Use of antihypertensives and the risk of Parkinson disease

Becker, Claudia; Jick, Susan S.; Meier, Christoph

doi:10.1212/01.wnl.0000303818.38960.44

Cited by 204 publications

(179 citation statements)

References 32 publications

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“…DHPs are use-dependent antagonists of LTCCs that have a long history of success in the treatment of hypertension in humans 9 . In agreement with the propositions that LTCCs contribute to pathogenesis, retrospective epidemiological studies conducted in the United Kingdom 10 and Denmark 11 have revealed that the treatment of hypertension with DHPs that cross the blood-brain barrier diminish the observed risk of PD.…”

supporting

confidence: 65%

CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

et al. 2012

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L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a Ca V 1.2 pore-forming subunit. L-type calcium channels with a Ca V 1.3 pore-forming subunit are much less abundant, but have been implicated in the generation of mitochondrial oxidant stress underlying pathogenesis in Parkinson's disease. Thus, selectively antagonizing Ca V 1.3 L-type calcium channels could provide a means of diminishing cell loss in Parkinson's disease without producing side effects accompanying general antagonism of L-type calcium channels. However, there are no known selective antagonists of Ca V 1.3 L-type calcium channel. Here we report high-throughput screening of commercial and 'in-house' chemical libraries and modification of promising hits. Pyrimidine-2,4,6-triones were identified as a potential scaffold; structure-activity relationship-based modification of this scaffold led to 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (8), a potent and highly selective Ca V 1.3 L-type calcium channel antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology. These studies describe the first highly selective Ca V 1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson's disease.

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confidence: 65%

CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

et al. 2012

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“…Parkinson's disease, 35,36,62,63 whereas others did not find a significant effect. 64,65,66,67 However, the consensus based upon systematic review of all available literature is that treatment with calcium channel blockers does appear to reduce the risk of Parkinson's disease 68,69 although the mechanism by which they do so is not completely understood.…”

Section: Introductionmentioning

confidence: 83%

Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson’s Disease: Therapeutic Rationale and Current Status

Swart¹,

Hurley

2016

CNS Drugs

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“…Calcium channel antagonists (CCAs), including the DHPs used in animal studies, are commonly used in clinical practice to treat hypertension, creating a potential database to be mined. A case-control study of hypertensive patients found a significant reduction in the observed risk of PD with CCA use, but not with medications that reduce blood pressure in other ways (9). More recently, a large Danish data set has been examined (100 …”

Section: Surmeier Et Almentioning

confidence: 99%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

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Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

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Use of antihypertensives and the risk of Parkinson disease

Cited by 204 publications

References 32 publications

CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson’s Disease: Therapeutic Rationale and Current Status

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

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