Perez Lloret2017

Expert Opinion on Investigational Drugs
ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20
Renin-angiotensin system as a potential target

for new therapeutic approaches in Parkinson’s
disease
Santiago Perez-Lloret, Matilde Otero-Losada, Jorge E. Toblli & Francisco

Capani
To cite this article: Santiago Perez-Lloret, Matilde Otero-Losada, Jorge E. Toblli &
Francisco Capani (2017): Renin-angiotensin system as a potential target for new therapeutic
approaches in Parkinson’s disease, Expert Opinion on Investigational Drugs, DOI:
10.1080/13543784.2017.1371133
To link to this article: http://dx.doi.org/10.1080/13543784.2017.1371133
Accepted author version posted online: 24

Aug 2017.
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Download by: [Australian Catholic University] Date: 25 August 2017, At: 05:09
Publisher: Taylor & Francis
Journal: Expert Opinion on Investigational Drugs
DOI: 10.1080/13543784.2017.1371133
Renin-angiotensin system as a potential target for new therapeutic
approaches in Parkinson’s disease
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Short title - Drugs targeting RAS for PD treatment
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Downloaded by [Australian Catholic University] at 05:09 25 August 2017
Santiago Perez-Lloret1, Matilde Otero-Losada1, Jorge E. Toblli1, Francisco
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Capani1,2
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Institute of Cardiology Research, University of Buenos Aires, National
Research Council (ININCA-UBA-CONICET), Marcelo T. de Alvear 2270,

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C1122, Buenos Aires, Argentina

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Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud,
Universidad Autónoma de Chile, Chile

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Address for correspondence: Santiago Perez-Lloret MD PhD,

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Institute of Cardiology Research,
Marcelo T. de Alvear 2270, CP 1122
Buenos Aires. Argentina
Telephone/Fax: +54 +11 45083880/1
Email: santiagopl@conicet.gov.ar
1
Keywords: Parkinson’s Disease, neuroprotection, treatment, renin,
angiotensin.
Abstract
Introduction: Currently, available therapies for Parkinson’s disease (PD) are
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symptomatic. Therefore, the search for neuroprotective drugs remains a top
priority.
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Areas covered: In this review, the potential symptomatic or disease-modifying
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effect of drugs targeting the Renin-Angiotensin System (RAS) in PD will be
explored.
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Expert opinion: The importance of nigrostriatal local RAS has only begun to be
unraveled in the last decades. On one hand, there is a complex feedback cycle
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between RAS and dopamine (DA). On the other hand, RAS affects
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dopaminergic neurons vulnerability. Neuroprotective effects in animal PD
models have been shown for the angiotensin-converting enzyme (ACE)

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inhibitors captopril and perindopril, and the AT1 receptor antagonists losartan,
candesartan and telmisartan. These effects appear to be mediated by a

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reduction in the overproduction of reactive oxygen species (ROS). In a proof-of-
concept, randomized, double-blind, crossover study in PD patients, perindopril

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enhanced the effect of levodopa without inducing dyskinesias. There has not
been any clinical trial exploring the neuroprotective effect of RAS drugs, but one
cohort study in hypertensive patients suggested a protective effect of ACE
inhibitors on PD risk. RAS is a promising target for symptomatic and
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neuroprotective therapies in PD. Further studies in PD animal models and
patients are warranted.
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Article highlights box
• There is a complex feedback cycle between the Renin-Angiotensin System
(RAS) and striatal dopamine (DA) tone.
• Neuroprotective effects in animal PD models have been shown for the
angiotensin-converting enzyme (ACE) inhibitors captopril and perindopril
and the AT1 receptor antagonists losartan, candesartan and telmisartan.
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• In a proof-of-concept, randomized, double-blind, crossover study in PD
patients, perindopril enhanced the effect of levodopa without inducing
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dyskinesias.
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• A large cohort study in hypertensive patients, suggested a protective effect
of ACE inhibitors on PD risk.

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• RAS is a promising target for symptomatic and neuroprotective therapies in
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PD.
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1. Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative
disorder, after Alzheimer’s Disease, affecting about 1 person out of every 1,000
in their fifth decade and 19 out of every 1,000 in their eighth decade or older [1].
The number of affected people in 2030 in USA and Europe has been estimated
at over 5 million [2]. Its main clinical symptoms are bradykinesia, rigidity, tremor
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and postural abnormalities [3]. Patients also frequently present non-motor
symptoms, including cognitive impairment, mood disorders, sleep alterations,
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dysautonomia, and hallucinations, among others [4].
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Histopathological changes are mainly, but not exclusively, characterized by the
progressive loss of the nigrostriatal dopaminergic pathway because of

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degeneration of dopaminergic neurons in the substantia nigra (SN) pars
compacta, which leads the most typical motor symptoms [5]. Administration of
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levodopa to parkinsonian patients has been considered the most effective

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symptomatic treatment for the last 40 years [6].
Nigrostriatal cell loss may be related to loss of redox control, alteration of

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lysosomal activity, abnormal protein control mechanisms in the endoplasmic
reticulum (ER) and perturbation of the ER-Golgi trafficking mechanisms [7].

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These cellular abnormalities are the main factors leading to abnormal
accumulation of misfolded protein aggregates [5]. Lewy bodies constitute a

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characteristic pathological finding resulting from protein aggregation, mainly
constituted by α-synuclein (a-syn) [8].
The currently available therapies for the disease remain purely symptomatic,
while the search for disease-modifying (i.e. neuroprotective) drugs remains a
top priority [9]. In this review, the potential symptomatic and disease-modifying
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effects of drugs affecting the Renin-Angiotensin System (RAS) will be explored.
Bibliographical references were searched in Pubmed by the following string:
(RAS OR angiotensin* OR renin) AND Parkinson's disease. Articles in English,
Spanish or French were retrieved. Reference sections from retrieved papers
were also explored for database enrichment.
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2. Renin-angiotensin system in diseases of the central nervous system
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2.1 RAS pathways
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RAS plays an important role in the control of cardiovascular, renal and cerebral
functions [10]. Classically, RAS has been considered a circulating hormonal

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system, but in last decades it has become clear that organs and tissues bear a
local RAS, which plays important regulatory paracrine and/or autocrine

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functions [11]. Interestingly, recent evidence links brain RAS to cerebral blood
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flow and neuroprotection, stress, depression, seizure, alcohol consumption, and
memory consolidation, with possible roles in the etiology of Alzheimer’s disease

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and other neurodegenerative diseases [12-14].

