DAPUS KW

1. http://www.ncbi.nlm.nih.gov/pubmed/19673610
Expert Rev Neurother. 2009 Aug;9(8):1233-50. doi: 10.1586/ern.09.68.
Functional mechanism of neuroprotection by inhibitors of type B
monoamine oxidase in Parkinson's disease.
Naoi M1, Maruyama W.
Department of Neurosciences, Gifu International Institute of
Biotechnology, Kakamigahara, Kakamigahara, Gifu 504-0838, Japan.
mnaoi@giib.or.jp
On abstract:
Abstract
Neuroprotective therapy has been proposed for age-related
neurodegenerative disorders, including Parkinson's disease. Inhibitors of
type B monoamine oxidase (MAOB-Is), rasagiline and (-)deprenyl, are the
most promising candidate neuroprotective drugs. Clinical trials of
rasagiline in patients with Parkinson's disease suggest that rasagiline may
have some disease-modifying effects. Results using animal and cellular
models have proved that the MAOB-Is protect neurons by the intervention
of 'intrinsic' mitochondrial apoptotic cascade and the induction of
prosurvival antiapoptotic Bcl-2 and neurotrophic factors. Rasagilinerelated MAOB-Is prevent mitochondrial permeability transition induced
by various insults and activation of subsequent apoptotic cascades:
cytochrome c release, casapase activation, and condensation and
fragmentation of nuclear DNA. MAOB-Is increase transcription of
prosurvival genes through activating the nuclear transcription factor-(NF)
system. Rasagiline increases the protein and mRNA levels of GDNF in
dopaminergic SH-SY5Y cells, whereas (-)deprenyl increases those of
BDNF. Systemic administration of (-)deprenyl and rasagiline increases
these neurotrophic factors in the cerebrospinal fluid from patients with
Parkinson's disease and nonhuman primates. This review presents recent
advances in our understanding of the neuroprotection offered by MAOB-Is
and possible evaluation of neuroprotective efficacy in clinical samples is
discussed
2. 19
januari
2015
pukul
21.00
http://www.ncbi.nlm.nih.gov/pubmed/20624440
Neurochem Int. 2010 Nov; 57(5): 525529.
Rasagiline protects against alpha-synuclein induced sensitivity to
oxidative stress in dopaminergic cells.
Chau KY1, Cooper JM, Schapira AH.
Department of Clinical Neurosciences, UCL Institute of Neurology,
London, United Kingdom.
1

On abstract :
Abstract
Rasagiline is a propargylamine and irreversible monoamine oxidase
(MAO) B inhibitor used for the treatment of Parkinson's disease (PD). It
has demonstrated neuroprotective properties in laboratory studies. Current
concepts of PD aetiopathogenesis include the role of alpha-synuclein,
protein aggregation, free radical metabolism and mitochondrial
dysfunction in contributing to cell death. We have used a combination of
alpha-synuclein and free radical mediated toxicity in a dopaminergic cell
line to provide a model of nigral toxicity in order to investigate the
potential molecular mechanisms that mediate rasagiline protection. We
demonstrate that rasagiline protects against cell death induced by the
combination of free radicals generated by paraquat and either wild-type or
A53T mutant alpha-synuclein over-expression. This protection was
associated with a reduction in caspase 3 activation, a reduction in
superoxide generation and a trend to ameliorate the fall in mitochondrial
membrane potential. Rasagiline induced an increase in cellular glutathione
levels. The results support a role for rasagiline in protecting dopaminergic
cells against free radical mediated damage and apoptosis in the presence of
alpha-synuclein over-expression. The data are of relevance to the
interpretation of the potential mechanisms of action of rasagiline in
explaining the results of disease modification trials in PD.
3. http://www.ncbi.nlm.nih.gov/pubmed/12057839
Neurosci Lett. 2002 Jun 28;326(2):105-8.
An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan
(rasagiline), enhances expression of anti-apoptotic bcl-2 in human
dopaminergic SH-SY5Y cells.
Akao Y1, Maruyama W, Yi H, Shamoto-Nagai M, Youdim MB, Naoi M.
ifu International Institute of Biotechnology, Mitake, Kani-gun, Gifu,
Japan.
On abstract:
Abstract
N-Propargyl-1(R)-aminoindan (rasagiline) is now under phase III clinical
trials for Parkinson's disease (PD), and it rescues dopamine neurons from
cell death in animal and cellular models of PD. Recently, we proved that
rasagiline protected dopaminergic SH-SY5 cells against apoptosis induced
by a dopaminergic neurotoxin, N-methyl(R)salsolinol, and the mechanism
was clarified to be due to suppression of death signal transduction in
mitochondria. In this paper, the effects of rasagiline on the levels of antiapoptotic bcl-2 gene family were studied. Rasagiline increased the levels
of bcl-2 and bcl-x(l) mRNA at 100-10 nM and 100-10 pM, but not the
level of pro-apoptotic bax mRNA. Enhanced expression of bcl-2 family
indicates the ability of rasagiline to adjust the apoptotic threshold and
2

protect degenerating neurons in PD.

