibition
of glial reaction to damage and further inflammatory processes could be considered as
a promising therapy to reduce neuronal damage during PD [10].

3.3. Oxidative stress and Parkinson: Role of astrocytes

In the brain, oxidative stress and other toxic insults can trigger the overexpression and acti‐
vation of neuronal nitric oxide synthase that increases NO production and may cause apop‐
totic cell death by inducing the release of cytochrome c from mitochondrial impairment, loss
of membrane potential, the opening of permeability transition pores, and the release of
proapoptotic molecules [46,47]. After brain damaging processes, neurons experience greater
metabolic deterioration than glial cells. For instance, astrocytes contain glycogen stores that
allow them to maintain ATP production through glycolysis and mitochondrial membrane
potential by reversal of the F0-F1-ATPase (EC 3.6.3.14) [48]. For example, cultured astrocytes
subjected to oxygen and glucose deprivation showed a decrease in mitochondrial membrane
potential, possibly caused by the mitochondrial permeability transition pore (mtPTP) open‐
ing, which leads to a loss of intramitochondrial contents, mitochondrial respiration and ATP
production [48].

Nowadays there is much evidence of the role of oxidative stress in the development of
neurodegenerative diseases, such as AD, PD, Amyotrophic Lateral Sclerosis (ALS) and
Huntington’s disease (HD). Much of these oxidative damaging processes are associated
with an imbalance on the production of ROS that leads to mitochondrial stress and im‐
pairment in energy production [47,49]. ROS, such as superoxide (O•2-), can be produced
496 Neurodegenerative Diseases

in mitochondrial complexes I and III in components of the tricarboxylic-acid cycle, in‐

cluding α-ketoglutarate dehydrogenase (EC 1.2.4.2), and in the outter mitochondrial
membrane, damaging cell components such as lipids, proteins and DNA [25, 47]. In PD,
oxidative damage is a common feature, as demonstrated by increased levels of ROS in
post-mortem PD brain samples [25]. Oxidative stress seems to affect various brain re‐
gions, including the SN and caudate nucleus, and it is accompanied by an increase in
GFAP and astrocytic proliferation [50]. Additionally, PD patients present deficiencies in
mitochondrial complex I in the SN, suggesting that a defect in this complex could con‐
tribute to neuronal degeneration in PD [25]. However, it is not clear whether the damage
induced by ROS is a cause or a consequence of other cellular dysfunctions [25]. For ex‐
ample, a previous study on PD brains showed an increase in lipid peroxidation prod‐
ucts, such as 4-hydroxinonenal, and in protein crosslinking and fragmentation [51],
suggesting that oxidative stress may affect other brain regions apart from the SN.

Astrocytes produce numerous antioxidant molecules, such as GSH, catalase (EC 1.11.1.6)
and SODs, providing further antioxidant protection to neurons. Unfortunately, it is known
that the astrocytic protection afforded to neurons is limited, possibly due to a decline in
GSH trafficking by chronic iNOS induction [52]. This depletion of GSH may facilitate the
production of ROS and reactive nitrogen species (RNS) by astrocytes, causing alterations in
neuronal proteins such as α-synuclein [25]. Furthermore, the nitration of α-synuclein by
RNS can significantly enhance the synuclein fibril formation in vitro, similarly to what hap‐
pens in PD brains [25]. In sum, the antioxidant properties of astrocytes have a fundamental
role in the development of neurodegenerative diseases, and are considered as promising
therapeutically targets.

