Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

Abstract

Background: Renin-angiotensin system (RAS) inhibitors have been suggested as protective agents in Parkinson’s disease (PD). However, epidemiological evidence on the association between RAS inhibitors and the development of PD is inconsistent.Objectives: To investigate the effect of RAS inhibitors on PD risk in patients with ischemic heart disease (IHD) by type and cumulative duration of RAS inhibitors and their degree of blood-brain barrier (BBB) penetration ability.Methods: This was a propensity score-matched retrospective cohort study using 2008–2019 healthcare claims data from the Korean Health Insurance Review and Assessment database. The association between RAS inhibitor use and PD in patients with IHD was evaluated using multivariate Cox proportional hazard regression analysis. The risks are presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).Results: Over a 10-year follow-up, 1,086 of 62,228 IHD patients developed PD. The Cox regression model showed that the use of RAS inhibitors was significantly associated with a lower risk of PD (aHR = 0.75; 95% CI 0.66–0.85) than the non-use of RAS inhibitors. Specifically, this reduced risk of PD only remained with the use of BBB-crossing angiotensin II receptor blockers (ARBs) (aHR = 0.62; 95% CI = 0.53–0.74), and this association was more definite with an increasing cumulative duration. A significantly reduced risk of PD was not observed with the use of BBB-crossing angiotensin-converting enzyme inhibitors.Conclusions: The use of ARBs with BBB-penetrating properties and a high cumulative duration significantly reduces the risk of PD in IHD patients. This protective effect could provide insight into disease-modifying drug candidates for PD.

Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson´s disease

“…The deleterious effect of AT1-AA is consistent with several previous studies showing the enhancing effect of AT1 overactivity on dopaminergic degeneration 16 , 33 , and the neuroprotective effects of drugs such as candesartan and telmisartan in PD animal models and clinical studies 15 , 16 , 33 . This is further supported by a recent study showing that the population of dopaminergic neurons most vulnerable to degeneration in PD can be identified by their high expression of the AT1 gen 11 .…”

“…The major role of the tissue RAS in inflammatory responses has been recently shown in COVID-19 pandemic, being ACE2 the entry receptor for SARS-CoV-2 and a key component for COVID-19 progression 14 . The use of AT1 antagonists such as candesartan for neuroprotection has been proposed from results in experimental models and clinical trials 15 , 16 . Interestingly, activation of endothelial AT1 receptors plays a key role in BBB disruption 17 , 18 .…”

Nigral Neurons Degenerating in Parkinson's Disease Express the Angiotensin Receptor Type 1 Gene

“…Furthermore, an intracellular RAS was identified in mitochondria and nuclei of dopaminergic neurons, including other RAS components such as AGTR2 and MAS receptors that may counteract the deleterious effects of AGTR1 activation 4 . Recent clinical studies also support a neuroprotective effect of AGTR1 inhibitors 3,5 . The findings of Kamath et al 1 further encourage the development of prodromal clinical trials for angiotensin receptor blockers (ARBS) that can cross the blood‐brain barrier or for molecules inhibiting AGTR1 effects, including those acting on RAS regulatory components (AGTR2, MAS) that counteract AGTR1 activation.…”

Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases

“…A large study in Korea clearly demonstrated that ARB only had protective effects on the development and evolution of PD, whereas the statistical significance of long-term ACEI use remained elusive, a phenomenon attributed by the authors to the increased BBB permeability of the ARBs [ 60 ].…”