Parkinson's Disease

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Parkinson's Disease

SZEGEDI TUDOMÁNYEGYETEM

Általános Orvostudományi Kar

Szent-Györgyi Albert Klinikai Központ

NEUROLÓGIAI KLINIKA

6725 Szeged, Semmelweis u. 6.

Levélcím: 6701 SZEGED, PF. 427.

Tel.: (62) 545-348, 545-351

Fax.: (62) 545-597

VECSEI@NEPSY.SZOTE.U-SZEGED.HU

UNIVERSITY OF SZEGED

Faculty of General Medicine

Albert Szent-Györgyi Clinical Center

DEPARTMENT OF NEUROLOGY

Director: Prof. László Vécsei

Semmelweis u. 6. H-6725 Szeged, Hungary

Postal address: P.O.Box 427.

H-6701 Szeged, Hungary

Phone: +36 (62) 545-348, 545-351

Fax/Message: +36 (62) 545-597

VECSEI@NEPSY.SZOTE.U-SZEGED.HU


A Parkinson-kór farmakoterápiája:

tények és lehetőségek. lehetőségek.

Prof. Vécsei László

MTA rendes tagja

Department of Neurology,

Albert-Szent-Györgyi Clinical Center,

University of Szeged

Hungary

2


Parkinson’s Disease – Definition

• Parkinson’s disease:

– A clinical and neuropathological entity characterised by:

• Bradykinesia

• Rigidity

• Tremor

– Onset usually asymmetric and responsive to dopaminergic treatment

– No historical or examination clues to indicate secondary

parkinsonism (e.g. Wilson’s disease, multiple system atrophy)

– The brunt of the early pathology falls on the dopaminergic

nigrostriatal pathway

• Parkinsonism:

– Any bradykinetic-rigid syndrome that is not Parkinson’s disease

Samii A, et al. Lancet 2004;363:1783-94.

Nutt JG, Wooten GF. N Engl J Med 2005;353:1021-7.


Epidemiology of Parkinson’s Disease – Incidence

• Idiopathic

Parkinson’s

disease is

uncommon

before the age

of 50

• There is a sharp

increase in

incidence after

the age of 60

Incidence Rate

(cases per 100,000 person-years)

de Lau LM, Breteler MM. Lancet Neurol 2006;5:525-35.

© 2006, with permission from Elsevier.

700

600

500

400

300

200

100

Spain

Rotterdam, the Netherlands

Hawaii, USA

Manhattan, USA

Taiwan, China

London, UK

Rochester, USA

Italy

China

0

30 40 50 60 70 80 90 100

Age (years)

Prospective population-based incidence studies

of Parkinson’s disease


Pathology of Parkinson’s Disease – Macroscopy

Normal Parkinson’s disease

Normal substantia nigra Depigmentation of substantia nigra

A: Rostral (R), intermediate (I) and caudal (C) transverse

planes of the mesencephalon on a sagittal MRI of the

brainstem.

B: MRI of the intermediate transverse plane. Arrows show the

emergence of the third cranial nerve fibres.

Damier P, Brain 1999;122:1421-36.

Images courtesy of JJ Hauw, Department of Neuropathology, Hôpital de la Pitié-Salpêtrière, Paris, France.


Pathology of Parkinson’s Disease – Microscopy

• Loss of pigmented dopaminergic neurons

Normal

Normal substantia nigra

Parkinson’s disease

Degeneration of nigral cells

Images courtesy of É tienne Hirsch, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France.

• Histopathological hallmark: Lewy bodies

Gibb WR, Lees AJ. Neuropathol Appl Neurobiol 1989;15:27-44.

Images courtesy of JJ Hauw,

Department of Neuropathology

Hôpital de la Pitié-Salpêtrière,

Paris, France.


Multicentric Neurodegeneration

Parkinson’s disease brain

Dopamine

Serotonin

Noradrenaline

STN subthalamic nucleus

GPi globus pallidus interna

Gpe globus pallidus externa

SNpc substantia nigra pars compacta

VTA ventral tegmental area

Lang AE, Obeso JA. Lancet Neurol 2004;3:309-16.

© 2004, with permission from Elsevier.

Caudate

Thalamus

Substantia innominata

Raphe nuclei

STN

GPi

GPe

Putamen

Amygdala

VTA

SNpc

Locus coeruleus

Pedunculopontine

nucleus


Cell Death in Parkinson’s Disease

Activation

Free radicals

signal

Iron

Nitric oxide

Excitotoxicity

Complex I deficiency

Proteasomal inhibition

Glial factors

Inflammation

Genetics ↔ Environment

?

