Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer’s disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3×Tg-AD) with accelerated amyloid-β (Aβ) deposition and tau pathology was treated with the TZD pioglitazone (PIO-Actos®) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short- and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain.

BackgroundThiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARγ) 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 Aβ accumulation. While TZD's actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects 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.Methods and FindingsWe used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos® a TZD) on several peripheral (blood and liver) and central (hippocampal) biomarkers of aging. 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 (final dose approximately 2.3 mg/kg body weight/day). A significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals, with no significant change in long-term potentiation maintenance or learning and memory performance. Blood insulin levels were unchanged with age, but significantly reduced by PIO. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory increases were not reversed by PIO.ConclusionsWhile current research efforts continue to identify the underlying processes responsible for the progressive decline in cognitive function seen during normal aging, available medical treatments are still very limited. Because TZDs have been shown to have benefits in age-related conditions such as T2DM and AD, our study was aimed at elucidating PIO's potentially beneficial actions in normal aging. Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling.

Type 2 diabetes mellitus is a metabolic disorder characterized by hyperglycemia and is especially prevalent in the elderly. Because aging is a risk factor for type 2 diabetes mellitus, and insulin resistance may contribute to the pathogenesis of Alzheimer’s disease (AD), anti-diabetic agents (thiazolidinediones-TZDs) are being studied for the treatment of cognitive decline associated with AD. These agents normalize insulin sensitivity in the periphery and can improve cognition and verbal memory in AD patients. Based on evidence that Ca2+ dysregulation is a pathogenic factor of brain aging/AD, we tested the hypothesis that TZDs could impact Ca2+ signaling/homeostasis in neurons. We assessed the effects of pioglitazone and rosiglitazone (TZDs) on two major sources of Ca2+ influx in primary hippocampal cultured neurons, voltage-gated Ca2+ channel (VGCC) and the NMDA receptor (NMDAR). VGCC- and NMDAR-mediated Ca2+ currents were recorded using patch-clamp techniques, and Ca2+ intracellular levels were monitored with Ca2+ imaging techniques. Rosiglitazone, but not pioglitazone reduced VGCC currents. In contrast, NMDAR-mediated currents were significantly reduced by pioglitazone but not rosiglitazone. These results show that TZDs modulate Ca2+-dependent pathways in the brain and have different inhibitory profiles on two major Ca2+ sources, potentially conferring neuroprotection to an area of the brain that is particularly vulnerable to the effects of aging and/or AD.

Objective Reduced expression or increased degradation of BK (large conductance Ca2+-activated K+) channel β1-subunits has been associated with increased vascular tone and hypertension in some metabolic diseases. The contribution of BK channel function to control of blood pressure (BP), heart rate (HR) and vascular function/structure was determined in wild-type and BK channel β1-subunit knockout mice fed a high-fat or control diet. Methods and Results After 24 weeks of high-fat diet, wild-type and BK β1-knockout mice were obese, diabetic, but normotensive. High-fat-BK β1-knockout mice had decreased HR while high-fat-wild-type mice had increased HR compared with mice on the control diet. Ganglion blockade caused a greater fall in BP and HR in high-fat mice than in mice on the control diet. β1-adrenergic receptor blockade reduced BP and HR equally in all groups. α1-adrenergic receptor blockade decreased BP in high-fat-BK β1-knockout mice only. Echocardiographic evaluation revealed left ventricular hypertrophy in high-fat-BK β1-knockout mice. Although under anesthesia, mice on a high-fat had higher absolute stroke volume and cardiac output, these measures were similar to control mice when adjusted for body weight. Mesenteric arteries from high-fat-BK β1-knockout mice had higher norepinephrine reactivity, greater wall thickness and collagen accumulation than high-fat-wild-type mesenteric arteries. Compared with control-wild-type mesenteric arteries, high-fat-wild-type mesenteric arteries had blunted contractile responses to a BK channel blocker, although BK α-subunit (protein) and β1-subunit (mRNA) expression were unchanged. Conclusions BK channel deficiency promotes increased sympathetic control of blood pressure, and vascular dysfunction, remodeling and fibrosis, but does not cause hypertension in high-fat fed mice.

Renal denervation (RDN) is a new therapy used to treat drug-resistant hypertension in the clinical setting. Published human trials show substantial inter-individual variability in the blood pressure (BP) response to RDN, even when technical aspects of the treatment are standardized as much as possible between patients. Widespread acceptance of RDN for treating hypertension will require accurate identification of patients likely to respond to RDN with a fall in BP that is clinically significant in magnitude, well-maintained over time and does not cause adverse consequences. In this paper we review and evaluate clinical studies that address possible predictors of the BP response to RDN. We conclude that only one generally reliable predictor has been identified to date, namely pre-RDN BP level, although there is some evidence for a few other factors. Experimental interventions in laboratory animals provide the opportunity to explore potential predictors that are difficult to investigate in human patients. Therefore we also describe results (from our lab and others) with RDN in spontaneously hypertensive rats. Since virtually all patients receiving RDN are taking three or more antihypertensive drugs, a particular focus of our work was on how ongoing antihypertensive drug treatment might alter the BP response to RDN. We conclude that patient age (or duration of hypertension) and concomitant treatment with certain drugs can affect the blood pressure response to RDN and that this information could help predict a favorable clinical response.