4. Experimental models in Parkinson

Various pesticides, herbicides and drugs have been used in animal and in vitro models of
Parkinson, as their effects mimic similar features of that seen in PD. Different epidemiologi‐
cal studies have shown a correlation between the exposure of these substances (especially in
the case of pesticides) and appearance of PD [14-15, 17, 53]. A common feature of many of
these neurotoxic compounds, such as rotenone, paraquat, or MPTP, is the inhibition of mito‐
chondrial complex I, followed by the overproduction of ROS, ATP exhaustion, and induc‐
tion of a wide range of abnormalities that can elicit neuronal and astrocytic cell death [54].
Additionally, neurotoxins induce nuclear fragmentation, endoplasmic reticulum (ER) stress
and unfolded protein response in catecholaminergic cells, which are associated with
changes in proteasomal and chaperone activities, similar to those observed in PD [45,55].
Other molecules used in PD models include the fungicide maneb, cyclodienes, organophos‐
phates such as deltamethrin, DDT (dichlorodiphenyltrichloroethane), 2,4-dichlorophenoxy‐
acetic acid, dieldrin, deguelin, diethyldithiocarbamate, paraquat, maneb, trifluralin and
parathion (Figure 2) [15,56].
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Figure 2. Experimental models in PD. Many molecules are currently used in cellular and animal models of PD, includ‐
ing pesticides as paraquat or rotenone and neurotoxins such as 6-OHDA and MPP+. Paraquat, 6-hydroxydopamine (6-
OHDA) and MPP+ easily cross cell membrane through the dopamine transporter (DA) thus inducing the formation of
α-synuclein aggregates and mitochondrial impairment with the subsequent production of ROS and quinones. Com‐
pounds, as rotenone, are extremely hydrophobic and penetrate easily the cellular membrane of neurons and astro‐
cytes. Rotenone may promote processes such as the formation of α-synuclein aggregates, and the genetic activation
through the nuclear translocation of NF-κB. Additionally, as an inhibitor of mitochondrial complex I, rotenone causes
the impairment of ATP, the generation of ROS and the release of proapoptotic molecules, such as cytochrome c that
activate caspase 9, which trigger caspases 3, 6 and 7, and induce apoptosis.

4.1. Rotenone as a Parkinson model

Rotenone is one of the most studied neurotoxic substances used as a model for PD features and
oxidative stress events in cellular and animal models [14,57]. Rotenone is a naturally occurring
isoflavonoid produced in the leaves, roots and rhizomes of the tropical legumes from the gen‐
res Derris, Lonchocarpus, and Tephrosia. It is extremely hydrophobic and crosses biological
membranes and serves as a high-affinity noncompetitive inhibitor of complex I, thus affecting
ATP generation [58]. Rotenone is commonly used in solution as a pesticide, insecticide, or in
emulsified liquid form as a piscicide [59,60].
498 Neurodegenerative Diseases

Rotenone, and other complex I inhibitors, such as MPTP, paraquat and maneb, are used as
models for assessing the environmental causes of PD [12]. Previous epidemiological studies
have supported the hypothesis that a prolonged exposure to pesticides is a risk factor for PD
[17, 57,61]. Furthermore, a recent case-control study from the NIH, which reviewed 110 PD cas‐
es and 358 controls, and observed that PD incidence was increased 2.5 times in individuals who
reported use of rotenone compared with nonusers [17]. Another study in agricultural workers
from East Texas identified a significant increased risk (OR = 10.9) of PD with the continuous use
of rotenone [53]. Although these reports raised important concerns on the use of rotenone, fur‐
ther studies are needed to assess the detailed global epidemiology of PD by this pesticide.

Much of the research on rotenone has used animal models and different routes of adminis‐
tration for evaluating its effects in the Central Nervous System (CNS), especially in neurons
[14,57]. Several groups have demonstrated that continuous systemic administration of rote‐
none to rats and mice reproduces key features of PD, including selective degeneration of the
nigrostriatal dopaminergic system, activation of astroglia and microglia, formation of cyto‐
plasmic inclusions in neurons, movement disorders, and defects in mitochondrial complex I
[11, 14, 57, 62-64]. Previous studies have shown that intracerebral administration of rotenone
damages the nigrostriatal dopaminergic pathway in rats, including the striatum fibers and
neurons [14,57]. However, the doses employed in those experiments were much higher than
the standard IC50 for rotenone. For example, doses of 2-3 mg/kg/day, similar to that reported
in platelets from PD patients, produced complex I inhibition with selective nigrostriatal de‐
generation and astrocyte activation [14,65]. In this matter, neuronal death is thought to be a
consequence of the inhibition of mitochondrial complex I, which leads to a reduction in the
energy supply and subsequent collapse of the mitochondrial membrane potential [66]. A re‐
cent study suggests that rotenone administration activates caspase-2 in mice neurons induc‐
ing the activation of downstream apoptotic effectors such as Bid, Bax, caspase 3 and 9, thus
initiating apoptosis [67]. Similarly, the exposure of human dopaminergic SH- SY5Y cells to
rotenone caused the nuclear translocation of nuclear factor κB (NF-κB) and the activation of
caspase-3, suggesting that complex I deficiency induced by rotenone can induce NF-κB-
mediated apoptosis (Figure 3) [68].