Healthy

DA neuron

Cell death

program

Damaged

DA neuron

Courtesy of Andreas Hartmann, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France

Apoptotic

DA neuron

Abbreviation: DA, dopamine


Therapeutic Strategies in Parkinson's Disease

Symptomatic

Neuroprotective

Neurorestorative- reparative


Potential Neuroprotective Approaches

Abbreviations:

AMPA, α-amino-3-hydroxy-5methyl-4-isoxazolepropionate;

DAT, dopamine transporter;

GAPDH, glyceraldehyde-3phosphate

dehydrogenase;

iNOS, inducible nitric oxide

synthase;

MAO-B, monoamine oxidase B;

MLK, mixed lineage kinase;

MPTP, 1-methyl-4-phenyl-

1,2,3,6-tetrahydropyridine;

NMDA, N-methyl-D-aspartate;

nNOS, neuronal nitric oxide

synthase;

PARP, poly (ADP-ribose)

polymerase;

ROS, reactive oxygen species;

PPARγ, peroxisome proliferatoractivated

receptors-gamma

Reprinted by permission from Macmillan

Publishers Ltd: Dawson TM, Dawson VL. Nat

Neurosci 2002;(5 Suppl):1058-61, © 2002.

MAO-B inhibitors

MAO-B

ROS scavengers

Energy mimetics

Coenzyme Q 10

Metal chelators

nNOS inhibitors

PARP inhibitors

DAT inhibitors

MPTP

MPP+

DA transporter

Complex I

ROS, ONOO-

Iron

Heavy metals?

Necrotic Death Pathways

nNOS activation

Microglial

activation

ROS

DNA damage

PARP activation

Cell death

Ca2+ Na + /Ca2+ NMDA antagonists AMPA

NMDA

receptor

H

Apoptotic Death Pathways

Generation of the apoptosome

Caspase activation

p53 activation

ER stress

Minocycline

iNOS inhibitors

PPARγ inhibitors

Inhibitors of α-syn

toxicity

AMPA

receptor

α–syn

Altered α-syn

Conformation

oligomer/fibrils

Cell death

Caspase inhibitors

Inhibitors of ER stress response

p53 inhibitors

MLK inhibitors

GAPDH translocation inhibitors

Pathways involved in MPTP toxicity and potential

neuroprotective drugs or strategies


Symptomatic treatment of Parkinson`s disease:

various considerations

• Treatment of motor and non-motor phenomena

• Treatment of various disease stages

• Young vs. old age patients

• Pharmacological vs. other therapeutic modalities

eg.surgical,physical and psychological treatments

• Treatment of levodopa complications


Continuous dopaminergic stimulation in PD:

Clinical approaches

• Oral drugs with long t 1/2

• Duodenal L-Dopa infusion

• Continuous s.c. infusions

(Apomorphine)

• Transdermal delivery systems

iiiiiiiiiii


Nicotine

Epidemiological studies have indicated consistently that smoking can reduce the

incidence of Parkinson's disease, suggesting that smoke may contain compounds

that are potentially neuroprotective. This observation is supported by experimental

studies showing a protective effect of nicotine against neurotoxic insults.

It has been demonstrated recently, that nicotine and hydroquinone

inhibit alpha-synuclein aggregation, indicating a protective action

against nigrostriatal damage.

Moreover a variable and moderate symptomatic effect of nicotine has been also

demonstrated in Parkinson's disease. On the other hand recent data in primates

show that nicotine can attenuate levodopa-induced dyskinesias.

Taken together these observations suggest that nicotine or nicotinic

receptor ligands may be beneficial to patients with Parkinson's

disease by reducing disease progression, improving motor

symptoms, and decreasing levodopa-induced dyskinesias.

To prove this hypothesis and to clarify the previous contradicting data, a phase II,

randomized, open label, efficacy study (NICOPARK2) of transdermal nicotine

administration is currently underway.


Inosine

The natural antioxidant urate has been proposed a predictor of both risk and

progression of PD. The neuroprotective effect of antioxidants is well

demonstrated in animal models of PD. One of the endogenous antioxidant, is the

urate.

Retrospective analysis of patients who participated in the

DATATOP and PRECEPT trials, those with baseline serum urate

levels in the upper normal range displayed a 40% slower rate of

clinical progression compared to those with lower baseline level.

Similarly, dopamine transporter SPECT indicated a slower rate of loss of striatal

DAT in patients with higher baseline urate levels. This association was verified in

a clinical trial. The oral, blood-brain-barrier-penetrant, urate precursor inosine can

readily elevate serum urate level, and its effect is going to be studied in patients.

The safety of urate elevation is to be answered in this phase II clinical trial

(SURE-PD).


