Pioglitazone Improves Cognitive Function via Increasing Insulin Sensitivity and Strengthening Antioxidant Defense System in Fructose-Drinking Insulin Resistance Rats

Insulin resistance (IR) links Alzheimer’s disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.

• Publication year

  2013

• Venue

  PLoS ONE

• Publication date

  2013-03-20

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1371/journal.pone.0059313PMID 23527159PMCID 3603906
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• PPARγ Agonist Pioglitazone Reverses Memory Impairment and Biochemical Changes in a Mouse Model of Type 2 Diabetes Mellitus

  2012cited by this paper
• Non-alcoholic fatty liver disease impairs hippocampal-dependent memory in male rats.

  2012cited by this paper
• PPARγ agonist pioglitazone improves scopolamine‐induced memory impairment in mice

  2012cited by this paper
• A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease.

  2011cited by this paper
• Insulin Resistance and Alzheimer’s Disease

  2011cited by this paper
• Effect of pioglitazone on altered expression of Aβ metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance.

  2011cited by this paper
• Rosiglitazone and pioglitazone aggravate doxorubicin-induced cardiomyopathy in Wistar rats

  2011cited by this paper
• Pioglitazone ameliorates behavioral, biochemical and cellular alterations in quinolinic acid induced neurotoxicity: possible role of peroxisome proliferator activated receptor-Upsilon (PPARUpsilon) in Huntington's disease.

  2010cited by this paper
• Rosiglitazone, peroxisome proliferator receptor-gamma agonist, ameliorates gentamicin-induced nephrotoxicity in rats

  2010cited by this paper
• RETRACTED: Rosiglitazone and pioglitazone aggravate doxorubicin-induced cardiomyopathy in Wistar rats.

  2010cited by this paper
• Effect of pioglitazone on insulin resistance in fructose-drinking rats correlates with AGEs/RAGE inhibition and block of NADPH oxidase and NF kappa B activation.

  2010cited by this paper
• Insulin resistance and Alzheimer's disease.

  2009cited by this paper
• Oxidative Stress in Diabetes and Alzheimer's Disease

  2009cited by this paper
• Exploring mechanism of pioglitazone‐induced memory restorative effect in experimental dementia

  2009cited by this paper
• Paeonol attenuates neurotoxicity and ameliorates cognitive impairment induced by d-galactose in ICR mice.

  2009influential reference
• Effects of Artemisia capillaris ethyl acetate fraction on oxidative stress and antioxidant enzyme in high-fat diet induced obese mice.

  2009cited by this paper
• Rejuvenation of antioxidant and cholinergic systems contributes to the effect of procyanidins extracted from the lotus seedpod ameliorating memory impairment in cognitively impaired aged rats.

  2009cited by this paper
• Oxidative Stress in Severely Obese Persons Is Greater in Those With Insulin Resistance

  2009cited by this paper
• Protective effect of stilbenes containing extract-fraction from Cajanus cajan L. on Abeta(25-35)-induced cognitive deficits in mice.

  2009influential reference
• Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats.

  2009cited by this paper
• A high fructose diet impairs spatial memory in male rats.

  2009cited by this paper
• Diet‐induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle‐aged rats

  2008cited by this paper
• Peripheral and central neurologic complications in type 2 diabetes mellitus: no association in individual patients.

  2008influential reference
• Prolonged pretreatment with carvedilol prevents 3-nitropropionic acid-induced behavioral alterations and oxidative stress in rats.

  2008cited by this paper
• Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach.

  2007cited by this paper
• Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease

  2007cited by this paper
• Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats.

  2006cited by this paper
• Ameliorative effects of dietary caloric restriction on oxidative stress and inflammation in the brain of streptozotocin-induced diabetic rats.

  2006cited by this paper
• Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug

  2005cited by this paper
• Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat.

  2005cited by this paper
• Fructose, insulin resistance, and metabolic dyslipidemia

  2005cited by this paper
• Aging affects oxidative state in hippocampus, hypothalamus and adrenal glands of Wistar rats.

  2005cited by this paper
• Differential regulation of insulin resistance and hypertension by sex hormones in fructose-fed male rats.