Figure 3. Rotenone-induced cell death. Astrocytic cell line ESP12 cells were treated with 30 nM of rotenone (right) or
control (right), and stained for Hoetsch 33258 to assess nuclear fragmentation. Rotenone-treated cells showed in‐
creased nuclear damage compared to controls. Scale bar, 50 μm.
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Alternatively, it has been postulated that rotenone-induced dopaminergic neuronal death

could be dependent on the inflammatory process associated with microglial activation [64]
thus indicating that rotenone differentially affects various types of CNS cells. Other previ‐
ous experiments have shown that subcutaneous administration of rotenone resulted in a
highly selective dopaminergic damage in neurons and α-synuclein aggregation, similar to
the Lewy bodies of PD [63,65]. The mechanisms by which rotenone upregulates α-synuclein
and causes its aggregation, are not well understood. A possible hypothesis is that aggrega‐
tion is probably a consequence of oxidative modifications of α-synuclein [69]. For instance,
neurons and astrocytes treated with rotenone (25 to 50 nM) showed an altered expression of
g-tubulin and a disorganization of the centrosome with aggregates of α-synuclein [70]. Simi‐
larly, other studies suggest that inhibition of mitochondrial complex I activity and facilita‐
tion of α-synuclein aggregation may be closely associated with rotenone’s selective
dopaminergic toxicity in neurons [14,65]. Furthermore, a different approach using intragas‐
trically administered rotenone (5 mg/Kg) in mice showed that the accumulation and aggre‐
gation of α-synuclein in neurons of the dorsal motor nucleus of the vagus (DMV) and the
intermediolateral nucleus (IML) in the spinal cord was accompanied by the selective loss of
dopaminergic neurons and astrogliosis, suggesting that the gastric administration of rote‐
none through the connection of the enteric nervous system (ENS) with anatomical structures
of the CNS also induces PD-like features [11,19]. Rotenone has also been shown to cause in‐
creased expression of connexin43 (Cx43), which forms gap junctions, and P2X7 receptors
that modulate cytokine secretion and gamma tubulin; these are important for the adequate
function of the cytoskeleton and organelles such as the Golgi apparatus [70-73]. Moreover,
rotenone induces astrogliosis and alterations in the expression of g-tubulin, signal transduc‐
er and activator of transcription 3 (STAT3), and connexin 43 in astrocytes [70, 72, 74].

In sum, the in vitro and in vivo evidences presented here show that dopaminergic neurons
are more sensitive to rotenone toxicity than non-dopaminergic neurons, amacrine cells of
retina and astrocytes [55, 75-77], possibly due to their lesser effective oxidative mechanisms
and reduced supply of antioxidants [30,78]. However, astrocytes are more resilient to rote‐
none treatment than neurons, being its mitochondrial dysfunction tightly associated with in‐
creased neuronal death [2-4,74].

4.2. MPTP and Parkinson

MPTP is a widely used neurotoxicant, known for the induction of Parkinson-like symptoms
such as bradikinesia, movement disorders, α-synuclein bodies, mitochondrial abnormalities,
sustained inflammation in the substantia nigra and activation of the microglia [6,10,15, 79-80].
It was initially shown that in drug addicts, who were accidentally exposed to MPTP, there was
a depletion of pigmented nerve cells in the substantia nigra, accompanied by astrogliosis and
clustering of microgliosis around nerve cells [41], thus presenting some PD-like features.

