Biochemistry

The predominant neuropathologic feature in Parkinson's disease is a degeneration of the dopaminergic cells in the substantia nigra pars compacta.  This results in a marked loss of cerebral, especially striatal dopamine. The severity of neuronal loss correlates with the clinical severity of Parkinson's disease. Therefore, the most common therapeutic strategy has been directed along the metabolic pathways of dopamine. The knowledge of dopamine biochemisty and receptor pharmacology will help understand the underlying principles of these drug actions. 

Dopamine

Synthesis  Tyrosine, an amino acid abundant in dietary proteins, is the starting point in the biosynthesis of dopamine.  Blood borne tyrosine is taken up into the brain by a low-affinity amino acid transport system and subsequently from brain extracellular fluid into dopaminergic neurons by specific amino acid transporters.  Once tyrosine has entered the neuron, it is first hydroxylated into L-DOPA.  The cytostolic enzyme, tyrosine hyroxylase, catalyses this conversion and is normally the rate-limiting step in dopamine biosynthesis.  Subsequently, aromatic amino acid decarboxylase (dopa-carboxylase) catalyses the cytostolic conversion of L-DOPA to dopamine.

Dopamine biosynthesis

Storage, release and reuptake
In dopaminergic neurons, dopamine is transported from the cytoplasm to specialized storage vesicles, in which the amine is concentrated to about 0.1M, 10-1000 times higher than the level in the cystosol.  Upon the arrival of an action potential which triggers subseqent exocytosis, vesicles discharge the neurostransmitters into the synapse. Dopaminergic terminals possess transporters (uptake mechanisms) that are critical in terminating transmitter action and in maintaining transmitter homeostatsis.  Under normal conditions, a potent, high-affinity membrane carrier recycle dopamine that has been released into synaptic cleft by actively pumping extracellular dopamine back into the nerve terminal.

Metabolism
The main enzymes responsible for the metabolism of dopamine in the brain are listed in Table 1.  Research has been directed toward developing specific enzyme inhibitors for enhancing dopaminergic transmission in Parkinson's disease, such as the selective monoamine oxidase type B (MAO-B) inhibitor Selegiline (L-deprenyl).  In the brain, dopamine is metabolized mainly to acidic metabolites, including 3,4-dihydroxyphenylacetic acid and homovanillic acid. Dopamine can also undergo auto-oxidation to form semiquinone and hydrogen peroxide, a reactive substance that is also produced in the monaminooxidase pathway (important in neuroprotection, see later).

Table 1

It is estimated that striatal dopamine is reduced by 70-90% and that there is a loss of 60-70% of substantia nigral neurons before the first clinical symptoms of Parkinson's disease occurs. In face of large loss of dopamine neurons, the surviving nigrostriatal dopamine neurons mount a compensatory response by increasing the rate of synthesis and release of dopamine.  One biochemical correlate of the compensation is an elevated ratio of the concentrations of dopamine metabolites:dopamine in striatum following severe dopamine depletion, reflecting upregulated metabolic activity in remaining neurons.

Receptors
There are now known to be at least six different forms of postsynaptic dopamine receptor.  The D₁ class of dopamine receptors has been divided into D₁ and D₅ receptor subtypes, and the D₂ class comprises D_2short, D_2long, D₃ and D₄ receptor subtypes.  When activated, the D₁-like receptor subtypes generally stimulate adenylate cyclase activity, whereas the D₂-like receptor subtypes generally inhibit adenylate cyclase activity. The effects of dopamine receptors on neurons are modulatory, mediating a complex interaction of dopamine-acetylcholine-glutamate systems in the striatum; this may explain the fact that some symptoms of Parkinson's disease can be relieved by other neurotransmitters.

The pharmacological profile and regional distribution in brain of each dopamine receptor subtype is different.  It appears that the striatal D₁ receptors are principally located on the striatonigral projecting neurons ("direct pathway"), while D₂ receptors are mainly located on striatopallidal neurons ("indirect pathway") (Review Neurology here).  In general, D₁ and D₂ are the subtypes of the dopamine receptor that are most abundant in the striatum, and are thought to be upregulated as a compensatory response in Parkinson's disease.  The upregulation of D₂ receptors is more reliably observed than that of D₁ receptors in the striatum in Parkinson's disease.

With more information about these receptor subtypes, one hopes that the introduction of new dopamine agonists with different receptor profiles will provide alternatives to patients no longer responding well to existing drugs.  Refer to the Treatment section for further details.

Free Radicals

Oxidant stress may contribute to cell death in Parkinson's disease because oxidative metabolism of dopamine has the potential to yield highly reactive and cytotoxic free radicals. Dopmaine is normally metabolized by enzymatic (monoaminooxidases) or auto-oxidation to form hydrogen peroxide. In the brain, hydrogen peroxide is cleared by glutathione. Consistent impairment of glutathione metabolism in the striatum is found in Parkinson's disease patients. Moreover, in some patients, a mitochondiral complex I deficiency and an increased superoxide dismutase activity are also established, resulting in increased hydrogen peroxide formation. Hence, if hydrogen peroxide levels are high or if glutathione levels are low, then hydrogen peroxide has the potential to react with ferrous iron to form hydroxyl radical, one of the prime mediator of oxidative damage.

Whether oxidative stress is a key mechanism on neuronal death and the pathogenesis of Parkinson's disease remains controversial, however. It is not clear whether levadopa (L-DOPA) therapy, in which the basal ganglia is bathed with nonphysiologic amounts of dopamine, is "neurotoxic" and contributes to the progression of disability in Parkinson's disease. Nonetheless, the concept of neuroprotective therapy is becoming increasingly popular and Selegiline, a monoamine oxidase inhibitor, is frequently prescribed in the hopes of providing some neuroprotection, at least in the early stages of Parkinson's disease. 

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Last Updated: March 28, 1998.
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