Parkinson’s disease is a disease with a wide variety of disabilities recognizable as changes in appearance, posture, walking, and balance. In 1817, the English physician James Parkinson described these symptoms in his patients and has had his name become synonymous with the disease. In 1893 the substantia nigra of the basal ganglia was identified as an area of disease for Parkinson’s. Examination with the naked eye reveals a lack of black pigment in this portion of the brainstem. Subsequent follow up with the microscope showed a deterioration of the nerve cells in this area. The circuitous relationship between the substantia nigra and the basal ganglia explains many of the symptoms of Parkinson’s disease. Today the cause of the disease remains unknown, however, the biochemistry is well documented and recently discovered neurotoxins have us hot on the trail of this disease.

Portions of the cerebellum are involved in the control of posture and balance and also modulate voluntary movement. The basal ganglia and the cerebellum interact with the cerebral cortex through a series of feedback circuits. The dentate and interpositus nuclei of the cerebellum project to the ventral lateral nucleus of the thalamus, which also receives projections from the globus pallidus and the substantia nigra. Recent evidence indicates, however, that none of these projections overlap in the ventral lateral nucleus. The ventral lateral nucleus projects to the primary motor and supplementary motor areas of the cerebral cortex. In turn, the motor cortex and other regions of the cerebrum project to the striatum to enter the basal ganglia circuit. Moreover, the motor cortex projects to the pons to enter the cerebellar circuit, including the cortico-ponto-cerebellar pathway, Purkinje cells, interpositus and dentate nuclei, and the cerebello-thalamic tract. Consequently, both the basal ganglia and the cerebellum are influenced by and return influence to the descending motor pathways (pyramidal and extrapyramidal), which affect the activity of the lower motoneurons.

The substantia nigra is a subcortical nucleus that is closely related to basal ganglia. It is reciprocally connected with the striatum and sends efferents to the ventral anterior and dorsomedial thalamic nuclei and, to some extent, to the ventral lateral thalamic nuclei. The substantia nigra pars reticulata also projects to the superior colliculus. Neurons that originate in the striatum and project to the substantia nigra are inhibitory and utilize the neurotransmitters GABA and substance P. Fibers that arise in the pars compacta of the substantia nigra use the neurotransmitter dopamine and synapse in the striatum, while GABAminergic cells in the pars reticulata receive striatal input and project to the thalamus.

Recordings from neurons in the basal ganglia of monkeys during various motor tasks reveal that the discharge of single cells in the neostriatum show a direct correlation with movements of the contralateral arm or leg, and that the discharge of substantial percentage of neurons precedes the onset of a movement. These studies suggest that the basal ganglia participate in movements at a high level, including the planning of movement synergy’s. Lesions of the basal ganglia resulting from disease in humans cause: disorders of the initiation of movement (akinesia), difficulty continuing or stopping an ongoing movement, abnormalities of muscle tone (rigidity), and the development of involuntary movements (tremor or chorea). The movements influenced by the basal ganglia include those related to posture, automatic movements, including eye movements. The basal ganglia are also important in cognition, a function that may be mediated through the circuit connections these nuclei have with the prefrontal cortex.

Parkinson’s disease, or paralysis agitans, is a common condition associated with degenerative changes (neuronal degeneration and depigmentation) in the substantia nigra and locus coeruleus. The pathologic changes in the substantia nigra involve dopaminergic neurons that project to the striatum and thus lead to the depletion of dopamine in the caudate nucleus and putamen. Patients with Parkinson’s disease develop akinesia, rigidity, and tremor. The akinesia is manifested as difficulty in initiating and performing volitional movements of the most common type, including standing, walking, eating, and writing. The lines of the patient’s face are smooth, the expression is fixed (the so-called masked face) , and there is little overt evidence of spontaneous emotional responses. The patient stands with the head and shoulders stooped and walks with short, shuffling steps. The arms are held at the sides and do not automatically swing in rhythm with the legs as they should. Although the patient has difficulty in starting to take the first steps, once underway, the pace becomes more and more rapid, and the patient has trouble in stopping the progress upon reaching his or her goal. This abnormality of walking is termed a festinating gait. Rigidity of the limbs (i.e., increased resistance to passive movement) is present in most patients with Parkinson’s disease and often consists of cogwheel rigidity. When the examiner passively flexes or extends one of the patients extremities, an increased resistance occurs that suddenly gives way and then returns sequentially as the movement continues, in the manner of a cogwheel. The muscle stretch (deep tendon) reflexes usually are normal. The tremor of Parkinson’s disease typically occurs with the patient at rest and consists of 4 to 6 cycle per second flexion-extension movements of the fingers and wrists, at times in the form of a "pill-rolling" movement.