MPTP is an alipophilic prototoxin that rapidly crosses the blood-brain barrier and damage
dopaminergic neurons due to the selective uptake of the active metabolite MPP+ via the dop‐
amine transporter [80]. Similarly to rotenone, its neurotoxicity is induced by the inhibition of
mitochondrial complex I, and subsequent energy depletion [80-81]. Additionally, MPP+ has
500 Neurodegenerative Diseases

high affinity for noradrenergic and serotonergic uptake transporters [6,82], and its precur‐
sor, MPTP, has been mainly used in neuronal models with dopaminergic characteristics,
such as the dopaminergic neuroblastoma cell line SH-SY5Y [83]. In astrocytes, MPTP has
shown different (and sometimes contradictory) effects according to the experimental evi‐
dence collected in cellular and animal models. For instance, Rappold and Tieu (2010)
showed that MPTP is metabolized by the astrocytic monoamineoxidase-B (MAO-B) and
converted to the toxic cation MPP+, which is extruded to the extracellular space through the
organic cation transporter 3 (oct3) [6, 84]. Afterwards, MPP+ is taken by neighboring dopa‐
minergic neurons, thus inducing neuronal death [84]. Interestingly, silencing of oct 3 trans‐
porter in mice attenuates both the MPP+ release from astrocytes and the subsequent
impairment of dopaminergic neurons, in which makes oct3 as an important molecular target
for dopaminergic related pathologies [6,84]. On the other hand, other authors have shown
that MPP+ induces negative effects in astrocytes, such as loss of viability, impairment of en‐
ergetic metabolism of mitochondria, ROS generation and decrease in the glutamate clear‐
ance by astrocytes [81,85,86]. Taking into account the importance of MPTP, as a model for
PD, it seems that further epidemiological research is needed to address more thoroughly the
role of MPTP in astrocytic damage and PD development.

4.3. Other toxic compounds involved in Parkinson development: Paraquat and 6-OHDA

The pesticide N,N′-dimethyl-4,4′-bipyridinium dichloride (paraquat), which shares similar

structure with MPP+, impairs mitochondrial functions by inducing an augmented produc‐
tion of oxidative stress and 4-hydroxynenal in vivo [87]. Although paraquat may not be an
efficient inhibitor of mitochondrial complex I, and so does not affect dopamine uptake
[87,88], it does cause α-synuclein aggregation in C57Bl/6 mice, and alters Parkin solubility,
decreasing proteasome activity and causing cellular damage [87].

Paraquat has been previously shown to induce PD-like neuronal dopaminergic lesions in ani‐
mal models and neuronal cell lines (Brown et al., 2006; Berry et al., 2010). Additionally, epide‐
miological studies suggest that long-term exposure to paraquat is associated with PD
development [15,89]. To counteract this oxidative damage induced by paraquat, and MPTP, as‐
trocytes seem to protect dopaminergic neurons by increasing expression of antioxidant mole‐
cules, such as heme oxigenase1 (EC 1.14.99.3), glutathione S-transferase P (EC 2.5.1.18) and
glutathione [90,91]. Although this protective role of astrocytes on neuronal death by paraquat
is quite promising, only few studies address this interaction and further research is needed in
order to establish the precise effect of paraquat in astrocytes metabolism and neuroprotection.

Similarly to paraquat, 6-Hydroxydopamine (6-OHDA) is another widely used for in vivo

and in vitro animal models of PD [92]. This compound has a structure similar to dopamine
and norepinephrine and exhibits a high affinity for catecholaminergic transporters such as
dopamine DAT (Dopamine transporter). 6-OHDA induces dopaminergic neuronal death by
the increased generation of H2O2 and quinones [92]. Additionally, it causes both microgliosis
and astrogliosis, which is characterized by increased astrocytic proliferation in rat cortex
and striatum accompanied by a marked expression of GFAP [92,93]. Taking into account
that reactive astrocytes may produce various neurotrophic factors and antioxidant mole‐
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cules targeting neuronal survival, it is possible that genetic manipulation of these functions
in astrocytes may represent a promising strategy to improve dopaminergic neurons or neu‐
ral progenitor cells survival [4,23]. These neuroprotective features of astrocyte in Parkinson
are further explored in the following topic.