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The classic pathway starts with the conversion of prorenin to renin in the
kidneys [15, 16]. Renin and prorenin can bind to the Prorenin/Renin Receptors
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and can also convert angiotensinogen to angiotensin I. In turn, angiotensin I is
metabolized to angiotensin II (Ang II) by the angiotensin-converting enzyme
(ACE). Angiotensin II is the main effector of this system and acts on Type I
(AT1) and type II (AT2) receptors. The signaling pathway of the AT1 receptor is
mediated by Gq/11 proteins, which activate the Ca2+ signal and protein kinase
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C (PKC)-mediated systems [17]. AT2 receptors couple to Gi protein, which
inhibits adenylyl cyclase reducing cAMP synthesis [17]. The well-known
cardiovascular effects of AT1 include vasoconstriction and the release of
catecholamines and aldosterone. Antagonists of the AT1 receptor (losartan and
related compounds) and angiotensin converting enzyme (ACE) inhibitors
(captopril and related compounds) are thus first-line antihypertensive agents.
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The AT2 receptor appears to have protective anti-inflammatory and anti-fibrotic
effects. A new type of Ang II receptor has been recently described (i.e. the non-
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AT1, non-AT2 receptor), which binds Ang II and Ang III, and appears to be an
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angiotensin clearance receptor or a highly specific angiotensinase [18].
Recently, an alternative pathway has been identified. Angiotensin converting

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enzyme 2 (ACE2) can convert Ang I to Ang(1-9) or Ang II to Ang(1-7). Ang(1-9)
can then be converted to Ang (1-7) by ACE. The latter acts on MAS1 receptors,
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which increase nitric oxide production, Akt phosporylation and have anti-
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inflammatory effects and thus may play a critical role in cardiovascular
homeostasis. Ang II can be converted to Ang III and Ang IV by the action of an
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aminopeptidase. Angiotensin III binds to the non-AT1/2 receptor while
angiotensin IV has an inhibitory effect on the interleukin 1 receptor antagonist

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(IRAP) receptor (sometimes called AT4 receptor) which results in nitric oxide
release and anti-inflammatory/anti-fibrotic effects. These pathways are

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summarized in Figure 1.
2.2 Interplay between Ang II and DA
AT1 and AT2 receptors have been observed in the basal ganglia of rats,
monkeys and human beings [19, 20] and their distribution is shown in Table 1.
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Striatal AT receptors are located in plasma membranes of spiny neurons all
through the direct and indirect pathways [20]. Angiotensin receptors are also
located at the cytoplasmic and nuclear levels [20] and, as recently shown, at the
mitochondrial level as well [21]. AT1 receptors have been reported to form
heterodimers with D2 receptors which contribute to blocking D1-dependent
neurotransmission [22].
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During the seventies, it was established that Ang II infusion could evoke
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dopamine (DA) release from rat striatal slices [23]. Further studies confirmed
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these findings and showed that Ang-induced DA release could be blocked by
the AT1 antagonists losartan or candesartan [24-26]. Furthermore, acute or

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chronic administration of losartan could per se reduce DA synthesis [27].
Notwithstanding, in one study, chronic treatment with candesartan did not

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modify striatal DA or DOPAC content but increased the expression of D1

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receptors and reduced D2’s [28]. Interestingly, Compound 21, a highly selective
non-peptide AT2 receptor agonist, also reduced DA synthesis [26]. These

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results suggest that Ang II modulates DA synthesis via AT1 and AT2 receptors
which may have opposite effects. Finally, Jenkins and colleagues tested the
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effect of chronic ACE inhibition on striatal DA content and release by using in
vivo microdialysis in awake, freely moving rats [29]. One-week perindopril

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treatment drastically increased striatal DA content compared with untreated
animals.
Effects of Ang IV and IRAP receptor inhibition on DA synthesis were studied by
microdialysis in freely moving rats [30]. Ang IV and inhibitors of the IRAP
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receptor increased striatal extracellular DA levels. These experiments are
summarized in Table 2.
Dopaminergic neurotransmission can also affect the renin-angiotensin system
(RAS). Reserpine-induced depletion of DA caused upregulation of AT1 and AT2
receptors which normalized following restoration of DA level [31]. Furthermore,
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D1 knock-out mice showed increased AT1 receptor expression in SN and
corpus striatum, decreased ACE activity and Ang I/II/III levels [32]. Conversely,
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mice overexpressing D2 receptors showed down-regulation of AT2 receptors
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[32].
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These findings suggest a complex feedback between DA and Ang II. Several
pieces of evidence suggest that activation of the AT1 receptor could induce DA
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synthesis [24-26], which might be inhibited by AT2 receptor [26]. Finally, Ang IV
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also stimulated DA synthesis, acting via the IRAP receptor [30]. This could
explain the effects of ACE inhibitors [29]. Along with this, DA could also affect
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the RAS in a tonic fashion, as observed in reserpinized rats [31]. Functional
D1/AT1 and D2/AT2 receptors’ coupling have been reported [32].

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The effects of drugs targeting RAS in dopaminergic cell lines, animal PD

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models, and PD patients are discussed herein.
3. Studies in dopaminergic cell lines
The potential neuroprotective effects of manipulating local RAS have been
assessed using PD cell lines (Table 3). Studies in vitro may offer some
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advantage over those in vivo by helping to exclude some confounding variables,
e.g.: Ang effects on brain vessel function.
Grammatopoulos and colleagues studied the effects of Ang II and losartan on 1-
methyl-4-phenylpyridinium (MPP+, a potent dopaminergic neurotoxin)-induced
neuronal loss in vitro [33]. Rat ventral mesencephalic tissue slices obtained
from E15 Sprague-Dawley embryos were cultured. Tyrosine-hydroxylase
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positive (TH+) neurons expressed by DA terminals comprised 2–5% of total
cells in cultures. After addition of MPP+, the cultures were treated with Ang II 1-
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100 nM and with either Losartan 1 µM or the AT2 antagonist PD123319 1 µM.
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Then, DA neurons were immunohistochemically quantified. Treatment with Ang
II or AT receptor antagonists alone did not affect MPP+-induced neuronal loss

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but attenuated cell death in a PD123319-sensitive fashion when they preceded
MPP+ addition to cultures, suggesting a neuroprotective effect.