Many of the symptoms of basal ganglia disease reflect disorders in the function of neurotransmitter systems. One of the hallmarks of Parkinson’s disease is a gross deficiency of dopamine-containing cells of zone compacta of the substantia nigra in Parkinson’s patients. Biochemical studies in post-mortem brain tissue of Parkinson’s patients show a general deficiency of dopamine content throughout the brain. Parkinson’s disease is a state characterized pharmacologically by decreased dopaminergic activity and relatively increased cholinergic activity in the basal ganglia, because of degeneration of nigrastriatal dopaminergic projections and preservation of striatal cholinergic interneurons. A prominent symptom is akinesia.

Individual presenting symptoms are now understood because of an understanding of the neurotransmitter dopamine. Bradykinesia can be attributed to damage of the inhibitory bundle of dopamine containing nerve fibers between the substantia nigra and the corpus striatum. Disturbance of function of inhibitory nerve fibers emanating from the substantia nigra allows unwanted and excessive excitatory message to escape from the corpus striatum, which are transformed in the neighboring thalamus into oscillating burst of nervous activity which are relayed through the cerebellum and the spinal cord. This oscillating drive of abnormal impulses results in limb tremor. Rigidity can be explained in terms of an excessive discharge of certain nerve impulses to muscle mechanisms responsible for tone. Both of these symptoms result from defective inhibitory mechanisms arising in the substantia nigra. Anti-cholinergic medications work to alleviate the symptoms of rigidity and tremor. They work by blocking the reaction of the neurotransmitter acetylcholine. Acetylcholine has an opposing action to dopamine. In Parkinson’s disease there is a deficiency of dopamine and a relative predominance of acetylcholine. Anti-cholinergic medications are often the first treatment prescribed for Parkinson’s patients. However, because acetylcholine is the parasympathetic neurotransmitter, too much can adversely effect digestion, heart rhythm, and glandular secretion.

Because dopamine is the deficient neurotransmitter one might conclude that increasing levels of dopamine would alleviate symptoms. While this is true, an understanding of the biochemistry of dopamine is necessary to deliver dopamine to the necessary site in the body. Ingesting dopamine directly presents two problems. First, dopamine cannot pass the blood brain barrier and as such is insufficient in ingested form. Second, dopamine is destroyed in the blood stream and will be excreted in the urine after destruction. Dopamine is formed in the body from L-dopa, or L-3,4-dihydroxyphenylalanine. L-dopa is made from tyrosine which in turn can be synthesized in the body by phenylalanine. The rate of formation of L-dopa is strictly controlled by tyrosine hydroxylase. Because of this strict control, a simple increase in tyrosine in the diet does not increase the levels of L-dopa. The L-dopa to dopamine reaction is controlled by dopa-decarboxylase. A subsequent increase in L--dopa does translate into an increase in the amount of dopamine, unlike the tyrosine to L-dopa reaction. However dopa--decarboxylase is present in large quantities in both the brain and in the blood vessels. Therefore, when L-dopa hits the blood stream, it is converted to dopamine and broken down before it can pass through to the brain. To circumvent this, L-dopa is packaged with a peripheral decarboxylase inhibitor and a much greater portion of L-dopa is able to reach the brain.

