Pharmacological Strategies

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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Neurosurgery was the first therapeutic approach to parkinsonism. Replacement by L-DOPA of the lost striatal DA (adopted in the early 1960s) was welcomed as a safer alternative to surgery. In the neuronal pathway of catecholamine biosynthesis, the enzyme tyrosine hydroxylase catalyzes the conversion of the amino acid tyrosine to dihydroxyphenylalanine (L-dopa, levodopa), which is then converted to DA by the action of dopa-decarboxylase. L-Dopa, unlike DA, can pass the BBB (see below), and when

TABLE 4 Major Dopaminergic Pathways

Substantia nigra to corpus striatum Substantia nigra to nucleus accumbens Limbic system

Hypothalamus

Neocortex administered as a drug, can then serve as a precursor of neuronal DA. Although treatment of patients with L-dopa may not provide a "cure," the treatment ameliorates some of the more disturbing symptoms and has been viewed as a model therapy for this aging-associated neurologic disorder. In clinical use, L-dopa must be administered concomitantly with a peripheral decarboxylase inhibitor (carbidopa); this is necessary (i) to minimize the peripheral (gastrointestinal, cardiovascular, and motor) side

Regulates control of motor function from cortex Controls locomotion (forward movement) Regulates emotion, behavior

(sexual and aggressive) Regulates secretion of releasing and inhibiting hormones Regulates locomotor activity

FIGURE 12 Dopaminergic nigral-striatal pathway in the normal (left dark arrow) and in parkinsonism (right dashed line). In parkinsonism, dopaminergic neurons of the substantia nigra are lost, reducing dopamine (right dashed line) to putamen-caudate (striatum) and subsequent control of cortical stimulatory effects. Increased excitatory transmission to extrapyramidal system (broad open arrow) is associated with tremor and rigor.

FIGURE 12 Dopaminergic nigral-striatal pathway in the normal (left dark arrow) and in parkinsonism (right dashed line). In parkinsonism, dopaminergic neurons of the substantia nigra are lost, reducing dopamine (right dashed line) to putamen-caudate (striatum) and subsequent control of cortical stimulatory effects. Increased excitatory transmission to extrapyramidal system (broad open arrow) is associated with tremor and rigor.

TABLE 5 Strategies for Treatment of Parkinson's Disease

Pharmacological

Neuroprotective

Surgical and electrostimulatory

Cell therapies effects of DA, and (ii) to prevent increasing tolerance to the drug and, therefore, (iii) its decreased availability to the brain.

The original pharmacological treatment had been designed to reduce neural activity with cholinergic inhibitors. The loss of dopaminergic input to the striatum, in the presence of persisting cholinergic excitatory activity, disrupts basal ganglia circuitry. Cholinergic inhibitors are still used as an adjunct to replacement L-dopa therapy.

Despite its beneficial effects, L-dopa treatment has some contraindications such as motor complications, negative general and systemic effects such as gastrointestinal disturbances. In addition, there is a gradual loss of effectiveness after three to five years of administration, probably due to continuing loss of dopaminergic neurons and reduction of dopa-decarboxylase, with consequent deficit in DA synthesis. Because neurotoxicity from L-dopa may be due to the generation of oxidative species (79,82), it is often recommended that antioxidants (e.g., tocopherol) be coadministered to prevent or reduce accumulation of free radicals (eventually capable of destroying the dopaminergic cells).

Treatment with L-dopa is often used in combination with other drugs such as DA agonists (e.g., bromocriptine, prami-pexole, ropinirole) (83,84), or inhibitors of the two enzymes involved in DA breakdown, monoamine oxidase (e.g., selegiline, rasagiline) (85), and catechol-o-methyltransferase (entaca-pone) (86), thereby extending the duration of action of L-dopa, or with a variety of anticholinergic drugs such as benzatropine and trihexyphenadyl.

Current pharmacological therapy will remain essentially ineffectual on a long-term basis until we understand more about the cause of dopaminergic cell loss. Recent evidence from postmortem brain and animal models of the disease (87) has suggested that early depletion of the antioxidant glutathione (88) and iron-mediated oxidative stress (89) may contribute to the loss of dopaminergic neurons of the substantia nigra (87-89). Basic research into the cause of dopaminergic cell death is needed to prevent the occurrence of cell loss.

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