A

Report

On

Recent advances and new targets for treatment

of Parkinson’s disease

By
GUNJA CHATURVEDI
(ID -2008H146101)

Submitted in partial fulfilment of the course

PHA G611: ADVANCED PHARMACOLOGY

Submitted on 13th April 2009

Submitted to

Mr. Shvetank Bhatt

(Instructor-in- Charge)

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE (BITS), PILANI,

RAJASTHAN – 333 031.
April 2009

Recent advances and new targets for treatment of Parkinson’s disease

 Recent advances and new targets for treatment of Parkinson’s
disease
What is Parkinson’s disease?

Parkinson disease (PD) is a relatively common disorder of the nervous system that afflicts patients later in
life with tremor, slowness of movement, gait instability, and rigidity.
Parkinson disease is a debilitating neurodegenerative disorder characterized by the selective loss of
nigrostriatal dopaminergic neurons and loss of DA in the striatum. Different groups of DA neurons in the
ventral midbrain exhibit differences in susceptibility to degeneration during PD. The most susceptible DA
neurons are theA9 group found in the ventral tier of the substantia nigra pars compacta.

Comparison between healthy state and PD at neuronal level

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Recent advances and new targets for treatment of Parkinson’s disease
Symptoms of PD:

 rigidity
 bradykinesia
 resting tremor
 abnormal postural reflexes
 Tremors in hands and fingers (pill-rolling) movements.
 Rigidity of muscles.
 Paucity of movement: short tottering steps, difficulty in getting started and in turning.
 Loss of balance.
 Handwriting becomes progressively smaller and gradually becomes illegible.
 Mask-like face of fixed expression; infrequent blinking.
 Excessive salivation.
 Speech is affected because patient cannot control muscles of speech; this may
give rise to false impression of mental impairment.
 Intellectual deterioration occurs in advanced cases.

List of causes of PD:

 common causes
o idiopathic Parkinson disease
o drug-related parkinsonism
o Alzheimer disease
o progressive supranuclear palsy
 uncommon causes
o hydrocephalus
o Wilson disease
o cortico-basal degeneration
o Huntington disease
o post-encephalitic parkinsonism
o manganese poisoning
o carbon monoxide poisoning
o Viral encephalitis, a rare brain inflammation that follows a flu-like infection

Some other types of PD:

1. Post encephalitic Parkinsonism – It is a viral disease.
2. Drug-induced Parkinsonism -A reversible form of Parkinsonism sometimes results
from use of certain drugs - chlorpromazine and haloperidol, for example - prescribed
for patients with psychiatric disorders. Some drugs used for stomach disorders
(metoclopramide) and high blood pressure (reserpine) may also produce parkinsonian
symptoms.

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Recent advances and new targets for treatment of Parkinson’s disease
 3. Striatonigral degeneration- In this form of Parkinsonism, the substantia nigra is only
mildly affected, while other brain areas show more severe damage than occurs in
patients with primary Parkinson's disease. People with this type of Parkinsonism tend to
show more rigidity and the disease progresses more rapidly.
4. Atherosclerotic parkinsonism- Sometimes known as pseudo Parkinsonism,
atherosclerotic Parkinsonism involves damage to brain vessels due to multiple small
strokes. Tremor is rare in this type of Parkinsonism, while dementia - the loss of mental
skills and abilities - is common. Antiparkinsonian drugs are of little help to patients with
this form of Parkinsonism.
5. Toxin-induced parkinsonism- Some toxins such as manganese dust, carbon disulfide, and
carbon monoxide - can also cause Parkinsonism. A chemical known as MPTP (1-methyl-
4-phenyl-1, 2, 5, 6- tetrahydropyridine) causes a permanent form of Parkinsonism that
closely resembles Parkinson's disease.
6. Parkinsonism accompanying other conditions- Parkinsonian symptoms may also appear
in patients with other, clearly distinct neurological disorders such as Shy-Drager
syndrome (sometimes called multiple system atrophy), progressive supranuclear palsy,
Wilson's disease, Huntington's disease, Hallervorden-Spatz syndrome, Alzheimer's
disease, Creutzfeldt-Jakob disease, olivopontocerebellar atrophy, and post-traumatic
encephalopathy.

