Calcium channel blockers and β-blockers in relation to Parkinson's disease
Introduction
Significantly decreased risks of Parkinson's disease (PD) associated with hypertension and blood pressure medication have been observed in several epidemiologic studies [1], [2]. Because specific classes of medications were not identified in these studies, we investigated two common classes of anti-hypertensive medications, calcium channel blockers (CCBs) and β-blockers, that may potentially affect the risk of PD through different mechanisms. The possibility that CCBs may inhibit the Ca2+-dependent process of apoptosis was first suggested in the cancer literature [3], [4], [5], [6]. Based on this anti-apoptotic model, CCBs were subsequently hypothesized to be neuroprotective in PD and other conditions in which apoptosis contributes substantially to cell death [7]. In neuronal cell culture, nimodipine significantly inhibited β-amyloid apoptotic neuronal injury [8]. In animal models of PD, nimodipine also prevented neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in non-human primates [9] and in mice [10]. Based primarily on experimental studies and mechanistic considerations, we hypothesize that CCBs are associated with a decreased risk of PD.
β-blockers compete for available receptor sites, effectively reducing the neurotransmission of norepinephrine in the brain. Disturbances in the norepinephrine system may play an important role in the pathogenesis of PD by affecting both the onset and progression of damage to the dopamine nigrostriatal tract [11]. Specifically, loss of norepinephrine may enhance neurotoxic damage from environmental toxins to nigrostriatal dopaminergic neurons. Injections of MPTP into the brains of adult mice resulted in significant loss of dopaminergic cells in the substantia nigra only on the side of the brain where lesions were induced in the locus coeruleus, the primary source of norepinephrine [12]. In humans, loss of norepinephrine neurons in the locus coeruleus has been documented in patients with PD [13], [14]. These findings support the hypothesis that the norepinephrine system may play a role in protecting the integrity of dopaminergic substantia nigral neurons [12]. Because β-blockers reduce the neurotransmission of norepinephrine, we hypothesize that β-blockers are associated with an increased risk of PD. To our knowledge, the current study is the first to examine the PD risk associated with CCBs and β-blockers. We assessed associations of PD with these anti-hypertensive medications using an automated pharmacy database in a population-based case-control study of idiopathic PD.
Section snippets
Methods
We conducted the study among enrollees of Group Health Cooperative (GHC), a health maintenance organization in the Seattle area, who participated in a population-based case-control study of idiopathic PD. The methods have been described elsewhere [15]. Briefly, newly diagnosed idiopathic PD cases between 35 and 89 years of age were identified from GHC neurology and general medical clinics between 1992 and 2002. Medical charts of cases were reviewed by study neurologists (PDS, GMF and WTL) to
Results
Medication data were available for 206 cases and 383 controls. Cases and controls did not differ with respect to age, sex, education, race, length of GHC enrollment and self-reported history of medical conditions including high blood pressure, stroke and heart disease. Smoking was inversely associated with PD [15] and a smaller proportion of cases had a history of diabetes relative to controls, as reported previously (Table 1) [18].
Verapamil and diltiazem were most commonly dispensed,
Discussion
We did not observe any clear association between PD risk and CCBs, either for ever use or in terms of length, dose, number of dispensed prescriptions or pattern of use. Except for ever use and pattern of use for which risk estimates were decreased, the trend in the risk estimates for increasing dose of CCBs were in the opposite direction from what we had hypothesized. We also did not observe any clear relation between PD risk and β-blockers. Among those exposed to β-blockers, estimates of
Acknowledgment
This study was supported by Grants ES04696, ES10750, ES07033 and T32 ES007262 by the National Institutes of Environmental Health Sciences.
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