  2005cited by this paper
• Insulin resistance syndrome and Alzheimer's disease: age- and obesity-related effects on memory, amyloid, and inflammation.

  2005cited by this paper
• Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity.

  2005cited by this paper
• Modulatory Effect of Gymnema montanum Leaf Extract on Brain Antioxidant Status and Lipid Peroxidation in Diabetic Rats

  2004cited by this paper
• Influence of α‐lipoic acid on lipid peroxidation and antioxidant defence system in blood of insulin‐resistant rats

  2004cited by this paper
• The effect of leptin, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production on insulin resistance in Otsuka Long-Evans fatty rats.

  2003cited by this paper
• Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide.

  2003cited by this paper
• The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development

  2003cited by this paper
• The Effect of Leptin, Tumor Necrosis Factor-α (TNF-α), and Nitric Oxide (NO) Production on Insulin Resistance in Otsuka Long-Evans Fatty Rats

  2003cited by this paper
• Increased intraabdominal adipose tissue mass in fructose fed rats: correction by metformin.

  2002cited by this paper
• Relationship among hyperinsulinemia, insulin resistance, and hypertension is dependent on sex.

  2002cited by this paper
• Female rats are protected against fructose-induced changes in metabolism and blood pressure.

  2002cited by this paper
• Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment.

  2001cited by this paper
• Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids.

  2001cited by this paper
• Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats.

  2001cited by this paper
• Thiazolidinediones: A Comparative Review of Approved Uses

  2000cited by this paper
• Dichlorophenyl phosphoramidates as substrates for avian and mammalian liver phosphotriesterases: activity levels, calcium dependence and stereospecificity.

  1999cited by this paper
• Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys.

  1997influential reference
• The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay.

  1996cited by this paper
• A simple method for determination of serum catalase activity and revision of reference range.

  1991influential reference
• Determination of carbonyl content in oxidatively modified proteins.

  1990cited by this paper
• Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine.

  1980cited by this paper
• Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase.

  1978cited by this paper
• Microsomal lipid peroxidation.

  1978cited by this paper
• [Sugar substitutes in the diabetic diet].

  1976cited by this paper
• Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat.

  1974cited by this paper
• Protein measurement with the Folin phenol reagent.

  1951cited by this paper
• Frontiers in Aging Neuroscience Aging Neuroscience Review Article Mechanism of Action

  year unknowncited by this paper

• Effect of antidiabetic drugs in Alzheimer´s disease: a systematic review of preclinical and clinical studies

  2025cites this paper
• Mitochondrial dysfunction and mitophagy as a driver of chronic kidney disease; an area for future exploration in feline chronic kidney disease?

  2025cites this paper
• Advancements in the molecular understanding of major depressive disorder uncovering novel targets with therapeutic promise: focus on recurrence of illness

  2025cites this paper
• Dementia risk across blood pressure categories: a South Korean nationwide study.

  2025cites this paper
• Comparative Analysis of Pioglitazone and Tirzepatide on Body Weight, Glucose Levels, Neuroinflammation, and Oxidative Stress in Diabetic Rats

  2025cites this paper
• Neuroprotective Effects of Sulforaphane in a Rat Model of Alzheimer's Disease Induced by Aβ (1-42) Peptides.

  2024cites this paper
• Canagliflozin Mitigated Cognitive Impairment in Streptozotocin-Induced Sporadic Alzheimer’s Disease in Mice: Role of AMPK/SIRT-1 Signaling Pathway in Modulating Neuroinflammation

  2024cites this paper
• Neuroprotective properties of a thiazolidine-2,4-dione derivative as an inhibitory agent against memory impairment and phosphorylated tau: In vitro and in vivo investigations.

  2024cites this paper
• Curcuma longa impact on behavioral, brain oxidative stress, and systemic inflammation in rats exposed to inhaled paraquat

  2024cites this paper
• Alpha-Lipoic Acid Ameliorates Doxorubicin-Induced Cognitive Impairments by Modulating Neuroinflammation and Oxidative Stress via NRF-2/HO-1 Signaling Pathway in the Rat Hippocampus

  2023cites this paper
• Behavioral phenotypes in Alzheimer’s disease: exploring novel therapeutic targets using animal models and behavioral assays

  2023influential citation
• Pioglitazone ameliorates DOX-induced cognitive impairment by mitigating inflammation, oxidative stress, and apoptosis of hippocampal neurons in rats.