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Similar cell cultures were also used to evaluate the effects of Ang II and
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losartan in the presence of rotenone, another dopaminergic neurotoxin [34].
Rotenone reduced positive TH immunolabeling by 50% compared with control

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cultures. Pre-treatment with Ang II 100 nM prevented TH+ neuronal loss.
Losartan potentiated while PD123319 abolished neuroprotection by Ang II.

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Joglar and colleagues studied the effects of Ang II and its receptors antagonists
on glial activation and DA neuron degeneration in cell cultures, and the possible
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cell signaling pathway involved as well [35]. Ensuing experiments were
performed using the pre-established protocol. Cell cultures were treated with
MPP+ and Ang II and incubated with or without AT1 or AT2 selective
antagonists. Some cultures were also incubated with either the NADPH-oxidase
inhibitor apocynin or with the NADPH-oxidase inhibitor apocynin, or both. As
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expected, blockade of AT1 receptors attenuated neurodegeneration, but only in
the absence of AT2 receptor antagonism. Interestingly, cell loss was paralleled
by microglia activation, which was also boosted by Ang II and attenuated by
AT1 antagonists. Ang II enhanced the activation of the NADPH-oxidase
complex which generates ROS and AT1 receptor antagonism reduced it.
Finally, PKC acted as a second messenger for the effects of AT1 receptor on
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NADPH activation. Inhibition of NADPH avoided dopaminergic neuronal loss
induced by MPP+ and Ang II stressing the relevance of NADPH activation to
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the pro-degenerative effects of Ang II. In microglial cells, this cascade appears
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to end with the secretion of TNF-alpha [36]. Furthermore, administration of TNF-
α inhibitors reduced dopaminergic cell loss.

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Other in vitro studies showed that Ang II increased VEGF expression in cultured
embryonic mesencephalic cells [37] and stimulated progenitor cells

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differentiation to dopaminergic neurons following Ang II 100 µM addition to the

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culture medium for 7 days [38]. This effect was insensitive to AT1 antagonists,
could be blocked by AT2 antagonists and did not affect GABAergic or

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serotoninergic neurons. Villar-Cheda and colleagues evaluated the contribution
of the RhoA/ROCK (Rho-associated protein kinase) pathway to neurotoxic

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parkinsonian neurodegeneration in mesencephalic cell cultures [39]. This
signaling pathway is involved in Ang II-induced inflammatory arteriosclerotic and

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coronary lesions [40]. Inhibition of ROCK protein protected against MPP+ lesion
in cultures treated with or without Ang II. As described above, renin effects have
been evaluated using primary mesencephalic cell cultures in the presence of
the potent dopaminergic neurotoxin hydroxydopamine (6-OHDA) [41]. The co-
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administration of the 'Handle Region Peptide' could reduce cell loss induced by
the neurotoxin acting as an antagonist of renin on prorenin receptor.
In Lu and colleagues’ study, rotenone was used to induce DA cell loss in
catecholaminergic CATH.a cell cultures derived from mouse DA-containing
neurons [42]. Cultures were treated with Ang II and with AT2 receptor agonists
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and antagonists. Results showed that the AT2 agonist CGP42112 reduced
rotenone-induced oxidative stress, elevated the concentration of ROS
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scavengers SOD (superoxide dismutase) and glutathione, and it reduced
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NADPH-oxidase activation by Ang II. The effects were fully abolished by the
AT2 receptor antagonist PD123319. Further studies revealed that Ang II

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induced apoptosis depending on mitochondrial activity and involving the
activation of AT1 receptors [43]. Ang II also activated autophagy and triggered
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apoptosis in a dose-dependent losartan-sensitive fashion in CATH cells [44].

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The effects of RAS manipulations on PD neurodegeneration have also been

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studied using a genetic approach. Alpha-synuclein (aSyn) overexpression in the
human neuroglioma H4 cell line reproduced a PD model in vitro [45]. Equimolar

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ratios of plasmids carrying untagged a-syn, its C-terminal tagged version, and
synphilin-1, were transfected to human H4 neuroglioma cells leading to

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overexpression and deposition of a-syn fibrils. Cultures were treated with Ang II
or Ang IV, and with AT1 and AT2 antagonists or without them. Transfection
resulted in remarkable overexpression of a-syn, which was reduced by Ang II.
Moreover, losartan or PD1243319 addition enhanced Ang II protective effects.
Ang IV reduced a-syn overexpression only in the presence of losartan and
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PD1243319. These results suggest that the alternative RAS pathway may be
involved in Ang inhibitory effect on a-syn overexpression [45].
In summary, the information provided by studies using in vitro PD models
suggests AT2 and AT1 receptors activation results in opposing effects so that
neuroprotection induced by Ang II would depend on their relative activity.
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Indeed, activation of the AT2 appears to significantly increase DA neurons
viability. RAS neuroprotective effects appear to be mediated by a reduction of
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NADPH oxidase activity, by an increase of ROS scavengers, and reduced a-syn
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overexpression. The purported role of the alternative RAS pathway in
neuroprotection merits further research.

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4. Animal studies
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Animal PD models developed in the 80s’, after the discovery of the neurotoxic
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effect of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [46]. Other
classical PD animal models include the 6-OHDA-lesioned rodents and the

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rotenone-treated rodents and primates characterized by neurotoxic-damaged
dopaminergic neurons that developed motor symptoms compatible with those of

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PD [47].
The use of toxin models is most useful in drugs screening for symptomatic
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treatment of the disease whereas transgenic or knockout models are useful in
genetic studies on PD [47]. However, the majority of toxin models have the
disadvantage of reproducing late stages of PD. In contrast, the use of genetic
models obtained via overexpression or knockout technology allow studying the
disease from early on.
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Potential neuroprotective effects of RAS-targeted drugs are summarized in
Table 4 and described below.
4.1 Effects of angiotensin-converting enzyme inhibitors
The neuroprotective effects of captopril have been explored in 6-OHDA-
lesioned rats [48]. Captopril prevented DA cell loss and the increase of the ROS
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markers thiobarbituric acid reactive substances (TBARS) in the striatum and
ventral midbrain. Similar results were observed in the MPTP-treated rodents
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[49, 50].
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Perindopril also showed neuroprotective effects in MPTP-lesioned mice [51].
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Furthermore, the drug could block the increases in GFAP (glial fibrillary acidic
protein)-positive astrocytes in the striatum and SN after MPTP treatment [52].

