Paraoxonase 1 ameliorates neurological symptoms and motor coordination impairment caused by cerebral ischemia-reperfusion injury

Abstract

The anti-atherosclerotic effects of high-density lipoprotein (HDL) prevent the onset of cerebral infarction and provide cerebroprotective effects against ischemia-reperfusion injury. These inhibitory effects have been attributed to its antioxidant, anti-inflammatory, and antithrombotic properties. However, pharmacotherapeutic strategies to clinically realize these effects have not been demonstrated. Therefore, we aimed to develop paraoxonase 1 (PON1), a hydrolytic enzyme associated with HDL that exhibits antioxidant and anti-inflammatory effects, as a novel therapeutic agent against ischemia-reperfusion injury in cerebral infarction. We established a method to extract PON1 from human plasma with high purity and recovery while maintaining its activity. The purified PON1 exhibited antioxidant activity against human-derived LDL and HDL. Furthermore, PON1 actively suppressed the oxidation chain reaction by hydrolyzing lipid peroxides. The HDL-binding ability of PON1 was evaluated based on its activity in fractionated HDL from mice administered PON1 intravenously, which showed that most intravenously administered PON1 specifically bound to HDL. The cerebroprotective effect of intravenously administered PON1 was assessed using a mouse middle cerebral artery ischemia-reperfusion model by measuring infarct volume, long-term neurological scores, and walking time on a rotarod. Administration of PON1 after reperfusion reduced infarct volume 24 h after ischemia-reperfusion. Additionally, daily administration of PON1 for three days significantly improved neurological scores and walking time by approximately one month. Analysis of gene arrays in brain tissue indicated that PON1 suppresses biological functions and pathways associated with oxidative stress, inflammation, vascular dysfunction, thrombosis, and fibrosis. PON1 enhances the cerebroprotective effects of HDL and is a potential candidate for acute stroke therapy.

Keywords: Antioxidant activity; Cerebroprotection; High-density lipoprotein; Ischemia-reperfusion injury; Paraoxonase 1; Stroke therapy.