Possible causes for development of PD:

 Neurochemical changes: PD develops as cells are destroyed in certain parts of the brain
stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells
in the substantia nigra send out fibres to the corpus stratia, grey and white bands of tissue
located in both sides of the brain. There the cells release essential neurotransmitters like.
Dopamine, (a chemical messenger in the brain) that help control movement and
coordination. Loss of dopamine in the corpus stratia is the primary defect in Parkinson's
disease. The PD disease process also appears to impair nerve endings in the heart, causing
dysautonomia-- changes in the autonomic (also called sympathetic) nervous system. Such
changes may impair the release of nor epinephrine, a hormone that regulates blood
pressure, pulse rate, perspiration, and other automatic responses to stress. Evidence
suggests this may be responsible for the abrupt drops in blood pressure when standing that
occur in PD.

 Genetic causes: Specific genetic factors appear to play a strong role in early-onset
Parkinson's disease, an uncommon form of the disease. Recent research suggests that
multiple genetic factors may also be involved in some cases of late -onset Parkinson’s
disease.

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Recent advances and new targets for treatment of Parkinson’s disease
α -SYNUCLEIN - The first genetic mutation causing PD was found in the gene encoding α- synuclein and
consisted of an alanine-to-threonine substitution (A53T).α-Synuclein likely is involved in synaptic vesicle
function, and its intracellular distribution and metabolism involve axonal transport and degradation via the
autophagic and proteasomal systems. The association of α-synuclein with vesicles has led to speculation that the
oligomerized protein may rupture cellular membranes through a pore-forming mechanism, leading to
neurotransmitter leakage and toxicity.

PARKIN - Mutations in the gene encoding parkin cause a form of autosomal-recessive, early-onset PD. Patients
with parkin-related PD show loss of nigrostriatal and locus ceruleus neurons, but, with rare exception, do not
develop classic Lewy bodies. Parkin is an E3 ligase that participates in the addition of ubiquitin molecules to
target proteins, thereby marking them for proteasomal degradation. Loss of normal parkin function is
postulated to lead to the abnormal accumulation of toxic substrates and resultant cell death.

DJ-1 - Mutations in the gene encoding DJ-1 similar to those in parkin lead to early-onset, autosomal-recessive
PD.Clinically; patients are levodopa responsive with asymmetric onset of symptoms, slow progression, and
variable severity. Behavioural, psychiatric, and dystonic features occur in patients with DJ-1 mutations. The
prevalence of DJ-1 mutations is likely less than 1% in the early-onset patient subgroup.
The exact function of the DJ-1 protein is unknown, though evidence suggests it may act as an antioxidant,
oxidation/reduction sensor and/or protease. DJ-1 is susceptible to protein S-nitrosylation that may be involved
in the control of protein activity. There is speculation as well that DJ-1 functions as a regulator of apoptosis
through interactions with several apoptosis-regulating proteins .The biology of DJ-1 links synuclein and parkin
function with the phenomenon of oxidative stress, apoptosis, and the mitochondrion — all of which play a role
in the pathogenesis of PD.

PINK-1(PTEN-induced putative kinase 1) - PINK-1 is a mitochondrial protein kinase whose substrates are
unknown.PINK-1 is induced by PTEN ( phosphatase and tensin homolog), the same protein whose activity is
suppressed by DJ-1. PINK-1 mutation may lead to mitochondrial dysfunction and increased sensitivity to cellular
stress through a defect in the apoptosis pathway.

LRRK2 (also called dardarin) - Mutation in the gene for LRRK2 (also called dardarin) was identified in 2004 as a
cause of autosomal-dominant PD. Most cases of LRRK2-related disease show typical late and asymmetric onset
of symptoms, levodopa responsiveness, and other features that are indistinguishable from sporadic disease,
although rarely, early onset, amyotrophy, gaze palsy, dementia, and psychiatric symptoms are observed. LRRK2
is a large protein, which is cytoplasmic, associated with mitochondria, and capable of autophosphorylation
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Recent advances and new targets for treatment of Parkinson’s disease
.Recent data suggests that an increase in LRRK2 kinase activity plays a role in the pathogenesis of at least 3 of
the known mutations. In addition, LRRK2 binds to parkin and leads to increased protein aggregation and
ubiquitination in a cell culture model, and disease-associated LRRK2 mutants are toxic to SH-SY5Y cells and
cortical neurons.

