Pioglitazone activates paraoxonase-2 in the brain: A novel neuroprotective mechanism

Abstract

Paraoxonase-2 regulates reactive oxygen species production in mitochondria. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology. Evidence suggests that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, brain trauma and ischemia, but the biochemical pathway(s) responsible has not been fully elucidated. Here we report that pioglitazone (10 mg/kg/day) for 5 days significantly increased paraoxonase-2 expression in mouse striatum. Thus, this result highlights paraoxonase-2 as a target for neuroprotective strategies and identifies pioglitazone as a tool to study the role of paraoxonase-2 in brain.

Keywords: Neuroprotection; Oxidative stress; Paraoxonase-2; Parkinson's disease; Peroxisome proliferator-activated receptor gamma; Pioglitazone; Striatum.

Figure 1:

PON2 protein expression in the striatum and hippocampus of mice treated with pioglitazone (PIO). (A) PON2 expression in PIO-treated mice relative to vehicle (VEH) in striatum and hippocampus. Optical density of PON2 bands were first normalized to total protein per lane and then to vehicle group. (B) Representative blot showing PON2 expression in striatum in vehicle (VEH) and PIO-treated mice, and corresponding image of total protein. (C) Nfe2l2 mRNA expression in striatum and hippocampus. mRNA levels were normalized to β-actin, Tubb, Ppid, and Alu-Seq. Results are presented as mean ± SEM, *p<0.025, **p<0.005.