Discontinuation of statin therapy associates with Parkinson disease

Lee, Yen-Chieh; Lin, Chin‐Hsien; Wu, Ruey‐Meei; Lin, Mong-Wei; Lin, Jou‐Wei; Chang, Chia‐Hsuin; Lai, Mei‐Shu

doi:10.1212/wnl.0b013e31829d873c

Cited by 112 publications

(123 citation statements)

References 35 publications

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“…Of the included studies, 6were from North America [14, 18-20, 22, 26] 4 were from Europe [8, 9, 17, 24], and 3 were from Asia [21, 23, 25]. The year of publication ranged from 2007 to 2016, thus spanning 10 years.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Association between Statin Use and the Risk of Parkinson’s Disease: A Meta-Analysis of Observational Studies

et al. 2017

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Background: Parkinson’s disease (PD) is a progressive disorder of the central nervous system. The prevalence of PD varies considerably by age group; it has a higher prevalence in patients aged 60 years and more. Several studies have shown that statin, a cholesterol-lowering medication, reduces the risk of developing PD, but evidence for this is so far inconclusive. The objective of this study is to evaluate the association between statin use and the risk of developing PD. Methods: PubMed, EMBASE, and the bibliographies of articles were searched for studies published between January 1, 1990, and January 1, 2017, which reported on the association between statin use and PD. Articles were included if they (1) were published in English, (2) reported patients treated with statin, and the outcome of interest was PD, (3) provided OR/HR with 95% CI or sufficient information to calculate the 95% CI. All abstracts, full-text articles, and sources were reviewed, with duplicate data excluded. Summary relative risk (RRs) with 95% CI was pooled using a random-effects model. Subgroup and sensitivity analyses were also conducted. Results: We selected 16 out of 529 unique abstracts for full-text review using our selection criteria, and 13 out of these 16 studies, comprising 4,877,059 persons, met all of our inclusion criteria. The overall pooled RR of PD was 0.70 (95% CI 0.58–0.84) with significant heterogeneity between estimates (I² = 93.41%, p = 0.000) for the random-effects model. In subgroup analysis, the greater decreased risk was found in studies from Asia (RR 0.62 95% CI 0.51–0.76), whereas a moderate reduction was observed in studies from North America (RR 0.69 95% CI 0.47–1.00), but less reduction was observed in studies from Europe (RR 0.86 95% CI 0.80–0.92). Also, long-term statin use, simvastatin, and atorvastatin showed a higher rate of reduction with significance heterogeneity. Conclusion: Our results showed that statin use is significantly associated with a lower risk of developing PD. Physicians should consider statin drug therapy, monitor its outcomes, and empower their patients to improve their knowledge, therapeutic outcomes, and quality of life. However, preventive measures and their associated mechanisms must be further assessed and explored.

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Section: Resultsmentioning

confidence: 99%

Exploring the Association between Statin Use and the Risk of Parkinson’s Disease: A Meta-Analysis of Observational Studies

et al. 2017

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“…Previous clinical studies revealed that Sim has the potential to decrease the risk of PD by lowering oxidative stress [12,13], and it can also affect the suppressive potential of pathological alpha-Syn by lowering cholesterol levels [14]. The fact that Sim can cross the blood-brain barrier as well as the considerable evidence supporting the beneficial effects of Sim on the central nervous system make Sim one of the more promising drugs for treating neurodegenerative diseases, including stroke [15,16] and PD [17,18]. Earlier investigations confirmed that ROS is produced during the maintenance of an essential metabolic balance in the body, as a series of anti-oxidant mechanisms stabilize the redox balance of cells [19,20].…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