5. Astrocytic neuroprotection in Parkinson

Over the last years, much research has focused on specific molecules produced by astrocytes
that exert neuroprotection during brain injuries and diseases including PD, both through the
reuptake of glutamate, or by producing gliotransmitters, antioxidant enzimes such as SODs,
growth factors, peptide hormones and heat shock proteins [4,94-98]. Many of them have
shown protective effects both in dopaminergic neurons and glial cells, and have been used
in animal models and clinical trials with remarkable results (Figure 4) [31,32].

5.1. Glutathione and Parkinson

Astrocytes produce beneficial antioxidants, including glutathione, superoxide dismutases

(SODs 1, 2 and 3), and ascorbate, which are important for neuronal survival during neuro‐
degenerative processes [95,99-101].
The tripeptid glutathione, as the main antioxidant in the brain, is needed for the conversion
of methylglyoxal, a toxic by-product of metabolism, into d-lactate by glyoxalase 1 (EC
4.4.1.5) [94,95]. GSH is also important in limiting and repairing the deleterious actions of
NO, but unfortunately GSH levels can be depleted by extremely high concentrations of NO
[23]. For example, glutathione becomes rapidly oxidized to glutathione disulfide either by
glutathione peroxidase (GPx) or by enzyme-independent chemical reactions [102]. This is an
important effect against ROS formation in PD, as it helps reducing the inhibition of complex
I by NO [103]. Astrocytes possess a greater concentration of glutathione (3,8 mmol/L) than
neurons (2.5 mmol), probably due to a higher content of the astrocytic enzyme y-glutamyl‐
cysteine synthethase (EC 6.3.2.2) [6]. For example, neurons co-cultured with astrocytes ex‐
hibit higher levels of glutathione compared to neurons cultured alone, demonstrating that
astrocytes provide additional antioxidant defenses to neurons [104-106]. Additionally, an in‐
crease in glutathione peroxidase-containing cells shows to be inversely correlated with the
severity of dopaminergic cell loss in cell populations from patients with PD, suggesting that
the quantity of glutathione peroxidase in cells might be critical for a protective effect against
oxidative stress during PD [107].
The greater production of GSH by astrocytes seems to be dependent on the preferential acti‐
vation of transcription factor Nrf2 in astrocytes, which leads to a more efficient GSH synthe‐
sis and higher GSH content in astrocytes than in neurons [108]. Interestingly, Nrf2 is known
to regulate the expression of cytoprotective genes, and factors essential to neuronal survival
[6,108]. Additionally, Nrf2 knockout mice are more sensitive to mitochondrial complex in‐
hibitors such as MPTP and 3-nitropropionic acid [108], suggesting an important role of this
transcription factor in scavenging free radicals. On the other hand, decrease in glutathione is
502 Neurodegenerative Diseases

one of the earliest biochemical changes in PD and incidental Lewy body disease [109]. Addi‐
tionally, the GSH content was significantly reduced in the substantia nigra of PD patients,
suggesting that GSH depletion enhances neuronal death under certain pathological condi‐
tions [6]. Interestingly, this evidence is consistent with the data in PD patients, in which glu‐
tathione-containing cells are in regions with preserved dopaminergic neurons [52].