4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/
-Synuclein in Parkinson's Disease
Leonidas Stefanis
Laboratory of Neurodegenerative Diseases, Biomedical Research
Foundation of the Academy of Athens, and Second Department of
Neurology, University of Athens Medical School, Athens 11527, Greece
Copyright 2012 Cold Spring Harbor Laboratory Press; all rights
reserved
On abstract:
-Synuclein is a presynaptic neuronal protein that is linked
genetically and neuropathologically to Parkinson's disease (PD). Synuclein may contribute to PD pathogenesis in a number of ways, but it
is generally thought that its aberrant soluble oligomeric conformations,
termed protofibrils, are the toxic species that mediate disruption of cellular
homeostasis and neuronal death, through effects on various intracellular
targets, including synaptic function. Furthermore, secreted -synuclein
may exert deleterious effects on neighboring cells, including seeding of
aggregation, thus possibly contributing to disease propagation. Although
the extent to which -synuclein is involved in all cases of PD is not clear,
targeting the toxic functions conferred by this protein when it is
dysregulated may lead to novel therapeutic strategies not only in PD, but
also in other neurodegenerative conditions, termed synucleinopathies.
The first link of Parkinson's disease (PD) to -synuclein was also
the first conclusive demonstration of a genetic defect leading to PD, and
thus has historical and conceptual value. Although familial contribution to
the disease was discussed by some, it was felt to be minor at best by most.
The tangible discovery of a gene defect linked to PD in particular families
was a ground-breaking discovery, as it opened the door to a flood of
studies investigating the genetic base of the disorder, culminating in more
recent genome-wide association studies (GWAS), that, remarkably, have
made a full circle back to the origins of the molecular genetic era of PD; it
turns out that one of the major genes identified as linked to sporadic PD is
none other than SNCA, the gene encoding for -synuclein.
A parallel story that has developed over the years is the abundant
abnormal -synuclein pathology that characterizes neuropathological
specimens derived not only from PD patients, but also patients with other
neurodegenerative conditions, collectively termed synucleinopathies.
The ability to model abnormal -synuclein accumulation in various
cellular and animal models has led to the study of the consequences of
such accumulation, to the deciphering of the molecular pathways involved,
3

and to the identification of potential therapeutic targets. Such targets may

prove of general utility, and provide the basis for future therapeutics in
most forms of PD, and, potentially, other synucleinopathies.
GENETICS OF PD AND OTHER DISORDERS WITH LINKS TO
SYNUCLEINOPATHIES
In 1997, Polymeropoulos et al. reported the first specific genetic
aberration linked to PD in a large Italian kindred, and in some Greek
familial cases. The mutation corresponded to a G209A substitution in the
SNCA gene encoding for -synuclein, resulting in an A53T amino acid
change. The pattern of inheritance was autosomal-dominant, and the
disease was early-onset, usually in the 40s. Although there was some
initial skepticism, based on the fact that the threonine was the amino acid
in position 53 in the rodent SNCA homolog, this was set aside following
the identification of two more point mutations in SNCA, leading to A30P
and E46K amino acid changes, which were associated with autosomaldominant PD (Kruger et al. 1998; Zarranz et al. 2004). The next landmark
study that linked SNCA to PD through a different mechanism identified
triplications of the SNCA locus in separate families with an autosomaldominant inheritance pattern (Singleton et al. 2003). This led to a potential
total of a duplication of the -synuclein load in such patients, and this was
confirmed later at the protein level (Miller et al. 2004). Other families
were subsequently described that harbored duplications of the gene, which
was similarly associated with autosomal-dominant disease (ChartierHarlin et al. 2004). Interestingly, a gene dosage effect exists, in that
triplication cases are earlier onset and have a more severe course compared
to the duplication cases (Fuchs et al. 2007).
When a specific genetic defect is identified in rare familial cases, it
is almost a reflex reaction to look at the same gene in the sporadic disease,
with the hope of identifying polymorphisms that may be linked to the
disease in association studies. This has not been particularly successful in
other diseases, but in the case of PD and the SNCA gene this approach has
borne fruit. Initial studies focused on the Rep1 polymorphic region located
approximately 10 kB upstream of the SNCA transcriptional initiation site.
Particular polymorphisms in this region conferred a relative risk for
sporadic PD in initial association studies, which were replicated and then
confirmed in a large metanalysis (Maraganore et al. 2006). Others studies
found associations of PD with 3 regions of the gene (Mueller et al. 2005;
Mizuta et al. 2006). Targeted association studies are, however, prone to
false positives; therefore, it is very important that the link of SNCA to
sporadic PD has been confirmed through large unbiased GWAS. SNCA,
and, in particular, the 3 region, has been a consistent hit in such studies,
and represents, of the links identified, probably the most robust one (Nalls
et al. 2011).
The conclusion from these genetic studies is that SNCA is linked to both
rare familial and sporadic PD from a genetic standpoint. It is notable that
4