Creatine

Creatine (CRT) exerts neuroprotective effects in vivo against various

neurotoxins and in transgenic mouse models of both ALS and Huntington’s

disease. The mitochondrial dysfunction and energy deficit are welldemonstrated

in all neurodegenerative disorders. The CRT acts in the

mitochondria; its administration increases the brain concentrations of both

CRT and phosphocreatine (PCr) and interacts with mitochondrial isoform

of creatine kinase (Mi-CK) to inhibit mitochondrial transient pore.

Neuroprotection against MPTP had been demonstrated in mice

deficient in the Mi-CK, which suggests that the neuroprotective

effects of creatine are not mediated by an effect on UbMi-CK to inhibit

the transient pore, but by an elevation of Cr and PCr.

Several clinical trials are conducted in different disorders without providing

a robust clinical benefit. A phase III, long term (5 years of follow-up),

multicenter, double-blind, placebo controlled study in Parkinson’s disease

is underway (NET-PD LS1).


Folic acid

Folate is an essential vitamin that takes part in many essential cell functions.

Folate deficiency is related with increased level of homocysteinemia,

which is characteristic for PD.

In some patients an antibody is produced against folate that prevents it from

entering the brain properly and could worsen certain symptoms of Parkinson’s

disease. A study is being conducted to assess the impact of folate on the

progression of Parkinson’s disease.


Fipamezole

Previous studies in the MPTP non-human primate model of

Parkinson's disease have demonstrated that alpha(2) adrenergic

receptor antagonists such as fipamezole can attenuate L-dopainduced

dyskinesia.

Unfortunately, data from these studies are not always consistent and can not

translate into direct clinically significant benefit. A well-designed, phase II,

randomized, double-blind, placebo-controlled, study of the efficacy, safety and

tolerability of fipamezole in the treatment of levodopa-induced dyskinesia in

advanced Parkinson’s disease is currently recruiting patients.


Vitamin D

Based upon several lines of evidence, that documented chronically inadequate

vitamin D intake, particularly in the elderly, is a significant factor in the pathogenesis

of PD.

A Retrospective systemic analysis suggests vitamin D deficiency

occurs in vast majority patients with PD, much more frequently than

in internal medicine clinics.

In addition, low vitamin D levels have been associated with slower walking speeds,

worse memory and thinking, and depression. A phase IV, randomized, double blind,

active control, efficacy study is being conducted to evaluate high dose of vitamin D

supplementation (54,200 IU/week) on clinical symptoms of PD (VIDIP PILOT).


Coenzym Q10 (CoQ10)

The major steps in the pathophysiology of Parkinson disease are

cellular energy depletion and consequent oxidative stress leading to

cellular dysfunction and cell death.

CoQ10 is an electron acceptor bridging mitochondrial complexes I and II/III and a

potent antioxidant that consistently partially recovers the function of neurons. In a

previous phase II clinical trial, investigators demonstrated that CoQ10 at dosages of

300, 600, and 1200 mg/day was safe and well-tolerated in patients with early,

untreated PD.

The data also indicated that CoQ may slow the progression of PD as

measured by the Unified Parkinson Disease Rating Scale (UPDRS).

A randomized, placebo-controlled, phase III trial of two doses (1200 and 2400

mg/day) CoQ is initiated to confirm and extend the results of the earlier phase II

study in early PD (QE3). The study also will evaluate independent function,

cognition, and quality of life.


Levetiracetam (LEV)

Levetiracetam is widely used antiepileptic drug, which can be used to treat chronic

pain also. In an open label, small study, LEV was not well tolerated in PD patients

with moderate to severe levodopa-induced dyskinesia resulting in worsening of

some PD symptoms, intolerable somnolence, and worsening of dyskinesia in most

patients. The LEV dose was titrated up to a high level.

In another open label, pilot study PD patients who experienced peakdose

dyskinesia LEV significantly improved ‘on time’ without

dyskinesia or with nontroublesome dyskinesia. In this case the mean

dose of LEV was lower (625+/-277 mg/day).

A multicenter, randomized, double-blinded, placebo-controlled trial (LeLeDys) is

designed to determine the efficacy and safety of levetiracetam on levodopa-induced

dyskinesias in advanced Parkinson's disease.


SYN 115

SYN-115 is a potent and selective inhibitor of the adenosine 2A

receptor (A2A), which modulates the production of dopamine,

glutamine and serotonin in specific regions of the brain.

In preclinical models of Parkinson's disease and in clinical trials with A2A

antagonists, the inhibition has resulted in increased levels of dopamine and

improved the motor deficits. To prove the efficacy a phase IIa and a phase IIb trial

SYN 115 is initiated in 2009. The efficacy measures are also included fMRI studies.


Safinamide

Safinamide is a unique molecule with a novel mode of action, targeting multiple

systems, and potentially provides better motor control.

This oral alpha-aminoamide derivative of milacemide, exert as a

MAO-B and glutamate release inhibitor, inhibitor of voltage sensitive

Na+ channels and Ca++ channels and inhibits glutamate release.

