According
to the Parkinson's Disease Foundation, there are approximately one million
individuals in the United States alone who live with Parkinson's disease with
about 50,000 individuals being diagnosed each year with no preference in
gender.1,2 While Parkinson's disease is generally considered a disease
that increases with age or primarily affects the elderly, approximately 4% of
patients under the age of 50 will be diagnosed with the disease.1
As
it relates to the basic pathophysiology of Parkinson's disease, patients are
known to have a deficiency of dopamine producing neurons in the brain.2
In particular, the dopaminergic neurons within the substantia nigra begin to
degenerate where they eventually will no longer send dopamine to the corpus
striatum. This decrease in dopamine production and release in the
striatum leads to an overall net inhibition of the thalamus and communication
to the cerebral cortex for proper modulation of motor movements (mainly
initiation and coordination of muscle movement). As such, patients with
Parkinson's disease will commonly experience or exhibit bradykinesia (slow
voluntary motor movement), rigidity (increased resistance to passive movements)
and resting tremor.2,3 In order to correct or minimize these
complications, patients will need drug therapy that can increase the amount of
dopamine available to influence the basal ganglia. The most common
approach to the management of Parkinson's disease is to increase the production
or availability of dopamine in the brain. One
of the most common medications used is the precursor to dopamine, levodopa
(L-Dopa; 3,4-dihydroxyphenyl-L-alanine). It is generally given in
combination with carbidopa to improve the efficacy and reduce the side effects.4
Why
doesn't peripheral dopamine administration work in the management of
Parkinson's disease if that is what these patients are in need of most?
Peripherally
administered (outside of the central nervous system) dopamine is not effective
because it cannot cross the blood brain barrier.4 The reason for its
inability to cross the blood brain barrier has to do with at least two
influencing factors. The first is that dopamine is a hydrophilic molecule
that has a greater degree of difficulty in crossing cell membranes. The
second is the absence of a transporter for dopamine to get past the blood brain
barrier and into the brain.6 Since the increase in dopamine
concentrations are needed in the brain and the peripheral administration of
dopamine cannot get into the brain, it does not work in the management of
symptoms seen in Parkinson's disease. However, the precursor to dopamine,
L-dopa, is able to get into the brain via a sodium-independent transport system
called, large neutral amino acid carrier system or L (leucine) system.7
Once L-dopa gets inside the brain it can then be metabolized by dopa
decarboxylase or amino acid decarboxylase to form dopamine within the
dopaminergic neurons within the substantia nigra.4 Therefore, L-dopa
versus peripherally administered dopamine is currently the main medication used
in the management of symptoms associated with Parkinson's disease.
References:
- Parkinson's Disease Foundation. Understanding Parkinson's. Accessed on May 19, 2009
- Shastry BS. Parkinson's disease: etiology, pathogenesis and future gene therapy. Neurosci Res 2001;41:5-12.
- Pahwa
R, Factor SA, Lyons KE et al. Practice parameter: treatment of
Parkinson disease with motor fluctuations and dyskinesia (an
evidence-based review): report of the Quality Standards Subcommittee of
the American Academy of Neurology. Neurology 2006;66:983-95.
- Aminoff MJ. Pharmacologic management of Parkinsonism & other movement disorders. In: Basic & Clinical Pharmacology. Katzung BG ed. 9th edition. Lange Medical Books/McGraw-Hill. New York, NY. 2004;447-449.
- Busti AJ, Lehew DS, Nuzum DS, Daves BJ, McKeever GC. PW Pharmacother Newsl 2009;1(19):1-4.
- Hashimoto
W, Kitayama S, Kumagai K et al. Transport of dopamine and levodopa and
their interaction in COS-7 cells heterologously expressing monoamine
neurotransmitter transporters and in monoaminergic cell lines PC12 and
SK-N-SH. Life Sci 2005;76:1603-12.
- Wade
LA, Katzman R. Synthetic amino acids and the nature of L-DOPA
transport at the blood-brain barrier. J Neurochem 1975;25:837-42.
