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Medical Author:

Charles Patrick Davis, MD, PhD

Charles Patrick Davis, MD, PhD

Dr. Charles "Pat" Davis, MD, PhD, is a board certified Emergency Medicine doctor who currently practices as a consultant and staff member for hospitals. He has a PhD in Microbiology (UT at Austin), and the MD (Univ. Texas Medical Branch, Galveston). He is a Clinical Professor (retired) in the Division of Emergency Medicine, UT Health Science Center at San Antonio, and has been the Chief of Emergency Medicine at UT Medical Branch and at UTHSCSA with over 250 publications.

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Medical Editor:

Melissa Conrad Stöppler, MD, Chief Medical Editor

Melissa Conrad Stöppler, MD, Chief Medical Editor

Melissa Conrad Stöppler, MD, is a U.S. board-certified Anatomic Pathologist with subspecialty training in the fields of Experimental and Molecular Pathology. Dr. Stöppler's educational background includes a BA with Highest Distinction from the University of Virginia and an MD from the University of North Carolina. She completed residency training in Anatomic Pathology at Georgetown University followed by subspecialty fellowship training in molecular diagnostics and experimental pathology.

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The causes of Parkinson disease remain unclear; clinicians and researchers have clear evidence that the nerve cells that produce dopamine in the brain's region known as the substantia nigra are altered and lost (destroyed). The challenge that remains is to discover how these neurons are destroyed to cause Parkinson's disease. Advances in genetics have lead researchers to discover that about 10% of people that develop the disease are due to multiple genetic factors, but these people usually are younger than 50. The majority of researchers suggest that a combination of genetic and environmental factors cause about 90% of cases of PD, but how these factors interact to alter and destroy brain cells thus producing PD is not well understood. A few theories and risk factors are listed below that may offer additional information and clues that may help lead to a better understanding of PD causes.

• Environment: Studies have found that living in a rural area, drinking well water, or being exposed to pesticides, herbicides, or wood pulp mills may increase a person's risk for developing Parkinson's disease.
• Oxidation hypothesis: Free radicals, generated from dopamine's oxidation, generate cell damage and death.
• It is thought that free radicals may play a role in the development of Parkinson's disease. Free radicals are atoms or groups of atoms with unpaired electrons that can damage cells and intracellular structures. Free radicals can be created when dopamine is broken down by combining it with oxygen.
• This breakdown of dopamine by an enzyme called monoamine oxidase (MAO) leads to the formation of hydrogen peroxide.
• A protein called glutathione normally breaks down the hydrogen peroxide quickly. If the hydrogen peroxide is not broken down correctly, it may lead to the formation of these free radicals, enhanced by the presence of iron, that then can react with cell membranes to cause lipid peroxidation (when the hydrogen peroxide interacts with lipids [fat-soluble substances] in the cell membrane). This leads to cell damage and cell death.
• The association of Parkinson's disease with increased dopamine turnover, decreased mechanisms (glutathione) to protect against free radical formation, increased iron (which makes it easier to create free radicals), and increased lipid peroxidation helps support the oxidation hypothesis.
• If this hypothesis turns out to be correct, it still does not explain why or how a loss of the protective mechanism occurs. An answer to this question may not be required. If the theory is correct, drugs may be developed to stop or delay these events.
• Alpha-synuclein alteration: The protein alpha-synuclein is involved in neurotransmitter release. This protein is a major component of Lewy bodies, which are found in the neurons of PD patients. The theory is that under certain conditions (genetic, environmental, or a combination of both) may lead to protein aggregates that develop in the Lewy bodies. During their development, some of the alpha-synuclein intermediates may be toxic to neurons. Other variations of this hypothesis suggest that lysosomes in the cells allow alpha-synuclein proteins to accumulate and then aggregate while other investigators suggest that Lewy bodies may develop like prions and may represent an autoimmune-like disease.
• Mitochondrial dysfunction: Mitochondrial activity in the cells of PD patients is reduced, so some investigators suggest that that whatever reduces this activity plays a causal role in PD. They conclude this because certain chemicals that can produce PD symptoms in humans cause disruption of mitochondrial functions and are effectively treated by dopamine.
• Some people have symptoms of PD that may have an identifiable cause. In this case, the syndrome is known as Parkinsonism or secondary PD. Parkinson's that is caused by drugs is probably far more common than reported and accounts for about 4% of all cases of Parkinson's. These findings give additional insight toward definition of potential PD causes.
• A change in the level of dopamine, whether by brain cell loss or drug use, can create the symptoms of PD.
• Interestingly, people who experience drug-induced Parkinson's may actually have a higher risk of developing PD later in life.
• A number of medications can cause Parkinson's by lowering dopamine levels. These are referred to as dopamine-receptor antagonists or blockers.
• Nearly all antipsychotic or neuroleptic medications such as chlorpromazine (Thorazine), haloperidol (Haldol), and thioridazine (Mellaril) can induce the symptoms of Parkinson's.
• The medication valproic acid (Depakote), a widely used antiseizure medication, may also cause a reversible form of Parkinson's.
• Medications such as metoclopramide (Octamide, Maxolon, Reglan), which is used to treat certain stomach disorders such as peptic ulcer disease, are capable of causing Parkinson's or making it worse.
• Antidepressants known as selective serotonin-reuptake inhibitors may cause symptoms similar to Parkinson's.
• These medications can alter the concentration of dopamine in the central nervous system.

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