Parkinson’s Disease Progression and Statins: Hydrophobicity Matters

Background: Recent randomized clinical trials using hydrophobic statins reported no influence on Parkinson’s disease (PD) clinical progression. Hydrophobicity is a key determinant for blood-brain barrier penetrance. Objective: Investigate a potential effect of statins on PD progression. Methods: Statin use was determined at baseline and subtyped according to hydrophobicity in 125 PD patients participated PD Biomarker Program (PDBP, 2012–2015) at our site. Clinical (N = 125) and susceptibility MRI (N = 86) data were obtained at baseline and 18-months. Movement Disorders Society-Unified PD Rating Scales were used to track progression of non-motor (MDS-UPDRS-I) and motor (MDS-UPDRS-II) symptoms, and rater-based scores (MDS-UPDRS-III) of patients in the “on” drug state. R2 * values were used to capture pathological progression in the substantia nigra. Associations between statin use, its subtypes, and PD progression were evaluated with linear mixed effect regressions. Results: Compared to statin non-users, overall statin or lipophilic statin use did not significantly influence PD clinical or imaging progression. Hydrophilic statin users, however, demonstrated faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 4.8, p = 0.010)] and nigral R2 * (β= 3.7, p = 0.043). A similar trend was found for MDS-UPDRS-II (β= 3.9, p = 0.10), but an opposite trend was observed for rater-based MDS-UPDRS-III (β= –7.3, p = 0.10). Compared to lipophilic statin users, hydrophilic statin users also showed significantly faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 5.0, p = 0.020)], but R2 * did not reach statistical significance (β= 2.5, p = 0.24). Conclusion: This study suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression. Future studies may have clinical and scientific implications.

Abstract P228: Mineralocorticoid Receptor Antagonist And Lipophilic Statin Reduce Urinary Kidney Injury Marker 1 (Kim-1) In Female Rats Receiving L-NAME And Angiotensin II

Statins have beneficial cardiovascular effects some of which appear to be cholesterol-independent and the mechanisms for these latter effects are still unclear. Urinary kidney injury molecule-1 (Kim-1) is a sensitive biomarker of acute renal injury and in clinical studies predicts cardiovascular disease. Aldosterone causes both cardiac and renal injury and a few studies suggest that aldosterone is associated with increased Kim-1. Therefore, in this study we used the N omega-nitro-L-arginine methyl ester (L-NAME)/Angiotensin II (AngII) model of cardiorenal injury to determine whether urinary Kim-1 correlates with the degree of cardiac injury/stroke and whether blockade of the mineralocorticoid receptor prevents increases in urinary Kim-1. Further, since our group reported previously that lipophilic statins, but not hydrophilic statins reduce aldosterone levels, we also asked whether administration of either a lipophilic or a hydrophilic statin affects Kim-1 levels. To test the hypothesis, 8-10 week-old, female Wistar rats consuming liberal salt diet (1.6% Na + ) were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/ml in drinking water)/AngII (225ug/kg/day for days 12-14 only); L-NAME/AngII + eplerenone (100 mg/kg/day p.o.); L-NAME/Ang II + pravastatin (hydrophilic statin-20 mg/kg/day p.o.); L-NAME/Ang II + simvastatin (lipophilic statin-20 mg/kg/day p.o.) groups. Groups treated with L-NAME/AngII had significantly higher blood pressure, urine aldosterone and plasma aldosterone levels compared to control. L-NAME/AngII treatment increased cardiac injury/stroke composite score, including cardiac histopathology evaluation and stroke status, and 24 hour-urinary Kim-1 compared to control. Eplerenone reduced cardiac injury/stroke composite score (p=0.04) and both eplerenone and simvastatin reduced urinary Kim-1 (p=0.0046, p=0.031, respectively). Pravastatin had no effect on these damage markers. Urinary Kim-1 correlated with cardiac injury/stroke composite score (p<0.0001, spearman ranked correlation=0.67). In conclusion, in a rat model of L-NAME/AngII induced cardiovascular injury, urinary Kim-1 predicts cardiac/stroke injury; eplerenone and simvastatin reduced urinary Kim-1.

The Different Cardiovascular Outcomes Between Long-Term Efficacy of Hydrophilic and Lipophilic Statin Therapy in Both Asian Diabetic Sexes

Purpose: To evaluate the long-term efficacy of hydrophilic and lipophilic statin therapy for cardiovascular outcomes in Asian diabetic patients. Method: Newly diagnosed cases of type 2 diabetes during the period from January 2000 to December 2011 were divided into 2 cohorts on the basis of their statin use, namely hydrophilic statin and lipophilic statin. We used Cox proportional hazard regression models to analyze the risks of cardiovascular outcomes. Result: In this study, 12 896 patients used statin, including 4259 patients using hydrophilic statin and 8637 patients using lipophilic statin. With 12-year follow-up, higher incidence rate of coronary artery disease and stroke was noted in the lipophilic statin use instead of hydrophilic statin use. Conclusion: According to our long-term cohort study, hydrophilic statin use may be a better choice than lipophilic statin to reduce cardiovascular events in Asian diabetic patients.

Rosuvastatin, Sildenafil and Their Combination in Monocrotaline-Induced Pulmonary Hypertension in Rat

There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline-induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development.