Figure 4. Astrocytes-mediate neuroprotection through multiple signaling pathways Astrocytes release glutathione,
which serves as precursors for neuronal GSH synthesis, and trophic growth factors such as bFGF, GDNF, and MANF. Activa‐
tion of the transcription factor Nrf2 leads to the expression of antioxidant genes, including γ-glutamylcysteine synthetase
(GS), which is involved in GSH synthesis and removal or degradation of cytotoxic molecules, such as α-synuclein.
 Astrocytes Role in Parkinson: A Double-Edged Sword 503
http://dx.doi.org/10.5772/54305

It is possible that the recovery of glutathione levels may enhance the survival of affected
neurons, either by increasing synthesis of GSH or by slowing its degradation [25]. However,
the GSH blood-brain barrier permeability is low, and clinical trials using injections of GSH
have shown little benefits [6,25,110]. Alternatively, it has been demonstrated that the use of
GSH precursors, such as glutamyl cysteine ethyl ester (GCEE) and gluthathione ethyl ester
(GEE), increases significantly the intracellular glutathione levels in neuronal cells, protecting
dopaminergic neurons against oxidative an nitrosative stress, both in animal and cellular
models [25,109]. Finally, the modulation of Nrf2 downstream signaling may be considered
as a promising strategy for enhancing the astrocytic production of GSH [108], which may
counteract the oxidative imbalance that likely affects neurons in neurodegenerative process‐
es such as PD.

5.2. Superoxide dismutases and Parkinson

Superoxide dismutases catalyze the dismutation of superoxide ions into oxygen and hy‐
drogen peroxide [23]. As such, they are an important antioxidant defense in nearly all
cells exposed to oxygen. In most mammalian cells, SOD is present in three isoforms: a
cytosolic copper, zinc superoxide dismutase (SOD1); a mitochondrial manganese super‐
oxide dismutase (SOD2); and an extracellular copper, zinc superoxide dismutase (SOD3)
[23, 112]. Given its importance in neuroprotection, SODs and other antioxidant molecules
released by astrocytes are highly studied in neurodegenerative diseases like PD and in
other oxidative-related events. Evidence that SODs defend against oxidative stress in situ
has been obtained using transgenic mutants that either overexpress or lack these antioxi‐
dant enzymes [111]. For example, the overexpression of Cu/Zn SOD was able to rescue
dopaminergic neurons and diminishes locomotor disabilities in a Drosophila mutant mod‐
el for α-synuclein overexpression [112]. Interestingly in PD patients, it has been shown,
an specific increase in SOD levels in the substantia nigra, with no changes in activities of
glutathione peroxidase, catalase and glutathione reductase (EC 1.8.1.7) [25]. A similar in‐
crease was observed in the mitochondrial isoform of SOD in the motor cortex from PD
patients [113], suggesting that SODs have a greater importance than other antioxidant
enzymes during PD development. Further research is needed in order to address the
therapeutic application of SOD in PD and other diseases.

5.3. Astrocytic chaperones and Parkinson

Chaperones belonging to the conserved family of Heat shock proteins (Hsps) are proteins
involved in the regulation of protein folding, translocation of proteins across membranes,
regulation of cell death and assembling of protein [114]. Interestingly, protein aggregates,
and misfolded proteins have been found in AD, Huntington, PD, prion disease, ALS and
other neurological injuries [115-117]. Furthermore, previous evidence suggests that forma‐
tion of unfolded proteins in astrocytes could induce the inflammatory responses previously
mentioned [117].

Many Hsps are currently being considered for the potential treatment of diseases involving
protein aggregation and misfolding such as the case of PD [116,118]. These include the chap‐
504 Neurodegenerative Diseases

