Pharmacy & Therapeutics - October 2008 - (Page 591)

Medical Management of Parkinson’s Disease nism of toxicity to the substantia nigra that may play a role is the creation of cellular damage from oxyradicals.14 Dopamine generates free radicals from auto-oxidation and from monoamine oxidase (MAO) metabolism. Normally, several antioxidative mechanisms are present within and outside the neurons to limit any damage that might be evoked by an attack by free radicals, but such protection may be overwhelmed or impaired in PD. Excitotoxicity, programmed activation of cell death, and chronic infection are also under consideration as the etiologic mechanism of PD.15 Some scientists have suggested that PD occurs when either an external or an internal toxin selectively destroys dopaminergic neurons.16 An environmental risk factor, such as exposure to pesticides or a toxin in the food supply, is an example of an external trigger that might cause PD. The theory is based on the fact that a number of toxins, such as 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) and neuroleptic drugs, induce parkinsonian symptoms in humans. So far, however, no research has provided conclusive proof that a toxin is the cause of the disease. The cause of nerve cell degeneration in PD has not been identified. Genetics may play a small role. Studies of toxic models of PD and the genes implicated in inherited forms of PD point to two major pathogenetic mechanisms: (1) misfolding and aggregation of proteins and (2) mitochondrial dysfunction leading to oxidative stress.16 LRRK2 is the first gene that is frequently mutated in autosomal-dominant late-onset PD.17 Genetic causes have been identified with several distinct mutations. Recently, nine mutations involving a novel gene, leucine-rich repeat kinase 2 (LRRK2), have been identified as the cause of autosomal-dominant PD in kindreds, and some of them have been previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. These mutations have also been identified in diverse populations. The clinical and pathological features of LRRK2associated PD are indistinguishable from those of idiopathic PD; however, considerable clinical and pathological variability exists even among kindreds.18 Mutations in the gene encoding LRRK2 have been recently linked with autosomal-dominant parkinsonism, which is clinically indistinguishable from typical, idiopathic, late-onset PD. Thus, the protein LRRK2 has emerged as a promising therapeutic target for treatment. LRRK2 is large and complex, with multiple enzymatic and protein-interaction domains, each of which is targeted by pathogenic mutations in familial PD.19 Several genes identified in familial PD (α-synuclein, parkin, and ubiquitin carboxy-terminal hydroxylase L1) encode for proteins involved in the ubiquitin–proteosome system, which is responsible for normal degradation and clearance of proteins in eukaryotic cells. Mutations in these genes appear to be linked to mishandling and accumulation of proteins, which in turn leads to cell death.16 The potential role of mitochondrial dysfunction and subsequent oxidative stress in the pathogenesis of PD was first suggested by the discovery that the administration of MPTP, a mitochondrial electron transport chain inhibitor, to rodents and primates, produced a phenotype similar to that observed in PD. Inhibition produces toxic products, including harmful reactive oxygen species that can cause cellular damage by reacting with proteins, lipids, and nucleic acids.16 A relatively new theory explores the role of genetic factors in the development of PD. From 15% to 20% of PD patients have a close relative who has experienced parkinsonian symptoms, such as a tremor.20,21 Several causative genes have been identified, usually eliciting young-onset parkinsonism. However, identified genetic and familial forms of PD are rare. Mutations in the gene for the protein α-synuclein, located on chromosome 4, result in autosomal-dominant parkinsonism. The function of this protein is not known. The most commonly occurring genetic defect affects the gene for the protein called parkin on chromosome 6.22 Mutations in this gene result in autosomal-recessive parkinsonism, which is slowly progressive with onset before the age of 40. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies are showing that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. Parkin and α-synuclein accumulation and mutations in these genes have been associated with familial PD. Accumulation of α-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. Such findings provide a new perspective on the potential nature of pathogenic α-synuclein and parkin interactions in PD.22 DIAGNOSIS There are no practical diagnostic laboratory tests for PD; the diagnosis rests on the clinical features or by excluding other causes of parkinsonism. Fluorodopa positron emission tomography (PET) measures levodopa uptake into dopamine nerve terminals, showing a decline of about 5% per year of striatal uptake. This diagnostic test reveals decreased dopaminergic nerve terminals in the striatum in both PD and the Parkinson-plus syndromes but does not distinguish between them. A marked response to levodopa is helpful in the differential diagnosis, indicating presynaptic dopamine deficiency with intact postsynaptic dopamine receptors, features typical of PD.23 Computed tomography (CT) and magnetic resonance imaging (MRI) may be performed to determine a structural disorder as the cause of symptoms. The diagnosis of PD is likely if drug treatment results in improvement.16 The diagnosis of PD is based on clinical symptoms. Mild, early disease may be difficult to recognize because it usually begins subtly. Detecting PD is especially difficult in older people because aging can cause similar problems, such as loss of balance, slow movements, muscle stiffness, and stooped posture. PD develops insidiously and progresses slowly in most patients. Symptoms such as tremor at rest can be intermittent in the beginning, becoming present only in stressful situations.23 Patients with PD can live 20 or more years, depending on the age at onset; the mortality rate is about 1.5 times that Vol. 33 No. 10 • October 2008 • P&T® 591

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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