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Protection from neuronal and glial SOD was noticed in both the striatum and SN
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after MPTP treatment as well.
In another study, administration of perindopril increased DA striatal content in

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both MPTP-lesioned and control animals [53]. Perindopril was administered
either immediately or two weeks after MPTP administration. In non-lesioned

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control animals, perindopril increased striatal DA content. Perindopril increased
striatal DA content and reversed the MPTP-related overexpression of D2

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receptors only 2 weeks after MPTP, though not immediately after. These results
are suggestively unrelated to neuroprotection and open the possibility that
perindopril pro-dopaminergic effects might involve unknown peripheral or
central factors.
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4.2 Effects of AT1 receptor antagonists
The effects of the AT1 receptor antagonist losartan p.o were studied in MPTP-
lesioned C57BL/6 mice [33]. Losartan pre-treatment reduced MPTP-induced
cell loss from 61.8% in saline-treated animals to 25% preserving dopaminergic
innervation of the striatum.
Candesartan induced comparable neuroprotection in MPTP- and 6-OHDA-
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lesioned C57BL/6 mice [35, 54] and in rotenone-trated rats [55]. Candesartan
could also counteract MPTP-induced microglial and astrocyte activation [35, 54]
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and prevented the increase in the expression of GRP78 (glucose-regulated
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protein), ATF4 (activating transcription factor 4), CHOP (CCAAT/Enhancer-
Binding Protein Homologous Protein) and Puma (p53 up-regulated modulator of

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apoptosis) proteins. The ATF4–CHOP–Puma signaling pathway has been
identified as a key regulator of the endoplasmic reticulum (ER) stress-induced

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neuronal death [56] contributing to abnormal protein folding in PD [7].

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Sathiya and colleagues observed that telmisartan pre-treatment could prevent
MPTP-induced dopaminergic neurodegeneration and motor impairment [57].

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Interestingly, telmisartan also reduced the expression of a-syn and increased
BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived

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neurotrophic factor) levels [57], and decreased ER stress-mediated neuronal
apoptosis and inhibited the IRE1α-TRAF2 (inositol-requiring enzyme 1- TNF

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receptor-associated factor 2) -caspase-12 apoptotic pathway [58]. Furthermore,
the PPAR-gamma receptor antagonist GW9662 completely blocked
neuroprotection by telmisartan in the MPTP-lesioned mice [59]. Activation of
PPAR-γ (peroxisome proliferator-activated receptor gamma) receptors have
proved neuroprotective in PD animal models [60].
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The neuroprotective role of the AT1 receptor was also studied comparing MPTP
effects in wild and in homozygous AT1a-deficient mice lacking the major mouse
AT1 isoform and the closest murine homolog to the single human AT1 [39]. The
number of TH+ neurons in the substantia nigra pars compacta was similar in
AT1-null and wild-type mice. Conversely, AT1-null mice showed less MPTP-
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induced neurotoxicity and were refractory to the MPTP-induced expression of
RhoA and Rock II proteins.
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4.2.1 Effects on levodopa-induced dyskinesias
Levodopa-induced dyskinesias (LIDs) are abnormal choreoathetotic movements

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resulting from dopaminergic hyperstimulation by striatum denervation [61]. They
eventually affect almost all PD levodopa-treated patients, are incapacitating and

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therapeutic options are by now limited.

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Muñoz and colleagues studied the effects of candesartan on LIDs using 6-
OHDA-lesioned rats [37]. As expected, l-DOPA subcutaneous administration

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induced severe LIDs. Simultaneous administration of candesartan reduced the
severity of limb and orolingual without modifying axial LIDs or affecting

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antiparkinsonian l-DOPA efficacy. Post-mortem experiments revealed an
increase of VEGF and IL-1β mRNA expression in the lateral striatum of 6-

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OHDA lesioned rats that could be blocked by candesartan. This evidence
positions the nigrostriatal local RAS system as a promising target for treating
LIDs.
5. Studies in PD patients
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Levodopa, DA agonists and inhibitors of the DA metabolizing enzymes MAO-B
and COMT restore the nigrostriatal dopaminergic tone and are efficacious for
the treatment of PD motor symptoms [62]. These drugs notwithstanding have
no effect on the underlying neurodegenerative process [9, 63]. The
development of new neuroprotective drugs capable of reducing PD progression
is therefore a major yet unmet need in PD [9, 63]. Alterations of RAS pathways
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in PD patients and the potential use of RAS-targeting drugs for its treatment
have been explored in a few studies which are reviewed in the next sections
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and summarized in Table 5.
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5.1 Alterations of the RAS pathway in PD patients
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The density of AT1 and AT2 receptors was studied using post-mortem human
brain tissue of patients with clinical and neuropathological PD diagnosis and

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age- and sex-matched neuropathologically healthy patients [19]. Specific AT1

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radiolabeling decreased by roughly 70% in both caudate and putamen nuclei
and 90% in the SN of Parkinson's compared with healthy patients. Also, specific
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AT2 radiolabeling decreased around 60% in the caudate nucleus of PD patients
but not in other basal ganglia nuclei compared with the healthy patients.
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Zawada and colleagues studied the distribution of the AT1 receptor and NADPH
oxidase in post-mortem nigral dopaminergic neurons and microglia of 5

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diagnosed PD patients, of 3 pre-symptomatic patients with PD neuropathology,
and of 7 neurologically and neuropathologically healthy age-matched patients
[64]. Both presymptomatic and PD showed reduced AT1 immunoreactivity
compared with healthy patients not only due to overall dopaminergic cell loss
but also to reduced binding per neuron. Conversely, AT1 nuclear expression
17
increased in presymptomatic PD and PD patients. Interestingly, NADPH
oxidase colocalized with nuclear AT1 receptors. The authors suggested that
pathologic changes involving nuclear AT1 activation by Ang II, which in turn
could switch-on NADPH oxidase activity damaging the nuclear material, could
be a physiopathological hallmark of PD.
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Plasma concentration of RAS components was determined using samples of 30
PD patients and 20 controls matched by age, gender, body mass index and
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educational level [65]. Plasmatic levels of Ang I, Ang II and Ang-(1-7) were
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lower in PD patients than in controls. The groups were indistinguishable
according to ACE activity. The decrease of RAS components was associated