The high selectivity for the sigma-1 receptor site does not entail psychotomimetic or

behavioral changes. In several experimental in vitro and in vivo conditions, SAF

exerts neurorescuing and neuroprotectant effects. In a small pilot study with high

dose of safinamide a symptomatic motor benefit was detected.

A phase III, double-blind, placebo-controlled, study is going on to investigate the

efficacy and safety of higher dose of safinamide (50-200 mg/day), as add-on

therapy in patients with early Parkinson’s disease.


Isradipine

Substantial body of evidence support the role of increased intracellular Ca++ in the

neurodegeneration. The elevated intracellular Ca++ level is produced oxidative

stress, mitochondrial dysfunction, energy deficit and excitotoxicity.

Systemic administration of isradipine, a blocker of L-type Ca++

channels confers neuroprotection in toxin models of PD, pointing to

a potential neuroprotective effect in PD with a drug class that has

been used safely in human beings for decades.

Isradipine-treated animals displayed a dose-dependent reduction in L-DOPAinduced

rotational behavior and abnormal involuntary movements. Involuntary

movements were not reduced when isradipine treatment was started concomitantly

with L-DOPA. These results indicate that isradipine, at a therapeutically relevant

dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia

in PD. To prove this hypothesis a phase II safety and tolerability trial was initialized

in 2008.


Neu 120

Neu-120 has been developed as adjunct therapy to levodopa in patients with motor

fluctuations and in patients who do not tolerate optimal doses of levodopa.

Neu-120 is a highly potent and selective uncompetitive NMDA

receptor modulator and it also inhibits MAO-B and GSK-3B activities

in vitro, without interaction with other receptors, transporters or

enzymes.

Neu-120 is aimed to improve motor symptoms and to reduce levodopa-induced

dyskinesia. Neu-120 has been tested in several experimental models of PD, and is

currently entering a randomized, double-bind, placebo controlled Phase IIa trial.


Sch 420814

Antagonism of the adenosine A(2a) receptor offers great promise in

the treatment of Parkinson's disease.

In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A)

antagonists, which led to clinical candidate SCH 420814. SCH 420814 are potent

competitive antagonists of the human A2A receptor. A randomized, single blind,

placebo control, pharmacodynamics study is initialized this year (Study

P05550AM1).


Kynurenines

Kynurenine is an intermediate in the pathway of the tryptophan metabolism. This

pathway is known to be responsible for nicotinamide adenine dinucleotide (NAD

metabolism. L-kynurenine, the central agent of this pathway, can be converted to

other important compounds: the neuroprotective, NMDA antagonist kynurenic acid

and the neurotoxic quinolinic acid. The abnormalities in the kynurenine pathwas

were demonstrated previously.

NMDA receptor antagonist can reduce L-DOPA induced dyskinesias

in animal model and administration of kynurenine-3-hydroxylase

inhibitor could delay the development of L-DOPA induced

dyskinesias in monkey.

Based on this data a clinical trial with chloro-kynurenine is being set up.


In the periphery, kynurenine has been known for decades as an intermediate in the catabolic conversion of

tryptophan to NAD (Heidelberger et al. 1949). Interest in kynurenine has increased markedly since it became

clear that two of its metabolic products quinolinic acid and kynurenic acid, act as agonist and antagonist,

respectively, at receptors for excitatory amino acids (Stone and Connick 1985).


The kynurenine/tryptophan-ratios were increased both in serum and CSF of patients

with Parkinson's disease as compared to controls. Serum tryptophan was lower in

patients with Parkinson's disease (Widner et al. 2002).

The level of 3-hydroxy-kynurenine is significantly increased in the putamen and

substantia nigra in patients with Parkinson's disease, which could contribute to the

neuronal loss in the disease (Ogawa et al. 1992).


SZEGEDI TUDOMÁNYEGYETEM

Általános Orvostudományi Kar

Szent-Györgyi Albert Klinikai Központ

NEUROLÓGIAI KLINIKA

6725 Szeged, Semmelweis u. 6.

Levélcím: 6701 SZEGED, PF. 427.

Tel.: (62) 545-348, 545-351

Fax.: (62) 545-597

VECSEI@NEPSY.SZOTE.U-SZEGED.HU

UNIVERSITY OF SZEGED

Faculty of General Medicine

Albert Szent-Györgyi Clinical Center

DEPARTMENT OF NEUROLOGY

Director: Prof. László Vécsei

Semmelweis u. 6. H-6725 Szeged, Hungary

Postal address: P.O.Box 427.

H-6701 Szeged, Hungary

Phone: +36 (62) 545-348, 545-351

Fax/Message: +36 (62) 545-597

VECSEI@NEPSY.SZOTE.U-SZEGED.HU

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