Increased lipid peroxidation and lowered lipid-associated antioxidant defenses mediate the effects of the paraoxonase 1 (PON1) Q192R polymorphism on disabilities and final stroke core volume in mild and moderate stroke

Abstract

AbstractIn acute ischemic stroke (AIS), there are no data on whether lipid and protein oxidation and antioxidant biomarkers are associated with the outcome of AIS above and beyond the effects of traditional risk factors, immune and metabolic biomarkers, and measurements of stroke volume. The present study was conducted in 135 mild to moderate AIS patients and 40 controls and assessed the modified raking scale (mRS) at baseline, and 3 and 6 month later. We measured lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products, paraoxonase 1 (PON1) activities and PON1 Q192R genotypes, high density lipoprotein cholesterol (HDL), sulfhydryl (-SH) groups), and diffusion-weighted imaging (DWI) stroke volume and fluid-attenuated inversion recovery (FLAIR) signal intensity. We found that a) AIS is characterized by lower chloromethyl acetate (CMPA)ase PON1 activity, HDL and -SH groups and increased LOOH and neurotoxicity (a composite of LOOH, inflammatory markers and glycated hemoglobin); b) oxidative and antioxidant biomarkers strongly and independently predict mRS scores 3 and 6 months later and DWI stroke volume and FLAIR signal intensity; c) the PON1 Q192R variant has multiple effects on stroke outcome that are mediated by its effects on antioxidant defenses and lipid peroxidation; and d) the PON1 RR variant has a protective effect against lipid peroxidation, neurotoxicity, infarct volume and stroke outcome. Increased lipid peroxidation and lowered activity of the PON1-HDL complex and -SH groups are drug targets to prevent AIS and consequent neurodegenerative processes with loss of function, and increased levels of oxidative reperfusion mediators due to ischemia-reperfusion injury.