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with increased severity of depressive symptoms in PD patients, as evaluated by
the Beck Depression Inventory (BDI). Interpretation of these results poses

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difficulties. It is uncertain whether plasma AT level variation mirrors CNS

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changes. In this regard, orthostatic hypotension was not determined and limits
stating such inference from the study outcome. Even though the inverse
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association between RAS component levels and depression agrees with some
findings in depressive patients [66], this relationship is unclear and merits more
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research.
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Cerebrospinal fluid (CSF) ACE activity had been hypothesized to reflect ACE
activity in non-cortical brain regions as the basal ganglia and was evaluated in
PD patients [67]. The study included 88 non-demented PD (35 untreated and 53
on antiparkinsonian drugs), 18 demented PD (5 untreated and 13 under
treatment), 18 MSA (multiple system atrophy) patients and 20 controls. The
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activity of ACE increased only in PD patients under dopaminergic treatment.
Nevertheless, the outcome of this study needs careful analysis as these results
may reflect the progression of the disease, or the effects of dopaminergic drugs.
Association between genetic polymorphism of the ACE gene and increased risk
of PD was found involving 127 sporadic PD patients and 198 healthy controls in
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a case-control study [68]. The results were independent of the presence of
hypertension, hyperlipemia, stroke or smoking. However, other studies reported
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no such association in nonchinese PD patients and controls [69, 70].
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5.2 Symptomatic effects of drugs targeting RAS
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The potential antiparkinsonian effects of perindopril were studied using a proof-
of-concept, double-blind, placebo-controlled, crossover study protocol in 7

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patients [71]. They all had mild to moderate PD (Hoehn & Yahr stage 3) and
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received mid-to-high doses of levodopa (375 to 900 mg/day). One patient was
on bromocriptine, another on amantadine and another one on selegiline,

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tolcapone, and trihexyphenidyl. All of them were fluctuators and had dyskinesia.
Exclusion criteria were the presence of renal impairment, postural hypotension,

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allergy to ACE inhibitors or prior treatment with ACE inhibitors, potassium
supplement, lithium or diuretics. Patients received perindopril 2 mg the first

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week and 2 mg the second week or matching placebo [71]. They received 200
mg L-dopa and 50 mg carbidopa challenge at the beginning and end of each
treatment period. Dyskinesia and parkinsonian symptoms severity according to
the modified Webster scale were assessed every 30 minutes from dosing. After
the standard dose, blood sampling was performed at frequent intervals.
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One patient withdrew from the study while on 2 mg of perindopril due to
symptoms of nausea, malaise and increased ‘off’ periods [71]. No other adverse
events were reported. Following perindopril, the area under the curve of
Webster score increased and the latency to motor response shortened.
Maximum dyskinesia score decreased during the acute challenge after
perindopril. Daily ‘on’ time increased according to home diaries. No significant
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changes were observed in subjects on placebo. These data suggest that
perindopril might have an interesting symptomatic antiparkinsonian effect.
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5.3 Neuroprotective effects of drugs targeting RAS
Attempts to retrieve clinical trials testing the potential neuroprotective effects of

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drugs affecting the RAS system were unsuccessful. Nevertheless, a few
epidemiological studies have evaluated the association between exposure to

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antihypertensive drugs, including those targeting RAS, and PD risk.

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Becker and colleagues investigated the association between exposure to
antihypertensive drugs and PD using the UK-based General Practice Research

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Database [72]. This case-control study compared the exposure to these drugs
between 3637 PD patients and a similar number of controls. PD patients and

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controls were not different as concerned to rate of exposure to ACE inhibitors or
AT1 receptor antagonists. However, having considered 90 days of exposure to

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ACE inhibitors before the index date could bias establishing a potential
relationship with the development of PD [73]. Notwithstanding, another case-
control study that defined exposure based on prescription dating from at least
two years before the index date yet reported similar results [74]. One cohort
study found a lower risk of PD associated with a higher cumulative use of ACE
20
inhibitors and Ang II receptor antagonists in 65000 hypertensive patients of the
Taiwanese National Health Insurance Research Database (NHIRD) [75].
6. Conclusion
In the beginning, the RAS was considered a key neuroendocrine circuit involved
in blood pressure regulation. Evidence over the last decades suggests the
t
ip
existence of local RAS in several organs playing other roles. Nigrostriatal local
RAS likely participates in the regulation of dopaminergic neurotransmission,
cr
blood flow, and inflammatory responses. The complex interplay between Ang
us
and DA depends on the balance between D1, D2, AT1 and AT2 receptors. The
D1 receptor stimulates while the D2 receptor inhibits Ang production. Likewise,

an
AT1 receptors increase while AT2 receptors inhibit DA tone. Interestingly, PD
patients appears to have reduced Ang II binging in basal ganglia [19], but it is
M
not clear if this a cause or a consequence of PD neurodegenerative process.

ed
Additional observations in non-parkinsonian animals, dopaminergic cell lines,
and PD animal models suggest that RAS-targeted drugs might have

pt
neuroprotective effects. In dopaminergic cell lines, Ang II administration
stimulated stem cells’ differentiation to dopaminergic neurons and reduced

ce
MPP+- or rotenone-toxicity acting on AT2 receptors. Ang II reduced a-syn
expression likely involving the additive effect of both AT1 and AT2 receptors.
Ac
The ACE inhibitors captopril or perindopril and the AT1 receptor blockers
losartan, candesartan and telmisartan showed significant neuroprotective
effects (Table 4). Perindopril also increased dopaminergic tone unrelated to
neuroprotection. Furthermore, candesartan reduced levodopa-induced
dyskinesias and did not affect levodopa antiparkinsonian efficacy.
21
Regrettably, these findings have not been translated into clinical trials,
notwithstanding a large cohort study in hypertensive patients suggests that ACE
inhibitors users might have a mildly but confirmed lower risk of PD.
A relatively small clinical trial in moderately affected PD patients showed that
perindopril could not only enhance levodopa antiparkinsonian effects but also
reduce their latency. Even though levodopa-induced dyskinesias might have
t
ip
decreased as well, results are less clear in this regard. These results agree with
those in MPTP-treated mice showing increased striatal DA content by
cr
perindopril [53].
7. Expert opinion
us
an
Currently, the role of nigrostriatal RAS in the pathogenesis and treatment of PD
is under study. This system modulates dopaminergic tone via a complex

