Parkinson’s Disease and Treatment

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Introduction

The shaking palsy (Parkinson - 1817)A prevalent, progressive neurodegenerative diseaseBiochemical lesion - neurodegenerationNo cure, no means to prevent the degeneration of neuronsTreatment based on knowledge of biochemical lesion

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Parkinson’s Disease

PD affects over 1 million Americans. It is second only to Alzheimer’s disease as the most common degenerative disease of neurons. Symptoms generally appear in middle age and continue becoming more and more severe with age. There is no cure available. Drug therapy can maintain functional mobility for years (prolongs/improves quality of life).

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Symptoms

TremorbradykinesiaRigidityPostural effectDementia

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Causes

Genetics?Environment?Drug inducedEnvironmental toxins?Parkinsonism and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

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Substantia nigra

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Dopamine restoration in brain

Need to restore dopamine in brainBlood brain barrier for dopamine

Levodopa as a precursor to dopamineDecarboxylation to dopamineUse of Levodopa (L-dopa)Aromatic L-Amino Acid decarboxylase

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Dopamine restoration in brain

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Central availability

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Preservation of L-DOPA and striatal dopamine

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COMT: Catechol-O-methyltransferase AADC: Aromatic L-amino acid decarboxylase DOPAC: 3,4- dihydroxyphenylacetic acid 3MT: 3-methoxyltyramine 3-O-MD: 3-O-methyl DOPA DA: Dopamine MAO-B: Monoamine oxidase-B

Side effectsPeripheral decarboxylation produces peripheral side-effectsGenerally dose-dependent and reversibleGastrointestinal (Caution: Don't use phenothiazines for nausea)Cardiac irregularities (ß-adrenergic receptors)Behavioral disturbances (role of dopamine)Special care: cardiac arrhythmias, major psychosesAbnormal involuntary movements - a serious side effect, no tolerance, may limit the dose

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Generally a combination of levodopa and carbidopa given

Gradual increase in doseCareful Individual titration neededComplications of dyskinesiasLimitations with respect to long-term treatmentNot a cure

L-Dopa/Carbidopa therapy

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Other drugsDopaminergic agonists - pramipexole, ropiniroleAnticholinergic drugs - benztropine, trihexyphenidyl

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Other drugsSelegiline & Rasagiline:

!Selective inhibition of MAO-B!MAO-B present predominantly in the striatum!Inhibition of the breakdown of dopamine by MAO-B

Entacapone: catechol-o-methyl transferase inhibitors - inhibition of dopamine degradation

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Other drugs

Amantadine: blockade of NMDA receptors -treatment of levodopa-induced dyskinesias

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Effectiveness of the treatment

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Effective relief from symptom for several yearsImplications of protection from progressive neurodegeneration

A possibility to prevent cell death?

Implications of protection from neurodegeneration

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MPTP Induced ParkinsonismA major advance in 1979 - the case of a young manLink with MPTPThe "Frozen Addict" patients

Drugs could also be protective if theyhalted other events set in motion by theinitial triggers of destruction. Iron che-lators (which segregate iron and thusblock many oxidative reactions), inhib-itors of nitric oxide formation and anti-oxidants are all being considered. Suchagents have been shown to protect dopa-mine-producing neurons of the substan-tia nigra from oxidative death in ani-mals. On the other hand, the same hu-man DATATOP trial that cast doubt onselegiline’s protective effects found thatvitamin E, an antioxidant, was ineffec-tive. But vitamin E may have failed be-cause very little of it crosses the blood-brain barrier or because the doses test-ed were too low. Antioxidants that canreach the brain deserve study; at leastone such compound is in clinical trialsat the NIH.

Regardless of the cause of the neu-ronal destruction, drugs that were ableto promote regeneration of lost neu-rons would probably be helpful as well.Studies of animals suggest that suchsubstances could, indeed, be effective inthe human brain. Researchers at severalAmerican facilities are now testing put-ting a molecule called glial-derived neu-rotrophic factor (GDNF) directly intothe brain of patients. Efforts are also un-der way to find smaller molecules thatcan be delivered more conveniently (viapill or injection) yet would still activateneuronal growth factors and neuronalgrowth in the brain. One agent, Rasagi-line, has shown promise in animal trialsand is now being tested in humans.Some studies imply that the nicotine intobacco might have a protective effect,and nicotinelike drugs are being studiedin the laboratory as potential therapies.Patients, however, would be foolish totake up smoking to try to slow disease

progression. Data on the value of smok-ing to retard the death of dopamineneurons are equivocal, and the risks ofsmoking undoubtedly far outweigh anyhypothetical benefit.