Yan

Qiao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Many clinical studies have demonstrated that statins, especially simvastatin, can decrease the incidence of Parkinson’s disease (PD). However, the specific underlying mechanism remains unclear. This study aimed to investigate how simvastatin affects experimental parkinsonian models via the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated activation of the anti-oxidant system. Methods: l-Methyl-4-phenylpyridine ion (MPP⁺)-treated SH-SY5Y cells and substantia nigra neurons were used to investigate the neuroprotective effect of simvastatin. After incubation with MPP⁺ and/or simvastatin for 24 h, the MTT assay was used to assess cell viability. Reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescin diacetate, while cellular superoxide dismutase (SOD) levels were determined based on the blue formazan produced by the reduction of nitroblue tetrazolium. The level of cellular grade micro-reduced glutathione (GSH) was measured with 5,5’-dithiobis-(2-nitrobenzoic acid). Meanwhile, the malondialdehyde content released from SH-SY5Y cells and substantia nigra neuronal cells exposed to different culture media was calculated based on the condensation reaction involving thiobarbituric acid. The mRNA levels of genes encoding nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were determined by a quantitative polymerase chain reaction assay, while the ERK, Nrf2, HO-1, NOX2, and NQO-1 protein levels were analyzed by western blot. Additionally, ERK small interfering RNA (siRNA) was used to investigate the mechanisms underlying MPP⁺-induced oxidative stress and the regulation of the endogenous anti-oxidant system. Results: Simvastatin (1.5 μM) enhanced the viability of SH-SY5Y cells and primary neurons treated with MPP⁺, and significantly alleviated the oxidative stress induced by MPP⁺ in SH-SY5Y cells by regulating the production of SOD, analytical grade micro-reduced GSH, and ROS, which may be associated with the activation of the Nrf2 anti-oxidant system. An analysis involving ERK1/2 siRNA revealed that simvastatin can inhibit NOX2 expression via the activation of ERK1/2 in the MPP⁺-treated PD cell model. Conclusion: Our results provide strong evidence that ERK1/2-mediated modulation of the anti-oxidant system after simvastatin treatment may partially explain the anti-oxidant activity in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin via the ERK1/2-mediated modulation of the anti-oxidant system, which may be relevant for treating PD.

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“…A populationbased study by Lee et al, indicated that the continuation of lipophilic statin, such as atorvastatin and simvastatin, therapy was associated with a decreased incidence of PD (Lee et al, 2013). During 12 years of follow-up (1994-2006) study, Gao et al, found that the regular statin medication was correlated to a reduction in PD risk .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to lowering cholesterol, statins have gradually been used to reduce the risk of heart attack, cerebral ischemia, and have been demonstrated to exert potential beneficial effects in different neurological diseases (Wang et al, 2007;Keener & Sanossian, 2008;van der Most et al, 2009;Sugawara et al, 2011;Ayer et al, 2013). Although the precise mechanisms are unclear and contrasting results have been observed (Reiss & Wirkowski, 2007;Becker et al, 2008), additional studies have found that statins display important effects on cognitive related neurological diseases such as PD van der Most et al, 2009;Wang et al, 2011;Lee et al, 2013;Xu et al, 2013). If statins would have a potentially useful impact on impaired memory regulation in the progression of PD, this presents an interesting challenge.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

et al. 2014

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. (2014). Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: the association with improvements in long-term memory. Neuroscience, 267 57-66.Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: the association with improvements in long-term memory AbstractBackground It is believed that muscarinic M1/4 receptors are closely correlated to the dopaminergic system and are strongly involved in the pathogenesis of Parkinson's disease (PD). In addition to regulating lipid metabolism and protection from stroke, statins have been used to regulate the declined cognition. We aimed to explore the regional changes in M1/4 receptors in the 6-hydroxydopamine (6-OHDA)-lesioned rat brain. Methods PD rat model was set up by injecting 6-OHDA into the unilateral medial forebrain bundle; while simvastatin (10 mg/kg/day) or saline was orally administrated for 3 weeks, respectively. Long-term memory was measured using the Morris water maze.[3H]pirenzepine binding autoradiography was applied to investigate the alterations of M1/4 receptors in the PD rat brains. Results 6-OHDA induced long-term memory deficits along with downregulation of M1/4 receptors in the hippocampus, the medial amygdala, the posteromedial cortical and the piriform cortex; simvastatin administration significantly ameliorated the impaired memory and reversed the downregulation of M1/4 receptors in the examined brain regions. Profound positive correlations were verified between the decline in long-term memory activity and the restoration of M1/4 receptors in different brain regions after simvastatin treatment. Conclusions/significance Our results provide strong evidence that M1/4 receptor modulation after simvastatin administration did, at least partially, contribute to the improvement in the long-term memory in 6-OHDA-induced PD rats. These results provide a possible mechanism for simvastatin treatment in psycho-neurological diseases such as PD via M1/4 receptors.

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Discontinuation of statin therapy associates with Parkinson disease

Abstract: Continuation of lipophilic statin therapy was associated with a decreased incidence of PD as compared to discontinuation in statin users, especially in subgroups of women and elderly. Long-term follow-up study is needed to clarify the potential beneficial role of lipophilic statins in PD.

Cited by 112 publications

References 35 publications

Exploring the Association between Statin Use and the Risk of Parkinson’s Disease: A Meta-Analysis of Observational Studies

Exploring the Association between Statin Use and the Risk of Parkinson’s Disease: A Meta-Analysis of Observational Studies

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

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