M
feedback mechanism. The possibility of modulating the D2-dependent indirect

ed
pathway by blocking AT1 receptors sounds promising, as it should theoretically
enhance antiparkinsonian levodopa effects without increasing dyskinesias [76].

pt
Interesting results come from studies with the ACE inhibitor perindopril. Chronic
perindopril administration increased DA levels in non-parkinsonian and MPTP-

ce
lesioned animals [53]. Besides, perindopril normalized the D2-indirect pathway
without altering the D1-direct pathway in MPTP-treated mouse. Accordingly,

Ac
perindopril enhanced levodopa effects while reducing dyskinesias in a proof-of-
concept, randomized, double-blind crossover study [71]. Regrettably enough,
no further clinical trials could be retrieved by now to confirm these data. These
results might be related to the activation of the alternative RAS pathway, which
merits further research in PD. A yet unanswered question is whether perindopril
22
effects are peripheral or central, which depends on the drug ability to cross the
blood-brain barrier. A recent study classified ACE inhibitors as central- or
peripheral-acting according to the ability to cross the blood-brain barrier
including perindopril in the former category [77]. The study compared the risk of
cognitive impairment in elder subjects exposed to drugs in each category. Only
those subjects exposed to central-acting drugs showed a reduction in the risk of
t
ip
cognitive impairment during the follow-up period. These results suggest that
perindopril might indeed be a central-acting antiparkinsonian drug. Peptide
cr
compounds like the majority of commercially available AT receptor antagonists
us
usually have restricted central bioavailability [78]. Indeed, results suggest that
candesartan and telmisartan inhibit brain AT1 receptors more effectively than
an
other AT1 antagonists like losartan or Irbesartan [79, 80]. Therefore,
development of non-peptide compounds with greater permeability at the blood-

M
brain barrier should be considered as a priority [78]. Furthermore, when

ed
exploring central effects of currently available AT1 receptor antagonists,
differences in permeability should be taken into account.

pt
Several studies have reported the neuroprotective properties of RAS-targeted
drugs using dopaminergic cell lines and rodent parkinsonian models (Tables 3
ce
and 4). Labandeira-Garcia and colleagues have recently summarized the
various mechanisms by which RAS may contribute to dopaminergic

Ac
neurodegeneration [81, 82] (Figure 2). Briefly, initial injury to dopaminergic cells
related to the presence of some factors, such as mitochondrial dysfunction,
aging-related changes, neurotoxins, and others, may be followed by increased
nigrostriatal RAS activation, which may accentuate injury feeding a vicious
circle. In dopaminergic neurons, Ang may activate NADPH oxidase, which
23
contributes to the increased intracellular production of ROS and pro-
inflammatory signals. In microglial cells, NADPH oxidase activation may
increase ROS release into the extracellular milieu, activate the RhoA/ROCK
pathway, and stimulate the release of cytokines and other pro-inflammatory
substances. Endoplasmic reticulum stress-induced apoptosis and release of
TNF-α might also contribute to neurodegeneration. The counterbalance of these
t
ip
effects via AT2 receptor activation encourages exploring AT2-targeted
neuroprotective drugs.
cr
To date, attempts to evaluate the potential effects of RAS-targeted drugs in PD
us
patients are not available. Nevertheless, ACE inhibitors showed an effect on PD
in a large cohort study but not in smaller case-control studies. The mild nature
an
of the effect may be responsible for this difference. Alternatively, high variability
in results may obey to a genetic idiosyncrasy in a selected subpopulation of

M
patients characterized by high responsiveness to ACE inhibitors, e.g.: those

ed
with RAS genes mutations. These patients might be those indicated for proof-
of-concept clinical trials. Dose selection may be another issue in PD patients

pt
who frequently experience orthostatic hypotension [83] having hypotensive
drugs contraindicated.
ce
Even though RAS classic pathway involvement in dopaminergic cell
vulnerability and function is well characterized, that of the alternative pathway is

Ac
not. Several pieces of evidence indicate that Ang(1-7), MAS or IRAP receptors
might have strong neuroprotective effects [11, 16]. Hopefully, their effects on
DA neurons vulnerability in PD animal models and the clinical effects of recently
developed Angiotensin IV analogs [84] will be investigated in the near future.
24
The RAS is a promising target for symptomatic and neuroprotective treatment in
PD. Further studies in PD animal models and patients are warranted.
Funding
National Scientific and Technical Research Council (PIP 11420100100159,
t
ip
CONICET, Argentina) and the University of Buenos Aires (UBACYT).
Declaration of Interest
cr
The authors have no relevant affiliations or financial involvement with any
us
organization or entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript. This includes

an
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

M
ed
pt
ce
Ac
25
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Syst 2015;16:459-68
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31
Reference to figures
Figure 1. Schematic representation of the classical and alternative Renin
Angiotensin System pathways. ACE: Angiontensin-converting enzyme type I;
ACE2: Angiotensin-converting Enzyme II; AT1R: Angiotensin II type I receptor;
AT2R: Angiotensin II type II receptor; NEP: neprilysin; MasR: MAS receptor.
t
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Reproduced unchanged from Arroja and colleagues [16] under a CC BY license
(https://creativecommons.org/licenses/by/4.0/).
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us
an
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ed
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32
Figure 2. Schematic representation of the role of nigrostriatal local Renin
Angiotensin System (RAS) in dopaminergic cell vulnerability. ANG:
angiotensinogen; AII: angiotensin II; AT1: angiotensin type I receptors; DA:
dopamine; E2: estrogen; NADPH: NADPH-oxidase complex; RAS: renin-
angiotensin system; ROCK: Rho-associated kinase; ROS: reactive oxygen
species. Reproduced unchanged from Labandeira-Garcia and colleagues [82]
t
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under a CC BY license (https://creativecommons.org/licenses/by/4.0/)
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an
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ed
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33
Table 1. Angiotensin receptors in brain regions relevant to PD
Region AT1 AT2 AT4
Striatum + + +
Globus Pallidus - - +
Substantia Nigra + + +
t
ip
Hippocampus + + +
cr
Locus Coeruleus + + +
Periaqueductal area - - +
us
Thalamus an
anterior + + +
centromedial - + +
M
mediodorsal - + +
reticular - + -
ed
ventrolateral - - +
ventroposterior - + +
pt
Modified from [85].