As work on protecting neurons ad-vances, so does research into compen-sating for their decline. One approachbeing perfected is the implantation ofdopamine-producing cells. Some pa-tients have been helped. But the resultsare variable, and cells available for trans-plantation are in short supply. Further,the same processes that destroyed theoriginal brain cells may well destroy theimplants. Other approaches include sur-gically destroying parts of the brain thatfunction abnormally when dopamine is

lost. This surgery was once unsafe butis now being done more successfully.

The true aim of therapy for Parkin-son’s disease must ultimately be to iden-tify the disease process long before symp-toms arise, so that therapy can be givenin time to forestall the brain destructionthat underlies patients’ discomfort anddisability. No one can say when earlydetection and neural protection will be-come a reality, but we would not be sur-prised to see great strides made on bothfronts within a few years. In any case,researchers cannot rest easy until thosedual objectives are met.

To obtain high-quality reprints of this

article, please see page 105.

Understanding Parkinson’s Disease Scientific American January 1997 59

The Authors

MOUSSA B. H. YOUDIM and PETER RIEDERERhave collaborated since 1974. Youdim, a pioneer in thedevelopment of monoamine oxidase inhibitors for thetreatment of Parkinson’s disease and depression, is profes-sor of pharmacology at Technion-Israel Institute of Tech-nology in Haifa, Israel. He is also director of the Eve Topfand U.S. National Parkinson’s Disease Foundation’s Cen-ters of Excellence for Neurodegenerative Diseases, bothat Technion, and a Fogarty Scholar in Residence at theU.S. National Institutes of Health, where he spends threemonths every year. Riederer heads the Laboratory ofClinical Neurochemistry and is professor of clinical neu-rochemistry at the University of Würzburg in Germany.The authors shared the Claudius Galenus Gold Medal forthe development of the anti-Parkinson’s drug selegiline.

Further Reading

James Parkinson: His Life and Times. A. D. Morris. Edited by F. CliffordRose. Birkhauser, 1989.

Emerging Strategies in Parkinson’s Disease. Edited by H. L. Klawans.Special issue of Neurology, Vol. 40, No. 10, Supplement 3; October 1990.

Iron-Melanin Interaction and Parkinson’s Disease. M.B.H. Youdim,D. Ben Shacher and P. Riederer in News in Physiological Sciences, Vol. 8,pages 45–49; February 1993.

Parkinson’s Disease: The L-Dopa Era. M. D. Yahr in Advances in Neurol-

ogy, Vol. 60, pages 11–17; 1993.Altered Brain Metabolism of Iron as a Cause of Neurodegenera-tive Diseases? M. Gerlach, D. Ben Shacher, P. Riederer and M.B.H. You-dim in Journal of Neurochemistry, Vol. 63, No. 3, pages 793–807; Septem-ber 1994.

Neurodegeneration and Neuroprotection in Parkinson’s Disease.Edited by C. W. Olanow et al. Academic Press, 1996.

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SO-CALLED FROZEN ADDICTS posed together in 1991, after having received treat-ment. Nine years earlier all suddenly became immobile, as if they had instantly ac-quired Parkinson’s disease, after taking an impure version of a narcotic. Studies of howan impurity in the drug led to the freezing has generated many insights into the bio-chemical reactions that could contribute to a more classical presentation of the disease.

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Insights from MPTP induced Parkinsonism

Parallels in symptoms, pathology, treatment, complicationsDopamine depletion without symptomsAnimal models using MPTPEnvironmental toxins and Parkinson's DiseaseRotenone and Parkinson's disease

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The objectives of the lecture on Parkinson’s Disease (PD) are to understand:

The pathology underlying PD

The role of dopaminergic neurotransmission in PD

Drug treatments available to reduce the symptoms of PD, including levodopa-carbidopa therapy and other drugs that may be useful

Enzymatic pathways involved in Dopamine synthesis and its breakdown.

MPTP induced Parkinsonism and the role of environmental toxins in PD

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