erones, DJ-1, Hsp70, Hsp9- and the co-chaperone Hsp40, and members from the Bag family,
such as Bag 5, CHIP and suppression of tumorigenicity 13 (ST13) [118]. Several of these
chaperones are colocalized or associated with the PD related proteins, E3-ubiquitin ligase (E
6.3.2.19), parkin, α-synuclein and the dopamine transporter (DAT) [119].
DJ-1, also known as PARK7, is upregulated in reactive astrocytes and serves as a redox-sen‐
sitive chaperone with antiapoptotic properties [119]. DJ-1, both in normal and mutant forms,
colocalizes with Hsp70 and CHIP in the cytosol. Following oxidative stress, this molecule is
translocated to the mitochondria, where it becames associated with the chaperone GRP75
[119,120]. It has been previously shown that DJ-1 can suppress the aggregation and oligome‐
rization of α-synuclein, thus promoting its degradation, which is dependent on the redox
state of the cell environment [119,121]. Additionally, DJ-1 regulates signaling pathways such
P38 mitogen-activated protein kinases (MAPK; EC 2.7.11.24), apoptosis signal-regulating
kinase 1 (ASK1; EC 2.7.11.25) and protein kinase B (AKT) following cellular production of
ROS, suggesting that this chaperone is an important redox-reactive molecule during oxida‐
tive stress in PD and other age-related disorders [120].
Hsp70 family of chaperones are thought to be critical in the regulation of protein oligomeriza‐
tion and aggregation, which are believed to be central in the molecular pathogenesis of PD and
other neurodegenerative diseases [118]. For example, the overexpression of Hsp70 has been
found to protect PC12 cells, and dopaminergic neurons against MPTP toxicity [118,119]. Addi‐
tionally, the overexpression of Hsp70 in mice has been shown to reduce the amount of misfold‐
ed and aggregated α-synuclein species, suggesting a protection of this chaperone against α-
synuclein-dependent toxicity [122]. It seems that α-synuclein degradation mediated by Hsp70
occurs in the proteasome or in the lisosomes by a selective process called chaperone-mediated
autophagy (CMA) [114]. The wild type, but not a mutant form of α-synuclein is degradated by
CMA, suggesting that this mechanism is important in the formation of α-synuclein aggregates
during PD [114]. Importantly, the astrocytic clearance of α-synuclein by chaperones, like
Hsp70, may confer additional neuroprotection to dopaminergic neurons [6,114].
Chaperones located in other organelles, such as the ER, have also been studied in the devel‐
opment of neurodegenerative processes. For example, homocysteine-induced endoplasmic
reticulum protein, which is located in the ER membrane of neurons and astrocytes in the
Central Nervous System (SNC), is found accumulated in Lewy bodies, suggesting a role in
their formation and further development of PD [117]. In sum, given the central importance
of chaperones in protein homeostasis, or proteostasis, they may serve as rational targets for
the design of therapeutic strategies in neurodegenerative diseases associated with aberrant
protein folding including PD.

5.4. Growth factors and Parkinson

Several neurotrophic and growth factors have been shown to protect dopaminergic neurons
and glial cells against induced excitotoxicity by the activation of specific signaling pathways
that are responsible for cell survival and axonal sprouting [31,32]. Some of them have also
been tested in PD clinical trials with some promising results [31,32]. For example, brain de‐
rived neurotrophic factor (BDNF) and TNF protect neurons against excitotoxicity through
 Astrocytes Role in Parkinson: A Double-Edged Sword 505
http://dx.doi.org/10.5772/54305