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Ac
34
Table 2. Effects of drugs targeting RAS in nigrostriatal dopaminergic
neurotransmission
Effects on
Study Subjects studied Drug and dose
DA synthesis
Dwoskin 1992 Freely moving rats Losartan 10 mg/kg s.c single dose ↓
[27]
t
Losartan 10 mg/kg s.c for 21 days ↑
ip
Ang II 0.1 ug/kg single i.v dose (after ↑
cr
chronic losartan)
Medelsohn Freely moving rats Ang II 1 µM by microdialysis at ↑ (Blocked by
us
1993 [24] striatum
an losartan 1 µM)
Losartan 1 µM by microdialysis at ↓
striatum
Brown 1996 Rat striatum slices Ang II 0.1-1.0 µM ↑ (Blocked by

M
[25] losartan 1 µM)
Losartan 1 uM 0
ed
Freely moving rats Ang II 0.1-1.0 µM by microdialysis at ↑ (Blocked by
striatum losartan 1 µM)

pt
Losartan 1 µM by microdialysis at none

ce
striatum
Jenkins 1997 Freely moving rats Perindopril 1mg/kg p.o for 7 d ↑

Ac
[29]
Mertens 2010 Freely moving rats Candesartan 10 nM and Compound ↓ (both drugs)
[26] 21 0.1-1.0 µM by microdialysis at
striatum
Dominguez- Freely moving rats Candesartan 1 mg/kg p.o for 14 d none but ↑ D1
Meijide 2014 and ↓ D2
[28]
35
Stragier 2004 Freely moving rats Ang IV 10-100 µM, various IRAP ↑
[30] inhibitors
DA: dopamine; DOPAC: 3,4-Dihydroxyphenylacetic acid (neuronal metabolite of
DA).
t
ip
cr
us
an
M
ed
pt
ce
Ac
36
Table 3. Effects of drugs targeting RAS in dopaminergic cellular lines
Cell culture / Neurotoxin Outcome Ang Ang II + Ang II +
study reference II AT1 antag. AT2 antag.
Mesencephalic
DA cells
Grammatopoulos Rotenone DA cell count ↑ ↑↑ ↓
t
2005 [34]
ip
Grammatopoulos MPP+ DA cell count 0 ↑ ↓
cr
2007 [33]
Joglar 2009 [35] MPP+ DA cell count ↓ ↑ ↓
us
Muñoz 2014 [37] MPP+ VEGF expression ↑ - -
Rodriguez None Differentiation of ↑ ↑ ↓

an
Pallares 2004 [38] progenitors to DA
neurons
M
Villar Cheda 2012 MPP+ DA cell count ↓ - -
[39]
Catecholaminergic
ed
CATH.a cell
Lu 2015 [42] Rotenone Cell viability 0 ↑ ↓

pt
Ou 2016 [43] None Mitochondria- ↑ ↓ ↑

ce
triggered apoptosis
Gao 2016 [44] None Autophagy-triggered ↑ ↓ ↑
apoptosis
Ac
Transfected
human H4 cell line
Grammatopoulos None a-syn ↓ ↓↓ ↓↓
2007 [45] overexpression
ZD7155 and PD123319 are AT1 and AT2 receptor antagonists respectively;
CGP42112 is an AT2 receptor agonist; a-syn= alpha-synuclein.
37
Table 4. Studies on drugs targeting RAS using animal PD models
PD model RAS treatments Results of RAS intervention
ACE inhibitors
Lopez-Real 2005 6OHDA / Captopril 55 mg/kg s.c. Reduced neuronal loss and
[48] rat before and after 6OHDA oxidative damage
Muñoz 2014 [37] MPTP / Captopril 20 mg/kg s.c before Reduced neuronal loss and
mouse MPTP oxidative damage
t
ip
Sonsalla 2013 MPTP / Captopril 20 mg/kg s.c before Reduced neuronal loss and
[50] mouse MPTP increased DA striatal content
cr
MPP+ Captopril 7.5 mg/kg/day s.c Reduced neuronal loss and
us
chronic during MPP+ increased DA striatal content
infusion /
rat
an
Kurosaki 2004 & MPTP / Perindopril 0.2-1 mg/kg Reduced neuronal loss and
2005 [51, 52] mouse before and after MPTP increased DA striatal content.
M
Reduced glial inflammatory
reaction and SOD activity

ed
Jenkins 1999 [53] MPTP / Perindopril 5 mg/kg/day 1 or Increased DA content and
mouse 14 days after MPTP reduced D2 receptor

pt
overexpression when
administered 14 days after

ce
MPTP
AT1 antagonists
Ac
Grammatopoulos MPTP / Losartan 90 mg/kg before Reduced neuronal loss
2007 [33] mouse and after MPTP
Joglar 2009 [35] MPTP / Candesartan 0.5 mg/kg/day Reduced neuronal loss, glial
mouse s.c before and after MPTP inflammatory reaction and
NADPH oxidase activity
Mertens 2011 6OHDA / Candesartan 3 mg/kg/day s.c Reduced neuronal loss and
[54] rat before or after 6OHDA. increased DA striatal content
38
only when adminiatered
before 6OHDA.
Wu 2013 [55] Rotenone Candesartan cilexitil 1 Reduced neuronal loss and
/ rat mg/kg/day p.o during restored motor functioning.
rotenone Reduced ER reticulum
stress-induced neuronal
death
t
Muñoz 2014 [37] 6OHDA / Candesartan 1 mg/kg/day s.c Reduction in levodopa-
ip
rat coadministered with induced dyskinesias. No
cr
levodopa effect on the efficacy of
levodopa
us
Sathiya 2013 [57] MPTP / Telmisartan 3-10 mg/kg/day Reduced cell loss and motor
mouse p.o before and after MPTP impairment. Reduced