  2023cites this paper
• New insights toward molecular and nanotechnological approaches to antidiabetic agents for Alzheimer’s disease

  2023cites this paper
• Tetramethylpyrazine Attenuates Cognitive Impairment Via Suppressing Oxidative Stress, Neuroinflammation, and Apoptosis in Type 2 Diabetic Rats

  2022cites this paper
• Sodium-glucose co-transporter inhibitor dapagliflozin attenuates cognitive deficits in sporadic Alzheimer’s rat model

  2022cites this paper
• Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature

  2022cites this paper
• Regulation of Neuroinflammatory Signaling by PPARγ Agonist in Mouse Model of Diabetes

  2022cites this paper
• Masseter muscle and gingival tissue inflammatory response following treatment with high-fructose corn syrup in rats: Anti-inflammatory and antioxidant effects of kefir.

  2021cites this paper
• Targeting Insulin Resistance to Treat Cognitive Dysfunction

  2021cites this paper
• Epigallocatechin-3-gallate Improves Chronic Alcohol Induced Cognitive Dysfunction in Rats by Interfering with the Neuro-inflammatory, Cell Death and Oxido-nitrosative Stress Pathways

  2021cites this paper
• Epigallocatechin-3-gallate improves chronic alcohol-induced cognitive dysfunction in rats by interfering with neuro-inflammatory, cell death and oxido-nitrosative cascade

  2021cites this paper
• Enhancement of Insulin/PI3K/Akt Signaling Pathway and Modulation of Gut Microbiome by Probiotics Fermentation Technology, a Kefir Grain Product, in Sporadic Alzheimer’s Disease Model in Mice

  2021cites this paper
• Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms

  2021cites this paper
• Chronic AdipoRon Treatment Mimics the Effects of Physical Exercise on Restoring Hippocampal Neuroplasticity in Diabetic Mice

  2021cites this paper
• Alleviation of fructose-induced Alzheimer's disease in rats by pioglitazone and decaffeinated green coffee bean extract.

  2021cites this paper
• Rational Design, Synthesis and Evaluation of Novel Rodanine Derivatives for Antihyperglycemic Activity

  2020cites this paper
• Pharmacological Inhibition of Galectin-3 Ameliorates Diabetes-Associated Cognitive Impairment, Oxidative Stress and Neuroinflammation in vivo and in vitro

  2020cites this paper
• Correlation between brain neurotransmitters and insulin sensitivity: Neuro-preservative role of resveratrol against high fat, high fructose-induced insulin resistance

  2020cites this paper
• Modulation of brain insulin signaling in Alzheimer’s disease: New insight on the protective role of green coffee bean extract

  2020cites this paper
• Therapeutic Strategies for Alzheimer's Disease in the View of Diabetes Mellitus.

  2019cites this paper
• Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia.

  2019cites this paper
• Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer’s disease

  2019cites this paper
• Divergent Mechanisms for PPARγ Agonism in Ameliorating Aging-Related Versus Cranial Irradiation-Induced Context Discrimination Deficits

  2019cites this paper
• Anticonvulsant and ameliorative effects of pioglitazone on cognitive deficits, inflammation and apoptosis in the hippocampus of rat pups exposed to febrile seizure

  2019cites this paper
• Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer’s disease using Box-Behnken design

  2019cites this paper
• Prospective of managing impaired brain insulin signalling in late onset Alzheimers disease with excisting diabetic drugs

  2019cites this paper
• Fenugreek seed extract ameliorates cognitive deficits in streptozotocin-induced diabetic rats

  2019cites this paper
• The effects of PPAR-γ agonist pioglitazone on anxiety and depression-like behaviors in lipopolysaccharide injected rats

  2019cites this paper
• Impact of Alpha-Lipoic Acid Chronic Discontinuous Treatment in Cardiometabolic Disorders and Oxidative Stress Induced by Fructose Intake in Rats

  2019influential citation
• Targeting Insulin for Alzheimer’s Disease: Mechanisms, Status and Potential Directions

  2018cites this paper
• PPARγ agonist-loaded PLGA-PEG nanocarriers as a potential treatment for Alzheimer’s disease: in vitro and in vivo studies

  2018influential citation
• Enhancement of cognitive functions by rice bran extract in a neuroinflammatory mouse model via regulation of PPARγ

  2018cites this paper
• Molecular determinants of PPARγ partial agonism and related in silico/in vivo studies of natural saponins as potential type 2 diabetes modulators.