activation of the transcription factor NF-kB, which induces the expression of antioxidant en‐
zymes such as Mn-SOD and the anti-apoptotic proteins, Bcl-2 and inhibitor of apoptosis pro‐
teins IAPs [123,124]. Additionally, the endogenous administration of BDNF was shown to
protect neurons within the substantia nigra from 6-OHDA and MPTP toxicity, both in rat
and primate Parkinson models [31].
The family of glial cell line-derived neurotrophic factor (GDNF) comprises ligands such as
GDNF, neurturin (NRTN), artemin (ARTN) and persephin. GDNF, secreted by astrocytes, is
essential for the survival of dopaminergic neurons [32]. It has been shown that GDNF ad‐
ministration by catheter increases dopaminergic neuronal resistance against 6-OHDA toxici‐
ty, but with preservation of motor functions in rat and rhesus monkey models [96].
However, clinical trials in patients that were administered GDNF in different regions of the
brain have shown mixed results and further research is needed [31, 125-127].
Insulin-like growth factors (IGFs) signaling through the phosphatidylinositol 3-kinase
(PI3K/Akt) downstream pathway can protect neurons against LPS excitotoxicity in cell cul‐
ture and in vivo [124, 128,129]. Furthermore, the activation of this signaling pathway by IGF-
I can suppress α-synuclein aggregation and toxicity, suggesting a possible therapeutically
strategy in PD [130]. Similarly to IGF-I, vascular endothelial growth factor (VEGF) affects
the survival and proliferation of endothelial cells, neurons and astrocytes in the brain, sug‐
gesting a potential therapeutic application in PD [32]. Additionally, VEGF-B (isorform B)
was found activated in a rat brain model following treatment with 40 nM rotenone, and
showed neuroprotective actions by improving neuronal survival (Falk et al., 2009). Some
studies suggest that VEGF promotes neuroprotection by signaling through the neuropilin
receptor expressed in DA neurons, and indirectly by activating the proliferation of astroglia
and by promoting angiogenesis [32,131,132]. Furthermore, the striatal injection of an adeno-
associated virus (AAV)-mediated VEGF expression provided neuroprotection and behavio‐
ral improvement in rats treated with 6-OHDA [133].
Basic fibroblast growth factor (bFGF) protects hippocampal and cortical neurons against
glutamate toxicity by changing the expression of N-methyl-D-aspartic acid (NMDA) recep‐
tors and antioxidant enzymes like superoxide dismutases and glutathione reductase [124].
Furthermore, a coculture of transgenic overexpressing FGF-2 Schwann cells with dopami‐
nergic neurons improved the survival of dopaminergic neurons and the behavioral outcome
in a parkinsonian rat model lesioned with 6-OHDA [134]. Finally, there are other neurotro‐
phic factors that have shown dopaminergical neuronal protection in Parkinson-like models,
including hepatocyte growth factor (HGF), mesencephalic astrocyte-derived neurotrophic
factor (MANF), cerebral dopaminergic neurotrophic factor (CDNF), granulocyte colony-
stimulating factor (G-CSF), and platelet derived growth factor (PDGF-CC) [31-32, 135-136].

6. Conclusions and future perspectives

In recent years a growing body of evidence has demonstrated that the malfunctioning of as‐
trocytes may contribute to various neurodegenerative diseases, including Alzheimer, ALS,
506 Neurodegenerative Diseases

multiple sclerosis, and Parkinson. Importantly, astrocytes are involved in both exacerbation
of damage and in neuroprotective mechanisms that are crucial for neuronal survival. In this
matter, astrocytes are essential for the regulation of oxidative stress and ROS production,
both in normal and in pathological circumstances.

The overexpression of antioxidant molecules such as GSH and SOD2, or chaperones such as
Hsp70 has proved to be a successful experimental approach in brain diseases, including PD.
The use of growth factors, both in animal models and in clinical trials, has shown promising
effects in protecting dopaminergic neurons and astrocytes in damaged regions by the activa‐
tion of different signaling pathways important in neuronal survival and regeneration. It is
important to mention that mitochondrial protection in astrocytes is an important asset to
maintain the energetic balance of the brain and the antioxidant production that contribute to
neuronal protection. Therefore future efforts in neuroprotective strategies should emphasize
the mitochondrial protection in astrocytes. Finally, the combination of novel drug therapies,
a better understanding of the α-synuclein clearance by astrocytes, the use of neurotoxic
models, growth factors use and other therapies that increase astrocyte survival and its anti‐
oxidant function may shed light on a prospective cure of PD in the near future.

Acknowledgements

This work was supported in part by grants PUJ IDs 4509 and 4327 to GEB.

Author details

Ricardo Cabezas1, Marco Fidel Avila1, Daniel Torrente1, Ramon Santos El-Bachá2,
Ludis Morales1, Janneth Gonzalez1 and George E. Barreto1

*Address all correspondence to: [email protected]

1 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad

Javeriana, Bogotá D.C., Colombia

2 Laboratorio de Neuroquímica e Biologia Celular, Universidade Federal da Bahía, Salvador,

Bahia, Brazil

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