Effects of Long-term Pioglitazone Treatment on Peripheral and Central Markers of Aging

Background: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer’s disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While some of the TZD actions are becoming clear in AD models and may mediate their reported beneficial impact in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions. Findings: The TZD pioglitazone (PIO) was incorporated into the diet to yield a final dose of approximately 2.3 mg/kg body weight/day. PIO reduced insulin levels irrespective of age. Interestingly, a significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals with no significant change in LTP maintenance or learning and memory performance. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory changes in brain and periphery were not reversed by PIO. Conclusions: While current research efforts continue to address the underlying processes responsible for the progressive decline in cognitive function seen during aging, available medical treatments are still very limited. Our study, therefore, was aimed at elucidating potentially novel actions of TZDs in the aging brain. Using a clinically-relevant dose and delivery method, PIO had no detectable impact on several indices of brain aging and failed to alter both peripheral and central age-related increases in inflammatory signaling. Keywords: hippocampus, rat, young or aged, control or pioglitazone-treated We used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos(R) a TZD) on several hippocampal biomarkers of aging associated with learning deficits. Starting at 3 months or 17 months of age, male rats were treated for 4-5 months with either a control or a PIO-containing diet. PIO was incorporated into the diet to yield a final dose of approximately 2.3 mg/kg body weight/day.