  2018cites this paper
• Healthy brain aging: Interplay between reactive species, inflammation and energy supply.

  2018cites this paper
• Title: Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia Authors: Veronia

  2018cites this paper
• Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential

  2018cites this paper
• Impairment of Novel Object Recognition Memory and Brain Insulin Signaling in Fructose- but Not Glucose-Drinking Female Rats

  2018cites this paper
• Crocin Attenuates Kindling Development and Associated Cognitive Impairments in Mice via Inhibiting Reactive Oxygen Species‐Mediated NF‐κB Activation

  2017cites this paper
• Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet.

  2017cites this paper
• Pioglitazone ameliorates Aβ42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3β activation

  2017cites this paper
• Evaluation of effects of resveratrol on brain nitric oxide and energy metabolism in metabolic syndrome model

  2017cites this paper
• Impairment of Novel Object Recognition Memory and Brain Insulin Signaling in Fructose- but Not Glucose-Drinking Female Rats

  2017cites this paper
• Pharmacological evaluation of metformin and N‐benzylbiguanide, a novel analogue of metformin, on the vasopressor responses to adrenergic system stimulation in pithed rats with fructose‐induced insulin resistance

  2017cites this paper
• Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats.

  2016cites this paper
• The effects of melatonin on brain nitrosative stress and energy balance in fructose-mediated metabolic syndrome model / Fruktoz-aracılı metabolik sendrom modelinde melatoninin beyinde nitrozatif stres ve enerji dengesi üzerine etkisi

  2016cites this paper
• Neurorestorative effects of eugenol, a spice bioactive: Evidence in cell model and its efficacy as an intervention molecule to abrogate brain oxidative dysfunctions in the streptozotocin diabetic rat.

  2016cites this paper
• Increased oxidative stress and apoptosis in peripheral blood mononuclear cells of fructose-fed rats.

  2015cites this paper
• Effects of Low-Dose Pioglitazone on Serum Levels of Adiponectin, Dehydroepiandrosterone, Amyloid Beta Peptide, and Lipid Profile in Elderly Japanese People with Type 2 Diabetes

  2015cites this paper
• Antidiabetic potential of a novel dual-target activator of glucokinase and peroxisome proliferator activated receptor-γ.

  2015cites this paper
• Pharmacological approaches for Alzheimer’s disease: neurotransmitter as drug targets

  2015cites this paper
• Role of insulin resistance in Alzheimer’s disease

  2015cites this paper
• Antioxidant and anti hyperglycemic role of wine grape powder in rats fed with a high fructose diet

  2015cites this paper
• Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway.

  2015cites this paper
• The effects of hydroalcoholic extract of Nigella sativa seed on oxidative stress in hippocampus of STZ-induced diabetic rats

  2015influential citation
• Effect of Soft Drink Consumption on Human Health

  2015cites this paper
• Hyperglycemia induces memory impairment linked to increased acetylcholinesterase activity in zebrafish (Danio rerio).

  2014cites this paper
• Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain.

  2014cites this paper
• Lycopene attenuates insulin signaling deficits, oxidative stress, neuroinflammation, and cognitive impairment in fructose-drinking insulin resistant rats.

  2014cites this paper
• Insulin resistance in Alzheimer's disease.

  2014cites this paper
• Cross-talk between heme oxygenase and peroxisome proliferator-activated receptors in the regulation of physiological functions.

  2014influential citation
• NMDA receptors interact with the retrieval memory enhancing effect of pioglitazone in mice.

  2014cites this paper
• Influence of Selected Diets on Neural Insulin Activity and Cognitive Function

  2014cites this paper
• Discovering new treatments for Alzheimer's disease by repurposing approved medications.

  2013cites this paper
• The effect of pioglitazone on non-pregnant female genital tract in experimental diabetes mellitus.

  2013cites this paper