We identified all cases with a primary diagnosis of PD in Denmark between 2001-2006 in the national Hospital Registry and relied on an ongoing national prescription database created in 1995 to adjust the index date to first prescription drug use for PD and to determine CCB and anti-hypertension drug use among cases and matched population controls. We found a 26-30% decrease in PD risk for subjects prescribed L-type calcium channel blockers of the centrally acting dihydropyridine class (excludes amlodipine) during the period between 1995 and two years prior to the index date. On the other hand, the more commonly prescribed, peripherally acting dihydropyridine amlodipine and several common non-dihydropyridine CCBs were not associated with PD risk in our study population.
Since CCBs are primarily used in the treatment of hypertension, we also investigated associations between PD and other common anti-hypertensive drugs. Animal and cell studies have suggested that AT II antagonists and ACE inhibitors may be neuroprotective due to antioxidant properties.16-17
We did not expect these drugs to affect Ca2+
channels (and by extension protect against PD) since AT II antagonists and ACE inhibitors act on the renin-angiotensin system, therefore our observed lack of association between AT II and PD in our study population is not unexpected. In contrast, the novel finding that direction of the associations for ACE inhibitor prescriptions depended on whether they were lipophilic (decreased risk) or hydrophilic (increased risk) warrants further investigation. Our observed increased risk of PD in subjects prescribed beta-blockers is likely explained by the use of these drugs in treating essential tremor, and thus the observed positive association may result from insidious symptoms during the prediagnostic phase of PD.18
This explanation is supported by the attenuated association in our 5-year lagged analyses and the fact that beta blockers act on the norepinephrine system, not on Ca2+
To date, three other epidemiologic studies have reported on CCB prescription use and PD. A study of 191 idiopathic PD cases and 383 controls identified between 1992 and 2002 in the Puget Sound health care system8
suggested a negative association between PD and ever use of any type of CCB, but was hampered by small sample size (OR 0.85, 0.43-1.66). This US-based study lagged exposure by 5 years but evaluated all CCBs together: two-thirds of which were the non-dihydropyridines verapamil and diltiazem, drugs with no known action on DA neuron L-type Ca2+
channels at therapeutic levels. The much larger UK General Practice Research Database9
case-control study compared current (within 90 days of PD diagnosis), longer term (≥30 prescriptions) users to non-users among 3,637 incident PD cases diagnosed between 1994 and 2005 and an equal number of matched controls. Their negative association with PD for current, long term use of dihydropyridine (OR 0.78, 0.62-0.99) as well as non-dihydropyridine type (OR 0.76, 0.52-1.10) CCBs are likely confounded by pre-clinical disease since PD patients are known to develop neurogenic orthostatic hypotension,19
which would lead to a discontinuation of anti-hypertensive medications.20
We attempted to minimize such bias by identifying the earliest possible PD diagnosis date and lagging our exposure 2 and 5 years from that index date. The most recent Spanish cohort study10
followed 5,278 subjects for 3 years and evaluated CCB use at baseline for associations with prevalent (n=81) and incident (n=30) PD, separately. While utilizing prospectively collected longitudinal data, the small number of exposed PD cases (N=11) basically rendered this study uninformative. Furthermore, unlike our study in the Danish population, this study did not distinguish between different types of CCBs.
Our study was hampered by the relatively short average follow-up time for CCB prescriptions which may explain the lack of an association for our measures of duration and intensity. Due to the recent establishment of the prescription drug database (est. 1995), we could only examine relatively short-term anti-hypertensive use with adequate statistical power. However, we likely captured nearly all regular, continuing, and compliant CCB users in Denmark as Ca2+ channel blockers are only available with a prescription and our data were derived from the nationwide prescription database. The universal coverage of most health care expenses in Denmark makes it less likely that drug prescriptions or PD diagnoses were influenced by factors determining access to care. Given the record-based nature of our dataset, we attempted to adjust for smoking using COPD diagnosis as a proxy for heavy smoking; most likely we controlled for smoking no more than partially.
Our findings might be affected by disease misclassification since PD cases were identified from hospital and clinic records and may have included some patients with non-idiopathic Parkinsonism which would have been largely excluded by a movement disorder specialist evaluation. Sensitivity analyses in which we excluded PD cases and controls with prior diagnoses of dementia and cerebrovascular diseases before the index date suggested this bias to be minimal. Controls were selected at random from a population registry and did not have to volunteer information for our study, thus, we have avoided bias due to selective non-participation. Because we identified PD cases from hospital and clinic records, we might have constructed a case set of less healthy PD patients compared to broader PD population of Denmark. The higher Charlson index among our study’s PD patients compared to controls 2 years prior to and at the index date (data not shown) might support the possibility for such a selection bias; but, given the long pre-clinical course of PD, these values may simply reflect the declining health of PD patients prior to diagnosis. Interestingly, differences in general health status were not evident 5 years prior to PD diagnosis/index date (p-value =0.42, ).
The L-type dihydropyridine calcium channel blockers nifedipine, nimodipine, and isradipine have been observed at 6 to 9 times the concentration of amlodipine in the brains of intravenously treated mice;11
the dihydropyridine ring of amlodipine is in a positively charged state at physiological pH whereas the other dihydropyridines are non-charged; 21,22
and amlodipine is hydrophylic23
while others such as nimodepine are strongly lipophilic.24
All of which provides biological support for the observed differences between dihydropyridine CCBs (excludes amlodipine) and amlodipine. Non-amlodipine dihydropyridine CBBs traverse the blood brain barrier more efficiently than amlodipine, which is likely to need a transporter due to its positive charge. Although verapamil and diltiazem CCBs traverse the blood brain barrier, neither is known to bind to the Cav
1.3 L-type channels that dominate SNc DA neurons;3
this is consistent with the absence of an association with PD for these frequently prescribed anti-hypertensives. A recent murine study has shown that bathing SNc DA neurons in or subcutaneous administration of the L-type calcium channel blocker isradipine or deletion of the Cacna1d
gene that encodes the Cav
1.3 subunit returns autonomous pacemaking to a latent ionic mechanism using Na+
Other members of the dihydropyridine class, like nimodipine, may act similarly as suggested by studies in non-human primates.7,26
The transition of pacemaking activity from Na+
/HCN channels to Cav
channels as cells age suggests that elevations in cytosolic Ca2+
might contribute to aging-related oxidative, mitochondrial, and endoplasmic reticulum stress. Supporting this claim, Chan et al.25
showed that isradipine treatment protected against SNc DA neuron loss and motor deficits in mice undergoing low dose repeated administration of the neurotoxin MPTP. Furthermore, nimodipine and nitrendipine treatment provided neuroprotection from cytosolic DA-induced cell death in SNc neurons.27
Our findings, in combination with these observations in model systems, support the hypothesis that centrally-acting CCBs targeting Cav
channels of DA neurons might decrease risk of PD, possibly through decreasing general cellular stress thereby attenuating the impact of environmental or genetic insults in aging DA neurons. Given that hypotension is a common feature and manifests preclinically in many PD patients, further investigations and a more complete understanding of their biological and potential neuroprotective role are essential before considering these anti-hypertensive medications for therapeutic uses in PD.