the association of SNCA variants to disease has now also been extended to
multiple-system atrophy (MSA), another prototypical synucleinopathy,
which is invariably sporadic (Al-Chalabi et al. 2009; Scholz et al. 2009).
THE
INVOLVEMENT
OF
-SYNUCLEIN
IN
THE
NEUROPATHOLOGICAL PICTURE OF PD AND RELATED
DISORDERS
The genetic link of SNCA to PD in 1997 led investigators to rapidly
develop appropriate antibodies against -synuclein and use them in
histopathological sections of PD patients. -Synuclein turned out to be
robustly expressed within Lewy bodies (LBs), and, in particular, in the
halo of the inclusions (Spillantini et al. 1997, 1998; Baba et al. 1998). In
fact, -synuclein immunohistochemistry is currently the gold standard in
the neuropathological evaluation of PD. With repeated studies, three major
insights emerged: (1) -synuclein pathology in PD is not confined to the
cell soma, but is also prominent in neuritic processes, (2) it is widespread
in various brain regions in PD, and (3) it is present in a number of other
synucleinopathies, such as MSA, dementia with Lewy bodies (DLBs),
many cases of Alzheimers disease (AD) (the so-called LB variant of AD),
neurodegeneration with brain iron accumulation (NBIA) type I, pure
autonomic failure (PAF), and even a subtype of essential tremor (reviewed
in Kahle 2008). The distribution of the pathology at the cellular and
regional level is different in each disease.
Braak et al. (2003), in their seminal study of the staging of PD pathology,
used -synuclein immunohistochemistry in a large number of autopsy
cases. Based essentially on -synuclein neuritic pathology (Lewy
neurites), they suggested a six-stage scheme in which the pathology
begins first at the olfactory bulb and the dorsal vagal nucleus and
gradually follows an ascending course, culminating in widespread synuclein pathology at the later stages, involving associative cortical
regions. Notably, substantia nigra is only affected in stage 3 of this
scheme. Although there have been criticisms against this hypothesis
(Burke et al. 2008), and it does not explain the absence of clinical
symptoms in subjects who on autopsy have widespread -synuclein
pathology, or the clinical picture of DLB, it appears to hold up for the
majority, but not all, of cases examined in large cohorts of LB cases
(Dickson et al. 2010). What is important to note here is that overall in the
PD brain the majority of abnormally deposited -synuclein is in neuritic
processes. The presence of -synuclein in LBs is likely the tip of the
iceberg. In fact, Kramer and Shulz-Schaeffer (2007), using a modified
protocol termed protein aggregate filtration, showed in DLB cases a
remarkable degree of aberrant neuritic -synuclein pathology, in the virtual
absence of LBs.
Overall, it is clear that abnormal -synuclein deposition occurs early in
PD. Given the fact that such pathology may develop secondarily, for
example, owing to iron mishandling in NBIA type I, we cannot be certain
5