Other Biologic Factors

Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in
the brain where dopamine is first released. These substances are also present in other diseases that cause
dementia, such as Alzheimer's, and can occur in people without neurologic symptoms. These substances renders
neurons susceptible to oxidative stess.Another protein, beta amyloid, also increases the build-up of synuclein.
Beta amyloid is a known factor in Alzheimer's disease, and may help explain the co-existence between
Alzheimer's and Parkinson's disease in many patients.

Treatment:

Drugs, physical therapy, and surgical interventions can manage Parkinson's disease. The goals of
treatment for Parkinson's disease are to:

 Relieve disabilities
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Recent advances and new targets for treatment of Parkinson’s disease
 Balance the problems of the disease with the side effects of the medications

Treatments for Onset of Parkinson's disease

 Levodopa (L-dopa)- Levodopa, or L-dopa, has been used for years and is the gold
standard for treating Parkinson's disease. L-dopa increases brain levels of dopamine. It is
probably the most effective drug for controlling symptoms and is used in nearly all
phases of the disease.
 Dopamine Agonists. Dopamine agonist drugs mimic dopamine to stimulate the
dopamine system in the brain. They may be considered as a first choice for treating
female patients 65 years and older. These drugs include pramipexole (Mirapex),
ropinirole (Requip), and bromocriptine (Parlodel). The Food and Drug Administration
(FDA) pulled the dopamine agonist pergolide (Permax) from the market in March 2007
over safety concerns that included potentially fatal heart valve damage. In 2008, a skin
patch dopamine agonist, transdermal rotigotine (Neupro), was recalled from the
market.
 Selegiline (Eldepryl) and rasagiline (Azilect) - Selegiline is a monoamine oxidase B
(MAO-B) inhibitor that may have some mild benefit as an initial therapy.

Treatments for Off Time

Drug treatments for Parkinson disease do not consistently control symptoms. At certain points during
the day, the beneficial effects of drugs wear off, and symptoms can return, including uncontrolled
muscular motor function, difficulty walking, and loss of energy.

 Entacapone (Comtan) belongs to a class of drugs called catechol-o-methyl transferase (COMT)

inhibitors. COMT inhibitors help prolong the effects of levodopa by blocking an enzyme that
breaks down dopamine.
 Rasagiline (Azilect) belongs to a class of drugs called monoamine oxidase (MAO) inhibitors.
These drugs slow the breakdown of dopamine that occurs naturally in the brain and dopamine
produced from levodopa

Treatments for Dyskinesia

Both levodopa and dopamine agonists can cause involuntary movements (dyskinesia). Weak evidence
suggests that the antiviral drug amantadine (Symmetrel) may help reduce stiffness and improve
dyskinesia. There is also weak evidence that deep brain stimulation of the sub thalamus area may be
helpful.

Treatments for Other Symptoms of Parkinson's

 Depression- Antidepressants used for PD include tricyclics, particularly amitriptyline (Elavil).

Some studies have found that selective serotonin-reuptake inhibitors (SSRIs) -- which include
fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) -- may worsen symptoms of
Parkinson's.

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Recent advances and new targets for treatment of Parkinson’s disease
  Psychotic Side Effects-Studies indicate that clozapine (Clozaril) and quetiapine (Seroquel),
antipsychotic drugs used to treat schizophrenia, may be the best drugs for treating psychosis in
patients with Parkinson's disease. A similar drug, olanzapine (Zyprexa), should not be used for
patients with PD because it can worsen their psychotic symptoms.

 Dementia-The cholinesterase inhibitor drugs donepezil (Aricept) and rivastigmine (Exelon) are
used to treat Alzheimer’s disease. Studies suggest that these drugs may also help treat dementia
associated with Parkinson’s disease.