an
expression of a-syn and
increases in BDNF and

M
GDNF
Garrido Gil 2012 MPTP / Telmisartan 5 mg/kg/day p.o Administration of a PPAR-g

ed
[59] mouse before and after MPTP antagonists blocked the
neuroprotective effect of
telmisartan
pt
Tong 2016 [58] rotenone / Telmisartan 3 mg/kg/day p.o Reduced ER stress-mediated

ce
rat during rotenone neuronal apoptosis
Other
Ac
Villar Cheda 2012 6OHDA / Homozygous mice deficient Reduced neurotoxic effect of
[39] mouse for AT1a receptor MPTP in AT1-null mice.
Abolished activation of Rho-
kinase pathway
ER= endoplasmatic reticulum. SOD= Superoxide dismutase
39
Table 5. Studies with drugs targeting RAS in PD patients
Study Sample Design Results
Pathophysiology
studies
Ge 1996 [19] 10 PD and Post-mortem Reduced expression of AT1
10 controls binding study receptors in the striatum and SN.
AT2 were reduced only in the
t
ip
caudate nucleus
Zawada 2015 [64] 5 PD, 3 Post-mortem Reduced AT1 membrane
cr
presympto- binding and immunoreactivity in PD. Increased
us
matic PD, 7 neurochemical nuclear AT1 and NADPH oxidase
controls study expression
Pessoa Rocha 2016 30 PD and Cross-sectional Lower Ang plasmatic levels in PD,
an
[65] 20 controls comparison which correlated with depression
Konings 1994 [67] 106 PD and Cross-sectional ACE activity was increased only
M
20 controls comparison in PD under dopaminergic
treatments.
ed
Lin 2002 [68] 127 PD and Case-control Genetic polymorphism of the ACE
198 controls study gene has been associated with

pt
increased risk of PD
Mellick 1999 [69] 178 PD and Case-control No association between ACE

ce
192 controls study gene mutations and PD risk
Symptomatic effects
Ac
Reardon 2000 [71] 7 modera- Double-blind, Increased response to levodopa
tely affected crossover trial and reduction in latency to motor
PD with perindopril response
PD risk studies
Becker 2008 [72] 3637 PD Case-control Similar exposure to ACE inhibitors
and 3637 study and AT1 antagonists in PD and
controls controls
40
Ritz 2010 [74] 2000 PD Case-control Similar exposure to ACE inhibitors
and 9000 study and AT1 antagonists in PD and
controls controls
Lee 2014 [75] 65000 Cohort study A mild albeit significant reduction
hypertensive in PD risk among users of ACE
patients inhibitors
t
ip
cr
us
an
M
ed
pt
ce
Ac
41

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Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Renin-angiotensin system as a potential target

Santiago Perez-Lloret, Matilde Otero-Losada, Jorge E. Toblli & Francisco

To link to this article: http://dx.doi.org/10.1080/13543784.2017.1371133

Accepted author version posted online: 24

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Journal: Expert Opinion on Investigational Drugs

approaches in Parkinson’s disease

Santiago Perez-Lloret1, Matilde Otero-Losada1, Jorge E. Toblli1, Francisco

Research Council (ININCA-UBA-CONICET), Marcelo T. de Alvear 2270,

C1122, Buenos Aires, Argentina

Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud,

Universidad Autónoma de Chile, Chile

Address for correspondence: Santiago Perez-Lloret MD PhD,

Institute of Cardiology Research,

Marcelo T. de Alvear 2270, CP 1122

Buenos Aires. Argentina

Telephone/Fax: +54 +11 45083880/1

Introduction: Currently, available therapies for Parkinson’s disease (PD) are

Areas covered: In this review, the potential symptomatic or disease-modifying

dopaminergic neurons vulnerability. Neuroprotective effects in animal PD

models have been shown for the angiotensin-converting enzyme (ACE)

candesartan and telmisartan. These effects appear to be mediated by a

reduction in the overproduction of reactive oxygen species (ROS). In a proof-of-

concept, randomized, double-blind, crossover study in PD patients, perindopril

cohort study in hypertensive patients suggested a protective effect of ACE

inhibitors on PD risk. RAS is a promising target for symptomatic and

patients are warranted.

• There is a complex feedback cycle between the Renin-Angiotensin System

(RAS) and striatal dopamine (DA) tone.

• Neuroprotective effects in animal PD models have been shown for the

angiotensin-converting enzyme (ACE) inhibitors captopril and perindopril

and the AT1 receptor antagonists losartan, candesartan and telmisartan.

patients, perindopril enhanced the effect of levodopa without inducing

of ACE inhibitors on PD risk.

Parkinson’s disease (PD) is the second most common neurodegenerative

symptoms, including cognitive impairment, mood disorders, sleep alterations,

dysautonomia, and hallucinations, among others [4].

progressive loss of the nigrostriatal dopaminergic pathway because of

levodopa to parkinsonian patients has been considered the most effective

symptomatic treatment for the last 40 years [6].

Nigrostriatal cell loss may be related to loss of redox control, alteration of

lysosomal activity, abnormal protein control mechanisms in the endoplasmic

reticulum (ER) and perturbation of the ER-Golgi trafficking mechanisms [7].

These cellular abnormalities are the main factors leading to abnormal

accumulation of misfolded protein aggregates [5]. Lewy bodies constitute a

characteristic pathological finding resulting from protein aggregation, mainly

constituted by α-synuclein (a-syn) [8].

while the search for disease-modifying (i.e. neuroprotective) drugs remains a

Bibliographical references were searched in Pubmed by the following string:

(RAS OR angiotensin* OR renin) AND Parkinson's disease. Articles in English,

Spanish or French were retrieved. Reference sections from retrieved papers

were also explored for database enrichment.

2.1 RAS pathways

functions [10]. Classically, RAS has been considered a circulating hormonal

local RAS, which plays important regulatory paracrine and/or autocrine

flow and neuroprotection, stress, depression, seizure, alcohol consumption, and

memory consolidation, with possible roles in the etiology of Alzheimer’s disease

and other neurodegenerative diseases [12-14].