Toxic Metabolites of Dopamine and PD Marta Madzelan Xiao Yu Wang Zhou (Joey) tong Puja Bose PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

What is Parkinson’s Disease? Progressive neurodegenerative disease of the CNS, primarily affecting voluntary, controlled movement It is a result of the chronic loss of dopaminergic neurons within the ventral component of the pars compacta region in the substantia nigra (midbrain) As the neurons die, less dopamine is produced and transported to the striatum (co-ordinates movement). In Canada, estimated prevalence rate is 100 to 200/100,000

What causes PD? Etiology is unknown (idiopathic) Genetic factors (small number of cases) around 15% of individuals with PD have a first-degree relative who has the disease. Environmental factors (chronic exposure to pesticides) correlation between exposure to pesticide use and wood preservatives. strong negative correlation between cigarette smoking and the development of the disease.

Symptoms of PD Motor Symptoms Non-motor Symptoms Resting Tremor Rigidity Slowness of movement Postural Instability Non-motor Symptoms Autonomic dysfunction Neuropsychiatric symptoms Sleep disorders Sensory abnormalities *The symptoms of Parkinson’s fluctuate throughout the course of the disease and intensify progressively over time.

Diagnosis of PD Diagnosed through clinical assessment based on the symptoms described by the patient and a complete neurologic examination by the physician. Two of the four motor symptoms must be present to make the diagnosis. No lab test that identifies the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms.

Who is at risk for PD? Most often occurs after the age of 50 and is one of the most common movement disorders of the elderly. Occurs about 50% more in men than women. Head trauma, illness, or exposure to environmental toxins such as pesticides A low % are at increased risk because of a family history (genetic factors) Parkinson’s can progress at a different rate for each person

Pathology of Parkinsons Death of dopaminergic neurons in the substantia nigra In particular, the pars compacta region Nigrostriatal pathway is one of the four major dopamine pathways Connects the substantia nigra to the striatum Is necessary for movement 80-90% of substantia nigra dopaminergic cells must die for symptoms to appear Presence of abnormal protein aggregates called Lewy Bodies

Dopamine Major neurotransmitter involved in a number of pathways Metabolism of dopamine generates reactive oxygen species Defensive mechanisms against ROS are overwhelmed in Parkinson’s Disease

Damage to Dopamine Cells D1 and D2 dopamine receptors signal through G-proteins to regulate transcription Both familial and environmental factors may contribute Accumulation of aggregated proteins is a key cause Mutations which increase ROS cause apoptosis and misfolding

Lewy Bodies are collections of misfolded protein Still unclear whether Lewy Bodies are a disease causing agent, an indirect consequence, or a protective measure to reduce harm

Treatments for Parkinson’s Disease •Currently there is no treatment for Parkinson’s Disease •Most “treatment” are meant to alleviate symptoms. •General treatment philosophy is to address for the lack of dopamine inside the brain

Levodopa •A metabolic precursor of dopamine. •Able to cross blood-brain barrier, a tight junction that protect brain and spinal cord from general circulation. •Molecules such as Decarboxylase inhibitor are usually used in combination with Levodopa in order to prevent peripheral decarboxylation of levodopa. (eg Levodopa/Carbidopa)

Levodopa •One of the most common drug used to alleviate symptoms. •Very effective in relieve symptoms like tremor and stiffness, but does not affect problems involve autonomic functions. •Possible side effects include dizziness, agitation and anxiety.

Dopamine Agonist •A type of molecule that directly stimulate the receptors in nerves in the brain that normally would be stimulated by dopamine. •It behaves like dopamine but does not change into dopamine. •General properties for these molecules are: easy to cross blood-brain barrier and have high affinity to dopamine receptors in brain such as D2 receptors. •One example of Dopamine Agonist is Apomorphine.

Dopamine Agonist •Less effective than Levodopa, but can help in reduce symptoms relate to motor function. •Can be used in combination with Levodopa in order to decrease the side effects from Levodopa.

MAO-B inhibitors Enzyme (monoamine oxidase B) in the brain that breaks down several chemicals in the brain including dopamine MAO-B levels increase as you age Increased levels of MAO-B contribute to cellular degeneration by producing H2O2 that are converted by iron to toxic O2 free radicals MAO-B inhibitors inhibit the activity of MAO-B allowing sustained dopamine levels

MAO-B Inhibitor Medications Selegiline and Rasagaline Usually given in the early stages but can also be given in conjunction with other drugs such as levodopa Stopping movements from getting worse Can also delay the time when patients need to start taking levodopa Should not be taken with antidepressants as it can raise blood pressure to dangerous levels

Surgery Surgery may be considered when drugs fail to control symptoms NOT A CURE! Deep brain stimulation - uses electrical impulses to stimulate a target area in the brain Pallidotomy - destruction a tiny area of the globus pallidus (tremor and stiffness) Thalamotomy - destruction of an area in the thalamus that controls some involuntary movement medications are still taken after surgery but at lesser quantities

Summary Parkinson’s is a progressive neurodegenerative disease of the CNS, primarily affecting voluntary, controlled movement It is a result of the chronic loss of dopaminergic neurons in the substantia nigra (midbrain) Currently, no cure is available for Parkinson’s disease, all treatment is meant to alleviate symptoms. Levodopa is a metabolic precursor of dopamine, it can cross the blood brain barrier, which separate brain from general circulation, and can be converted into dopamine inside the brain. Dopamine agonist is a type of molecule that stimulate the receptor that normally would be stimulated by dopamine. MAO (monoamine oxidase) is an enzyme in the brain that breaks down several chemicals in the brain including dopamine MAO-B inhibitors inhibit monoamine oxidase B which allows elevated dopamine to remain in the brain Parkinson results from death of over 80% of the dopaminergic neurons in the pars compacta region of the substantia nigra The Nigrostriatal pathway, which is responsible for movement, is disrupted during PD, causing severe motor impairment Degradation of dopamine naturally causes production of reactive oxygen species, but mutations in -PD patients may cause defensive mechanisms to malfunction causing abnormal oxidative stress in neurons Mutations in alpha-synuclein cause protein misfolding, which in turn causes increased ROS and toxicity These misfolded proteins aggregate into Lewy Bodies. The exact function of Lewy Bodies is unclear

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