 Daytime Sleepiness-Modafinil (Provigil), a drug used to treat narcolepsy, is proving to be very

helpful for patients with sleepiness related to their disease.

 Drooling-Injections of very small amounts of botulinum toxin effectively reduce saliva

production and drooling. In such small amounts, the toxin is safe. Speech therapy may also help
in managing the secretions and reducing the risk of aspiration .

 Voice Loss-A relatively simple procedure using collagen injections in the neck to augment the
collagen in the vocal fold may be tried in patients who can still initiate speech. There is minimal
evidence from controlled trials for this technique, however. Speech therapy is also an option.

 Erectile Dysfunction-Sildenafil (Viagra) is proving to be very helpful for men with Parkinson's
disease who suffer from impotence.

FUTURE TRENDS:

 α –SYNUCLEIN-Methods to interrupt synuclein aggregation by reducing its expression,

increasing its degradation, impairing the formation of toxic aggregates, or inhibiting its
truncation are logical therapeutic targets.

 PARKIN- Interventions that increase proteasomal function or perhaps induce parkin expression
may be a means of neuroprotection in PD.

 DJ-1 - DJ-1 functions as a regulator of apoptosis through interactions with several apoptosis-
regulating proteins. So it is considered to be one of the genes which can be modulated in order
to slower the apoptosis of the neurons.

 PINK-1 – The role that mitochondrial dysfunction and oxidative stress play in PD pathogenesis
has led to trials of antioxidant and promitochondrial compounds, including coenzyme Q10
(CoQ10), vitamin E, and creatine, as possible neuroprotectants in the disease.

 LRRK2- Abnormal kinase activity is responsible for LRRK2-mediated disease, kinase inhibitors,
particularly LRRK2 kinase inhibitors, may have therapeutic relevance.

 Neuroprotective drugs may slow the progression of neuron loss and hence PD
onset. Several of the most promising lines of investigation include the antioxidant
coenzyme Q10 (ubidecarenone) and anti-apoptotic agents such as CEP-1347. Studies in
patients with PD with coenzyme Q10 have suggested that it slows functional decline.
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Recent advances and new targets for treatment of Parkinson’s disease

Inflammation-promoting molecules increase cell death after treatment with the toxin
MPTP. Inhibiting the inflammation with drugs or by genetic engineering prevented some
of the neuronal degeneration in these studies. Other research has shown that
dopamine neurons in brains from patients with PD have higher levels of the
inflammatory enzyme COX-2 than those of people without PD. Inhibiting COX-2 doubled
the number of neurons that survived in a mouse model for PD.

 Gene therapy is an exciting arena and includes potentially neuroprotective and

neurorestorative agents. A clinical trial aiming to replace GABA, an inhibitory
neurotransmitter with inputs to several basal ganglia structures, using sub thalamic
glutamic acid decarboxylase gene therapy is currently in Phase I trials.

 Neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) which
support survival, growth, and development of brain cells, have been shown to protect
dopamine neurons and even reverse the degeneration of nigrostriatal neurons in animal
models of PD. This drug has been tested in several clinical trials, and appeared to cause
regrowth of dopamine nerve fibres in one person who received the drug. Other
neurotrophics, such as neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF),
and fibroblast growth factor 2 (FGF-2) are under investigation, along with novel delivery
methods of administration, including direct delivery via infusions into the basal ganglia
and the use of viral vectors; thus far, these approaches have shown promising results.

 Another approach to treating PD is to implant cells to replace those lost through the
disease. Clinical trials of a cell therapy are being conducted in which human retinal
epithelial cells attached to microscopic gelatine beads are implanted into the brains of
people with advanced PD. The retinal epithelial cells produce levodopa. The
investigators hope that this therapy will enhance brain levels of dopamine.

