ABSTRACT
Acute kidney injury (AKI) is a common clinical problem and an efficacious treatment is lacking. Ferroptosis, a newly discovered type of programmed cell death, has been reported to alleviate renal tubular injury in ischemia/reperfusion-induced acute kidney injury (I/R-AKI). Entacapone is a specific inhibitor of catechol-O-methyltransferase, which is used as an adjuvant drug against Parkinson's disease. We demonstrated that entacapone prevents renal I/R injury by inhibiting ferroptosis. Compared with a sham group, entacapone treatment mitigated I/R-induced pathological alterations, improved renal function, and inhibited ferroptosis. In HK-2 cells, entacapone treatment significantly reduced the lipid peroxidation and iron accumulation induced by the ferroptosis inducers erastin and RSL3, and significantly regulated expression of ferroptosis-related proteins. Entacapone upregulates p62 expression and affects the p62-KEAP1-NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Our results identify entacapone as a ferroptosis inhibitor that enhances antioxidant capacity. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, I/R-AKI.
Subject(s)
Acute Kidney Injury , Ferroptosis , Reperfusion Injury , Acute Kidney Injury/metabolism , Catechol O-Methyltransferase/metabolism , Catechol O-Methyltransferase/therapeutic use , Catechols , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Nitriles , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolismABSTRACT
INTRODUCTION: Opicapone (OPC) is a well-established catechol-O-methyltransferase (COMT) inhibitor that is approved for the treatment of Parkinson's disease (PD) associated with L-DOPA/L-amino acid decarboxylase inhibitor (DDI) therapy allowing for prolonged activity due to a more continuous supply of L-DOPA in the brain. Thus, OPC decreases fluctuation in L-DOPA plasma levels and favors more constant central dopaminergic receptor stimulation, thus improving PD symptomatology. AREAS COVERED: This review evaluates the preclinical development, pharmacology, pharmacokinetics and safety profile of OPC. Data was extracted from published preclinical and clinical studies published on PUBMED and SCOPUS (Search period: 2000-2019). Clinical and post-marketing data are also evaluated. EXPERT OPINION: OPC is a third generation COMT inhibitor with a novel structure. It has an efficacy and tolerability superior to its predecessors, tolcapone (TOL) and entacapone (ENT). It also provides a safe and simplified drug regimen that allows neurologists to individually adjust the existing daily administration of L-DOPA. OPC is indicated as an adjunctive therapy to L-DOPA/DDI in patients with PD and end-of-dose motor fluctuations who cannot be stabilized on those combinations.