An interesting side effect of L-dopa is discoloration of the urine and body secretions. This occurs because some of the breakdown products of dopamine are melanin’s (These melanin’s are responsible for the black color of the substantia nigra). These melanin pigments can cause orange through red and brown to black color of secretions. A more serious side effect of long term L-dopa therapy is abnormal involuntary movements called dyskinesia’s. They are characterized by twitching of the lips and face, eyebrow raising, tongue protrusion, and curling of the toes. Other effects are writhing, jerky movements of the upper limb and neck, and uncontrollable paddling and kicking of the legs may also develop.

Another possible treatment of Parkinson’s involves monoamine oxidase (MAO) inhibitors. Monamine oxidase’s catabolize excessive amounts of adrenaline, noradrenaline, and dopamine. The use of monoamine oxidase inhibitors can be dangerous because a buildup of noradrenaline can cause headaches, palpitations, and increase in blood pressure. The monoamine oxidase inhibitor Deprenyl can selectively block only the MAO which breaks down dopamine and not adrenaline and noradrenaline. Deprenyl is used in conjunction with small doses of L-dopa. The use of Deprenyl can forestall some of the long term side effects of L-dopa therapy.

MAO is located on the outer membrane of the mitochondria and converts dopamine to 3,4-dihydroxyphenylacetaldehyde which in turn is converted to 3,4-dihydroxyphenylacetic acid (DOPAC). DOPAC is converted to 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) by COMT. Brain MAO occurs in at least two isoenzymes, designated type A and type B. This division is based on substrate specificity and sensitivity to inhibitors. For example, type A has a preference for serotonin and noradrenaline, and clorgyline is a specific inhibitor. In contrast, type B has a preference for B-phenylethylamine and benzylamine, and deprenyl is a selective inhibitor. COMT is a soluble enzyme present in the cytoplasm, and may also be present extracellularly. It catalyses the transfer of methyl groups form S-adenyl methionine to the m-hydroxy group of dopamine. Under the influence of COMT, dopamine is converted to 3--methoxytyramine, which in turn is converted to 3-methoxy-4--hydroxyphenyl-acetaldehyde by MAO. This compound can then either be converted to 3-methoxy-4-hydroxyphenylethanol by aldehyde reductase or to homovanillic acid by aldehyde dehydrogenase.

The main metabolites found in the brain are HVA and DOPAC, and the accumulation of HVA in either the brain or the cerebrospinal fluid can be of use as a monitor of the activity of dopamine neurons.

One of the reasons that some key questions about Parkinson’s disease are unanswered, lies in the fact that until recently no good animal models existed. In 1979 a chance occurrence resulted in the discovery that 1-methyl-4-phenyl-1,2,3,6--tetrahydropyridine (MPTP), a dopaminergic neurotoxin, causes Parkinsonism in humans, monkeys and mice. Since that discovery other endogenous and environmental neurotoxins structurally similar to MPTP have been examined. 1,2,3,4--Tetrahydroisoquinoline (TIQ) was discovered in Parkinsonian human brains and subcutaneous injection of TIQ produced Parkinsonism in monkeys.

1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (N-methylsalsinol; NMSAL) and 2-methyl-6,7-dihydroxy-1,2,3,4--tetrahydroisoquinoline (N-methylnorsalsolinol; NMNSAL) have also been found in Parkinsonian brains and various foods. NMSAL shows various neurotoxicities in vitro. NMSAL is thought to be synthesized for salsolinol by an N-methyltransferase in the human brain. It has also been shown that N-methyldopamine (epinine), which occurs in Parkinsonian and normal human brains, can synthesize NMSAL in the presence of acetylaldehyde in vitro. These exciting developments are being followed up by trying to find whether N-methyldopamine and other Parkinsonism-related compounds, such as NMSAL and NMNSAL, can be synthesized from epinine in vivo. One of the most disappointing aspects of the current understanding of Parkinson’s disease is the lack knowledge on what causes the disease and the fact that we don’t know how to halt its progression. With the new animal models, a cure, or at least a more effective treatment, is a much more realistic hope.

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