 Another type of cell therapy involves stem cells. Stem cells derived from embryos can
develop into any kind of cell in the body, while others, called progenitor cells, are more
restricted. Neural progenitor cells derived from human embryonic stem cells were
transplanted into a rat model of PD. The cells appeared to trigger improvement on
several behavioural tests, although relatively few of the transplanted cells became
dopamine-producing neurons.
Researchers are also exploring whether stem cells from adult brains might be useful in
treating PD. They have shown that the brain's white matter contains multipotent
progenitor cells that can multiply and form all the major cell types of the brain, including
neurons.
 Non-dopaminergic strategies - Two emerging treatment approaches under
investigation are adenosine A(2a) receptor antagonists (such as istradefylline) and
glutamate AMPA receptor antagonists (such as talampanel). A2a receptors are localised
on medium spiny striatal neurons and modulate the release of GABA. A2a antagonists
also affect the release of acetylcholine from striatal cholinergic interneurons and release
dopamine from the nigrostriatal tract. Such drugs may be important not only in

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Recent advances and new targets for treatment of Parkinson’s disease
 controlling the symptoms of PD, but also in preventing the wearing off seen with chronic
treatment.

 Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique
molecule with multiple mechanisms of action and a very high therapeutic index. It
combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-
dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has
neuroprotective and neurorescuing effects in MPTP-treated mice. Safinamide
potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses
the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned
rats.

 Sarizotan, Levetiracetam and Istradefylline are being studied for improvement in Parkinson's
signs and symptoms and possibly for reduction in dyskinesias.
 Mucuna prurins is the natural source of therapeutic qualities of L-Dopa.

References:

 Goodman and Gillman

 Surgical Treatment For Parkinson's Disease , Update article by G K K Leung, MBBS, BSC, FRCS K N Hung,
MBBS, FRCS, FHKAM ,Y W Fan, MBBS, FRCS, FRACS, FHKAM Department of Neurosurgery Queen Mary
Hospital

 www.MedicineNet .com

 SPECIAL REPORT: PARKINSON'S DISEASE by The centre of Neurologic studies.


Journal of Clinical Investigation: Diagnosis and treatment of Parkinson disease: molecules to medicine by
Joseph M. Savitt, 1, 2 Valina L. Dawson, 1,2,3,4 and Ted M. Dawson1, 2, 3. 1Institute for Cell Engineering,
2
Department of Neurol ogy, 3Department of Neuroscience, and 4Department of Physiology, Johns Hopkins
University School of Medicine, Baltimore, Maryland, USA.

 Recent advances in cell-based therapy for Parkinson disease

ARNAR ASTRADSSON, M.D., OLIVER COOPER, PH.D., ANGEL VINUELA, M.D., PH.D.,AND OLE ISACSON,
M.D., PH.D.NINDS Udall Parkinson’s Disease Research Centre of Excellence, Harvard University and
McLean, Hospital, Belmont, Massachusetts ( Neurosurg Focus 24 (3&4):E5, 2008

 Novel pharmacological targets for the treatment of Parkinson's disease

Authors: Anthony H V Schapira, Erwan Bezard, Jonathan Brotchie, Frédéric Calon, Graham L
Collingridge, Borris Ferger, Bastian Hengerer, Etienne Hirsch, Peter Jenner, Nicolas Le Novère, José A
Obeso, Michael A Schwarzschild, Umberto Spampinato, Giora Davidai

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Recent advances and new targets for treatment of Parkinson’s disease
 Safinamide, from molecular targets to a new anti-Parkinson drug
C. Caccia, PhD, R. Maj, PhD, M. Calabresi, S. Maestroni, PhD, L. Faravelli, PhD, L. Curatolo, PhD, P. Salvati,
PhD and R. G. Fariello, MD NEUROLOGY 2006;67:S18-S23
© 2006 American Academy of Neurology

 www.Medscape .com

 Neuropsychiatric aspects of Parkinson’s disease: Recent advances

 Journal- Current Psychiatry Reports . Laura Marsh1 and Ariel Berk , Division of Psychiatric
Neuroimaging, Geriatric and Neuropsychiatry Programs, Department of Psychiatry and Behavioural
Sciences , Johns Hopkins University School of Medicine, 600 North W olfe Street, Phipps 300-C,
21287 Baltimore, MD, USA

 Ten Most Recent Important Advances in Parkinson's disease, BY DEE E. SILVER M.D. Coastal
Neurological Medical Group, Inc.

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Recent advances and new targets for treatment of Parkinson’s disease