that it is a primary factor in the disease process. However, the generally

quite defined pattern of -synuclein pathology in PD, the cellular and
animal models of -synuclein overexpression that will be discussed, and,
most importantly, the combination with the genetic data mentioned above,
suggest that this aberrant deposition is the driving force in PD
pathogenesis. Such deposition, as mentioned, may be subtle and difficult
to detect in the absence of elaborate immunohistochemical techniques that,
it is hoped, will become more widely applicable and available.
THE STRUCTURE AND FUNCTION OF -SYNUCLEIN
The SNCA gene encodes for a 140 amino acid protein, which in aqueous
solutions does not have a defined structure, hence the term natively
unfolded protein. -Synuclein, however, does form -helical structures on
binding to negatively charged lipids, such as phospholipids present on
cellular membranes, and -sheet-rich structures on prolonged periods of
incubation. The protein is composed of three distinct regions: (1) an amino
terminus (residues 160), containing apolipoprotein lipid-binding motifs,
which are predicted to form amphiphilic helices conferring the propensity
to form -helical structures on membrane binding, (2) a central
hydrophobic region (6195), so-called NAC (non-A component), which
confers the -sheet potential, and (3) a carboxyl terminus that is highly
negatively charged, and is prone to be unstructured (Fig. 1). There are at
least two shorter alternatively spliced variants of the SNCA gene
transcript, but their physiological and pathological roles have not been
well characterized (Maroteaux and Scheller 1991; Ueda et al. 1993;
Maroteaux et al. 1988).
CONCLUDING REMARKS
It is clear from the above that -synuclein represents a valid therapeutic
target in PD and possibly in related synucleinpathies. Possible therapeutic
strategies that could be envisioned are depicted in Figure 2. Perhaps the
most promising strategy would involve small molecules that would have
the potential to alter the conformation of protofibrillar forms of synuclein and render them nonpathogenic. An example of such natural
products could be the green tea derivative EGCG (Bieschke et al. 2010) or
the natural product scyllo inositol (Vekrellis et al. 2009). It may be that
multiple therapeutic approaches will need to be used, in view of the feedforward amplification loops involved in the pathogenic effects of synuclein.
(Olanow, Stern, & Sethi, 2009)
5. Harsono, 2008. Buku Ajar Nuroogis Klinis. Yogyakarta: UGM, p.231-243
6. Zuhroni. 2010. Pandangan Islam Terhadap Kedokteran Dan Kesehatan.
Jakarta: Universitas Yarsi
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7. Jankovic J. Parkinsons disease: clinical featutes and diagnosis. J Neurol

Neurosurg Psychiatry 2008; 79:368-376.
8. C. Warren Olanow, M.D., Olivier Rascol, M.D., Ph.D., et all. A DoubleBlind, Delayed-Start Trial of Rasagiline in Parkinsons Disease.
The new england journal of medicine
N Engl J Med 2009;361:1268-78.
Copyright 2009 Massachusetts Medical Society.
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9. http://www.medicinesia.com/kedokterandasar/neurosains/penyakitparkinson/
Fauci A et al.Harrisons principal of internal medicine. 17th Ed.
San Francisco : McGraw-Hill. [e-book].
Kumar V, Abbas AK, Fausto N, Mitchell RN. Robbins basic
pathology. 8thed. Philadelphia: Saunders, 2007. p.893-895
Rahayu RA. Penyakit parkinson. In: Sudoyo AW et al [editor].
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Joesoef AA, Agoes A, Purnomo H, Dalhar M, Samino. Konsensus
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12. http://www.ncbi.nlm.nih.gov/pubmed/20517484 (Leegwater & Bortan,
2010)
Leegwater-Kim J1, Bortan E.
Clin Interv Aging. 2010 May 25;5:149-56.
The role of rasagiline in the treatment of Parkinson's disease.
Department of Neurology, Tufts University School of Medicine, Lahey
Clinic, Burlington, MA 01805, USA. leegwa00@lahey.org
Rasagiline is a novel, potent, and irreversible monoamine oxidase type B
(MAO-B) inhibitor which has been approved for treatment of PD.
Rasagiline inhibits MAO-B more potently than selegiline and has the
advantage of once-daily dosing. In several large, randomized, placebocontrolled trials, rasagiline has demonstrated efficacy as monotherapy in
early PD and as adjunctive therapy in advanced PD. In addition, rasagiline
has been shown to have neuroprotective effects in in vitro and in vivo
studies. The recently completed delayed-start ADAGIO (Attenuation of
7

Disease Progression with Azilect Given Once-daily) trial suggests a

potential disease-modifying effect for rasagiline 1 mg/day, though the
clinical import of this finding has yet to be established.
Rasagiline merupakan inhibitor monamine oxidase tipe B (MAO-B)
terbaru yang sangat poten dan memiliki efek yang irreversible. Rasagiline
telah disetujui sebagai terapi medikamentosa bagi Penyakit Parkinson.
Efek rasagiline sebagai MAO-B inhibitor lebih poten dibandingkan
selegiline dan memiliki keuntungan pada penggunaan dengan dosis sehari
sekali. Pada beberapa penelitian rasagiline telah menunjukan
kemanjurannya sebagai monotherapy maupun sebagai terapi adjuvant pada
Parkinsons Disease. Sebagai tambahan, rasagiline juga menunjukan efek
neuroprotektif pada studi in vivo dan in vitro.